Bio

Academic Appointments


Administrative Appointments


  • Curriculum Committee, BioEngineering (2007 - Present)
  • K-12 Steering Committee, School of Education (2007 - Present)
  • Executive Committee, Human Biology (2006 - Present)
  • Chair, Curriculum Committee, Human Biology (2006 - Present)
  • Chair, Wallenberg Global Learning Network Steering Committee (2001 - Present)
  • Chair, Biological Sciences (1997 - 2001)
  • Associate Dean, Dean of Research (1994 - 1997)

Honors & Awards


  • Kenneth M. Cuthertson Award for Exceptional Contributions to Stanford University, University (2010)
  • William and Lynde Steere University Fellow, University (2004-present)
  • Lorry I. Lokey Business Wire Professor, Biology/Human Biology (1993-present)
  • Bing Professor of Human Biology, Human Biology (1987-1993)
  • Walter J. Gores Award for Excellence in Teaching, University (1977)

Professional Education


  • PhD, Yale University, Biology (1970)

Research & Scholarship

Current Research and Scholarly Interests


Neurobiology of sleep, circadian rhythms, regulation of body temperature, mammalian hibernation, and human exercise physiology. We study neural mechanisms controlling arousal states and arousal state transitions, the function of sleep, and the neural mechanisms of circadian rhythms. Research on human exercise physiology focuses on the effects of body temperature on physical conditioning and performance. The focus on Down syndrome is exploring the mechanism whereby reduction of GABA activity restores learning and memory in DS mice and also in mouse models of Alzheimer's disease.

Teaching

2014-15 Courses


Postdoctoral Advisees


Graduate and Fellowship Programs


Publications

Journal Articles


  • Millisecond Flashes of Light Phase Delay the Human Circadian Clock during Sleep JOURNAL OF BIOLOGICAL RHYTHMS Zeitzer, J. M., Fisicaro, R. A., Ruby, N. F., Heller, H. C. 2014; 29 (5): 370-376
  • Retino-hypothalamic regulation of light-induced murine sleep. Frontiers in systems neuroscience Muindi, F., Zeitzer, J. M., Heller, H. C. 2014; 8: 135-?

    Abstract

    The temporal organization of sleep is regulated by an interaction between the circadian clock and homeostatic processes. Light indirectly modulates sleep through its ability to phase shift and entrain the circadian clock. Light can also exert a direct, circadian-independent effect on sleep. For example, acute exposure to light promotes sleep in nocturnal animals and wake in diurnal animals. The mechanisms whereby light directly influences sleep and arousal are not well understood. In this review, we discuss the direct effect of light on sleep at the level of the retina and hypothalamus in rodents. We review murine data from recent publications showing the roles of rod-, cone- and melanopsin-based photoreception on the initiation and maintenance of light-induced sleep. We also present hypotheses about hypothalamic mechanisms that have been advanced to explain the acute control of sleep by light. Specifically, we review recent studies assessing the roles of the ventrolateral preoptic area (VLPO) and the suprachiasmatic nucleus (SCN). We also discuss how light might differentially promote sleep and arousal in nocturnal and diurnal animals respectively. Lastly, we suggest new avenues for research on this topic which is still in its early stages.

    View details for DOI 10.3389/fnsys.2014.00135

    View details for PubMedID 25140132

  • Short-term treatment with the GABAA receptor antagonist pentylenetetrazole produces a sustained pro-cognitive benefit in a mouse model of Down's syndrome BRITISH JOURNAL OF PHARMACOLOGY Colas, D., Chuluun, B., Warrier, D., Blank, M., Wetmore, D. Z., Buckmaster, P., Garner, C. C., Heller, H. C. 2013; 169 (5): 963-973

    Abstract

    BACKGROUND AND PURPOSE: Down's syndrome (DS) is a common genetic cause of intellectual disability yet there are no drug therapies. Mechanistic studies in a model of DS (Ts65Dn mice) demonstrated that impaired cognitive function is due to excessive neuronal inhibitory tone. These deficits can be normalized by low doses of GABAA receptor (GABAA R) antagonists in adult animals. In this study, we explore the therapeutic potential of pentylenetetrazole (PTZ), a GABAA R antagonist which has a history of safe use in man. EXPERIMENTAL APPROACH: Long-term memory was assessed by the Novel Object Recognition (NOR) test in different cohorts of Ts65Dn mice after a delay following a short-term chronic treatment with PTZ. Seizure susceptibility, as an index of treatment safety, was studied by means of EEG, behavior and hippocampus morphology. EEG spectral analysis was used as a biometric of the treatment. RESULTS: PTZ has a broad therapeutic window (0.03-3mg.kg(-1) ) that is >10-1000 fold below the seizure threshold for this drug, and chronic PTZ treatment does not lower the seizure threshold. Remarkably, short-term, low, chronic dose regimens of PTZ elicit long-lasting (>1week) normalization of cognitive function in young and aged mice. PTZ effectiveness is time of day dependent: cognitive performance improves when PTZ is delivered during the light (inactive) phase, but not during the dark (active) phase. Chronic PTZ treatment results in EEG power normalization. CONCLUSIONS: PTZ at very low dosage can be administered safely, produces long lasting cognitive improvements and has the potential of fulfilling an unmet therapeutic need in DS.

    View details for DOI 10.1111/bph.12169

    View details for Web of Science ID 000320270200002

    View details for PubMedID 23489250

  • Permanent Genetic Access to Transiently Active Neurons via TRAP: Targeted Recombination in Active Populations NEURON Guenthner, C. J., Miyamichi, K., Yang, H. H., Heller, H. C., Luo, L. 2013; 78 (5): 773-784

    Abstract

    Targeting genetically encoded tools for neural circuit dissection to relevant cellular populations is a major challenge in neurobiology. We developed an approach, targeted recombination in active populations (TRAP), to obtain genetic access to neurons that were activated by defined stimuli. This method utilizes mice in which the tamoxifen-dependent recombinase CreER(T2) is expressed in an activity-dependent manner from the loci of the immediate early genes Arc and Fos. Active cells that express CreER(T2) can only undergo recombination when tamoxifen is present, allowing genetic access to neurons that are active during a time window of less than 12 hr. We show that TRAP can provide selective access to neurons activated by specific somatosensory, visual, and auditory stimuli and by experience in a novel environment. When combined with tools for labeling, tracing, recording, and manipulating neurons, TRAP offers a powerful approach for understanding how the brain processes information and generates behavior.

    View details for DOI 10.1016/j.neuron.2013.03.025

    View details for Web of Science ID 000320743400005

  • The acute effects of light on murine sleep during the dark phase: importance of melanopsin for maintenance of light-induced sleep EUROPEAN JOURNAL OF NEUROSCIENCE Muindi, F., Zeitzer, J. M., Colas, D., Heller, H. C. 2013; 37 (11): 1727-1736

    Abstract

    Light exerts a direct effect on sleep and wakefulness in nocturnal and diurnal animals, with a light pulse during the dark phase suppressing locomotor activity and promoting sleep in the former. In the present study, we investigated this direct effect of light on various sleep parameters by exposing mice to a broad range of illuminances (0.2-200 μW/cm(2) ; equivalent to 1-1000 lux) for 1 h during the dark phase (zeitgeber time 13-14). Fitting the data with a three-parameter log model indicated that ∼0.1 μW/cm(2) can generate half the sleep response observed at 200 μW/cm(2) . We observed decreases in total sleep time during the 1 h following the end of the light pulse. Light reduced the latency to sleep from ~30 min in darkness (baseline) to ~10 min at the highest intensity, although this effect was invariant across the light intensities used. We then assessed the role of melanopsin during the rapid transition from wakefulness to sleep at the onset of a light pulse and the maintenance of sleep with a 6-h 20 μW/cm(2) light pulse. Even though the melanopsin knockout mice had robust induction of sleep (~35 min) during the first hour of the pulse, it was not maintained. Total sleep decreased by almost 65% by the third hour in comparison with the first hour of the pulse in mice lacking melanopsin, whereas only an 8% decrease was observed in wild-type mice. Collectively, our findings highlight the selective effects of light on murine sleep, and suggest that melanopsin-based photoreception is primarily involved in sustaining light-induced sleep.

    View details for DOI 10.1111/ejn.12189

    View details for Web of Science ID 000319834600001

    View details for PubMedID 23510299

  • WORK VOLUME AND STRENGTH TRAINING RESPONSES TO RESISTIVE EXERCISE IMPROVE WITH PERIODIC HEAT EXTRACTION FROM THE PALM JOURNAL OF STRENGTH AND CONDITIONING RESEARCH Grahn, D. A., Cao, V. H., Nguyen, C. M., Liu, M. T., Heller, H. C. 2012; 26 (9): 2558-2569

    Abstract

    Body core cooling via the palm of a hand increases work volume during resistive exercise. We asked: (a) "Is there a correlation between elevated core temperatures and fatigue onset during resistive exercise?" and (b) "Does palm cooling between sets of resistive exercise affect strength and work volume training responses?" Core temperature was manipulated by 30-45 minutes of fixed load and duration treadmill exercise in the heat with or without palm cooling. Work volume was then assessed by 4 sets of fixed load bench press exercises. Core temperatures were reduced and work volumes increased after palm cooling (Control: Tes = 39.0 ± 0.1° C, 36 ± 7 reps vs. Cooling: Tes = 38.4 ± 0.2° C, 42 ± 7 reps, mean ± SD, n = 8, p < 0.001). In separate experiments, the impact of palm cooling on work volume and strength training responses were assessed. The participants completed biweekly bench press or pull-up exercises for multiple successive weeks. Palm cooling was applied for 3 minutes between sets of exercise. Over 3 weeks of bench press training, palm cooling increased work volume by 40% (vs. 13% with no treatment; n = 8, p < 0.05). Over 6 weeks of pull-up training, palm cooling increased work volume by 144% in pull-up experienced subjects (vs. 5% over 2 weeks with no treatment; n = 7, p < 0.001) and by 80% in pull-up naïve subjects (vs. 20% with no treatment; n = 11, p < 0.01). Strength (1 repetition maximum) increased 22% over 10 weeks of pyramid bench press training (4 weeks with no treatment followed by 6 weeks with palm cooling; n = 10, p < 0.001). These results verify previous observations about the effects of palm cooling on work volume, demonstrate a link between core temperature and fatigue onset during resistive exercise, and suggest a novel means for improving strength and work volume training responses.

    View details for DOI 10.1519/JSC.0b013e31823f8c1a

    View details for Web of Science ID 000308445500033

    View details for PubMedID 22076097

  • Enhancing Thermal Exchange in Humans and Practical Applications Disruptive Science and Technology H. Craig Heller, Dennis A. Grahn 2012; 1 (1): 11 - 19
  • Pumilio-2 Function in the Mouse Nervous System PLOS ONE Siemen, H., Colas, D., Heller, H. C., Bruestle, O., Pera, R. A. 2011; 6 (10)

    Abstract

    Coordinated mRNA translation at the synapse is increasingly recognized as a critical mechanism for neuronal regulation. Pumilio, a translational regulator, is known to be involved in neuronal homeostasis and memory formation in Drosophila. Most recently, the mammalian Pumilio homolog Pumilio-2 (Pum2) has been found to play a role in the mammalian nervous system, in particular in regulating morphology, arborization and excitability of neuronal dendrites, in vitro. However, the role of Pum2 in vivo remains unclear. Here, we report our investigation of the functional and molecular consequences of Pum2 disruption in vivo using an array of neurophysiology, behavioral and gene expression profiling techniques. We used Pum2-deficient mice to monitor in vivo brain activity using EEG and to study behavior traits, including memory, locomotor activity and nesting capacities. Because of the suspected role of Pum2 in neuronal excitability, we also examined the susceptibility to seizure induction. Finally, we used a quantitative gene expression profiling assay to identify key molecular partners of Pum2. We found that Pum2-deficient mice have abnormal behavioral strategies in spatial and object memory test. Additionally, Pum2 deficiency is associated with increased locomotor activity and decreased body weight. We also observed environmentally-induced impairment in nesting behavior. Most importantly, Pum2-deficient mice showed spontaneous EEG abnormalities and had lower seizure thresholds using a convulsing dosage of pentylenetetrazole. Finally, some genes, including neuronal ion channels, were differentially expressed in the hippocampus of Pum2-deficient mice. These findings demonstrate that Pum2 serves key functions in the adult mammalian central nervous system encompassing neuronal excitability and behavioral response to environmental challenges.

    View details for DOI 10.1371/journal.pone.0025932

    View details for Web of Science ID 000295970300040

    View details for PubMedID 22016787

  • Optogenetic disruption of sleep continuity impairs memory consolidation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Rolls, A., Colas, D., Adamantidis, A., Carter, M., Lanre-Amos, T., Heller, H. C., de Lecea, L. 2011; 108 (32): 13305-13310

    Abstract

    Memory consolidation has been proposed as a function of sleep. However, sleep is a complex phenomenon characterized by several features including duration, intensity, and continuity. Sleep continuity is disrupted in different neurological and psychiatric conditions, many of which are accompanied by memory deficits. This finding has raised the question of whether the continuity of sleep is important for memory consolidation. However, current techniques used in sleep research cannot manipulate a single sleep feature while maintaining the others constant. Here, we introduce the use of optogenetics to investigate the role of sleep continuity in memory consolidation. We optogenetically targeted hypocretin/orexin neurons, which play a key role in arousal processes. We used optogenetics to activate these neurons at different intervals in behaving mice and were able to fragment sleep without affecting its overall amount or intensity. Fragmenting sleep after the learning phase of the novel object recognition (NOR) task significantly decreased the performance of mice on the subsequent day, but memory was unaffected if the average duration of sleep episodes was maintained at 62-73% of normal. These findings demonstrate the use of optogenetic activation of arousal-related nuclei as a way to systematically manipulate a specific feature of sleep. We conclude that regardless of the total amount of sleep or sleep intensity, a minimal unit of uninterrupted sleep is crucial for memory consolidation.

    View details for DOI 10.1073/pnas.1015633108

    View details for Web of Science ID 000293691400068

    View details for PubMedID 21788501

  • Response of the Human Circadian System to Millisecond Flashes of Light PLOS ONE Zeitzer, J. M., Ruby, N. F., Fisicaro, R. A., Heller, H. C. 2011; 6 (7)

    Abstract

    Ocular light sensitivity is the primary mechanism by which the central circadian clock, located in the suprachiasmatic nucleus (SCN), remains synchronized with the external geophysical day. This process is dependent on both the intensity and timing of the light exposure. Little is known about the impact of the duration of light exposure on the synchronization process in humans. In vitro and behavioral data, however, indicate the circadian clock in rodents can respond to sequences of millisecond light flashes. In a cross-over design, we tested the capacity of humans (n?=?7) to respond to a sequence of 60 2-msec pulses of moderately bright light (473 lux) given over an hour during the night. Compared to a control dark exposure, after which there was a 3.5±7.3 min circadian phase delay, the millisecond light flashes delayed the circadian clock by 45±13 min (p<0.01). These light flashes also concomitantly increased subjective and objective alertness while suppressing delta and sigma activity (p<0.05) in the electroencephalogram (EEG). Our data indicate that phase shifting of the human circadian clock and immediate alerting effects can be observed in response to brief flashes of light. These data are consistent with the hypothesis that the circadian system can temporally integrate extraordinarily brief light exposures.

    View details for DOI 10.1371/journal.pone.0022078

    View details for Web of Science ID 000292657200045

    View details for PubMedID 21760955

  • Repeatability Is Not the Same as Accuracy SLEEP Heller, H. C. 2011; 34 (7): 839-840

    View details for DOI 10.5665/SLEEP.1108

    View details for Web of Science ID 000292926500010

    View details for PubMedID 21731132

  • Hibernation in Black Bears: Independence of Metabolic Suppression from Body Temperature SCIENCE Toien, O., Blake, J., Edgar, D. M., Grahn, D. A., Heller, H. C., Barnes, B. M. 2011; 331 (6019): 906-909

    Abstract

    Black bears hibernate for 5 to 7 months a year and, during this time, do not eat, drink, urinate, or defecate. We measured metabolic rate and body temperature in hibernating black bears and found that they suppress metabolism to 25% of basal rates while regulating body temperature from 30° to 36°C, in multiday cycles. Heart rates were reduced from 55 to as few as 9 beats per minute, with profound sinus arrhythmia. After returning to normal body temperature and emerging from dens, bears maintained a reduced metabolic rate for up to 3 weeks. The pronounced reduction and delayed recovery of metabolic rate in hibernating bears suggest that the majority of metabolic suppression during hibernation is independent of lowered body temperature.

    View details for DOI 10.1126/science.1199435

    View details for Web of Science ID 000287455100056

    View details for PubMedID 21330544

  • Acute Light Exposure Suppresses Circadian Rhythms in Clock Gene Expression JOURNAL OF BIOLOGICAL RHYTHMS Grone, B. P., Chang, D., Bourgin, P., Cao, V., Fernald, R. D., Heller, H. C., Ruby, N. F. 2011; 26 (1): 78-81

    Abstract

    Light can induce arrhythmia in circadian systems by several weeks of constant light or by a brief light stimulus given at the transition point of the phase response curve. In the present study, a novel light treatment consisting of phase advance and phase delay photic stimuli given on 2 successive nights was used to induce circadian arrhythmia in the Siberian hamster ( Phodopus sungorus). We therefore investigated whether loss of rhythms in behavior was due to arrhythmia within the suprachiasmatic nucleus (SCN). SCN tissue samples were obtained at 6 time points across 24 h in constant darkness from entrained and arrhythmic hamsters, and per1, per2 , bmal1, and cry1 mRNA were measured by quantitative RT-PCR. The light treatment eliminated circadian expression of clock genes within the SCN, and the overall expression of these genes was reduced by 18% to 40% of entrained values. Arrhythmia in per1, per2, and bmal1 was due to reductions in the amplitudes of their oscillations. We suggest that these data are compatible with an amplitude suppression model in which light induces singularity in the molecular circadian pacemaker.

    View details for DOI 10.1177/0748730410388404

    View details for Web of Science ID 000286424800008

    View details for PubMedID 21252368

  • Separating the Contribution of Glucocorticoids and Wakefulness to the Molecular and Electrophysiological Correlates of Sleep Homeostasis SLEEP Mongrain, V., Hernandez, S. A., Pradervand, S., Dorsaz, S., Curie, T., Hagiwara, G., Gip, P., Heller, H. C., Franken, P. 2010; 33 (9): 1147-1157

    Abstract

    The sleep-deprivation-induced changes in delta power, an electroencephalographical correlate of sleep need, and brain transcriptome profiles have importantly contributed to current hypotheses on sleep function. Because sleep deprivation also induces stress, we here determined the contribution of the corticosterone component of the stress response to the electrophysiological and molecular markers of sleep need in mice.N/A SETTINGS: Mouse sleep facility.C57BL/6J, AKR/J, DBA/2J mice.Sleep deprivation, adrenalectomy (ADX).Sleep deprivation elevated corticosterone levels in 3 inbred strains, but this increase was larger in DBA/2J mice; i.e., the strain for which the rebound in delta power after sleep deprivation failed to reach significance. Elimination of the sleep-deprivation-associated corticosterone surge through ADX in DBA/2J mice did not, however, rescue the delta power rebound but did greatly reduce the number of transcripts affected by sleep deprivation. Genes no longer affected by sleep deprivation cover pathways previously implicated in sleep homeostasis, such as lipid, cholesterol (e.g., Ldlr, Hmgcs1, Dhcr7, -24, Fkbp5), energy and carbohydrate metabolism (e.g., Eno3, G6pc3, Mpdu1, Ugdh, Man1b1), protein biosynthesis (e.g., Sgk1, Alad, Fads3, Eif2c2, -3, Mat2a), and some circadian genes (Per1, -3), whereas others, such as Homer1a, remained unchanged. Moreover, several microRNAs were affected both by sleep deprivation and ADX.Our findings indicate that corticosterone contributes to the sleep-deprivation-induced changes in brain transcriptome that have been attributed to wakefulness per se. The study identified 78 transcripts that respond to sleep loss independent of corticosterone and time of day, among which genes involved in neuroprotection prominently feature, pointing to a molecular pathway directly relevant for sleep function.

    View details for Web of Science ID 000281473600005

    View details for PubMedID 20857860

  • Circadian Locomotor Rhythms Are Normal in Ts65Dn "Down Syndrome" Mice and Unaffected by Pentylenetetrazole JOURNAL OF BIOLOGICAL RHYTHMS Ruby, N. F., Fernandez, F., Zhang, P., Klima, J., Heller, H. C., Garner, C. C. 2010; 25 (1): 63-66

    Abstract

    Ts65Dn mice are used extensively as a model for Down syndrome. Recent studies have reported conflicting evidence as to whether these mice express circadian rhythms. The authors therefore recorded locomotor activity patterns from these animals while they were housed under a standard light-dark cycle, constant darkness (DD), and constant light (LL). Contrary to expectations, Ts65Dn mice had more robust circadian rhythms with slightly shorter periods compared with their wild-type littermates. They also exhibited increased rhythm period and marked activity suppression when moved from DD to LL (i.e., Aschoff's rule). Administration of the GABA(A) antagonist pentylenetetrazole did not influence any of these circadian parameters. Thus, locomotor activity is under strict circadian control in Ts65Dn mice, suggesting that their cognitive deficits and sleep disturbances are not due to dysfunctional circadian timing as proposed previously.

    View details for DOI 10.1177/0748730409356202

    View details for Web of Science ID 000273624700008

    View details for PubMedID 20075302

  • Heat Loss Through the Glabrous Skin Surfaces of Heavily Insulated, Heat-Stressed Individuals JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Grahn, D. A., Dillon, J. L., Heller, H. C. 2009; 131 (7)

    Abstract

    Insulation reduces heat exchange between a body and the environment. Glabrous (nonhairy) skin surfaces (palms of the hands, soles of the feet, face, and ears) constitute a small percentage of total body surface area but contain specialized vascular structures that facilitate heat loss. We have previously reported that cooling the glabrous skin surfaces is effective in alleviating heat stress and that the application of local subatmospheric pressure enhances the effect. In this paper, we compare the effects of cooling multiple glabrous skin surfaces with and without vacuum on thermal recovery in heavily insulated heat-stressed individuals. Esophageal temperatures (T(es)) and heart rates were monitored throughout the trials. Water loss was determined from pre- and post-trial nude weights. Treadmill exercise (5.6 km/h, 9-16% slope, and 25-45 min duration) in a hot environment (41.5 degrees C, 20-30% relative humidity) while wearing insulating pants and jackets was used to induce heat stress (T(es)>or=39 degrees C). For postexercise recovery, the subjects donned additional insulation (a balaclava, winter gloves, and impermeable boot covers) and rested in the hot environment for 60 min. Postexercise cooling treatments included control (no cooling) or the application of a 10 degrees C closed water circulating system to (a) the hand(s) with or without application of a local subatmospheric pressure, (b) the face, (c) the feet, or (d) multiple glabrous skin regions. Following exercise induction of heat stress in heavily insulated subjects, the rate of recovery of T(es) was 0.4+/-0.2 degrees C/h(n=12), but with application of cooling to one hand, the rate was 0.8+/-0.3 degrees C/h(n=12), and with one hand cooling with subatmospheric pressure, the rate was 1.0+/-0.2 degrees C/h(n=12). Cooling alone yielded two responses, one resembling that of cooling with subatmospheric pressure (n=8) and one resembling that of no cooling (n=4). The effect of treating multiple surfaces was additive (no cooling, DeltaT(es)=-0.4+/-0.2 degrees C; one hand, -0.9+/-0.3 degrees C; face, -1.0+/-0.3 degrees C; two hands, -1.3+/-0.1 degrees C; two feet, -1.3+/-0.3 degrees C; and face, feet, and hands, -1.6+/-0.2 degrees C). Cooling treatments had a similar effect on water loss and final resting heart rate. In heat-stressed resting subjects, cooling the glabrous skin regions was effective in lowering T(es). Under this protocol, the application of local subatmospheric pressure did not significantly increase heat transfer per se but, presumably, increased the likelihood of an effect.

    View details for DOI 10.1115/1.3156812

    View details for Web of Science ID 000268439900006

    View details for PubMedID 19640130

  • New neurons in the adult brain: The role of sleep and consequences of sleep loss SLEEP MEDICINE REVIEWS Meerlo, P., Mistiberger, R. E., Jacobs, B. L., Heller, H. C., McGinty, D. 2009; 13 (3): 187-194

    Abstract

    Research over the last few decades has firmly established that new neurons are generated in selected areas of the adult mammalian brain, particularly the dentate gyrus of the hippocampal formation and the subventricular zone of the lateral ventricles. The function of adult-born neurons is still a matter of debate. In the case of the hippocampus, integration of new cells in to the existing neuronal circuitry may be involved in memory processes and the regulation of emotionality. In recent years, various studies have examined how the production of new cells and their development into neurons is affected by sleep and sleep loss. While disruption of sleep for a period shorter than one day appears to have little effect on the basal rate of cell proliferation, prolonged restriction or disruption of sleep may have cumulative effects leading to a major decrease in hippocampal cell proliferation, cell survival and neurogenesis. Importantly, while short sleep deprivation may not affect the basal rate of cell proliferation, one study in rats shows that even mild sleep restriction may interfere with the increase in neurogenesis that normally occurs with hippocampus-dependent learning. Since sleep deprivation also disturbs memory formation, these data suggest that promoting survival, maturation and integration of new cells may be an unexplored mechanism by which sleep supports learning and memory processes. Most methods of sleep deprivation that have been employed affect both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Available data favor the hypothesis that decreases in cell proliferation are related to a reduction in REM sleep, whereas decreases in the number of cells that subsequently develop into adult neurons may be related to reductions in both NREM and REM sleep. The mechanisms by which sleep loss affects different aspects of adult neurogenesis are unknown. It has been proposed that adverse effects of sleep disruption may be mediated by stress and glucocorticoids. However, a number of studies clearly show that prolonged sleep loss can inhibit hippocampal neurogenesis independent of adrenal stress hormones. In conclusion, while modest sleep restriction may interfere with the enhancement of neurogenesis associated with learning processes, prolonged sleep disruption may even affect the basal rates of cell proliferation and neurogenesis. These effects of sleep loss may endanger hippocampal integrity, thereby leading to cognitive dysfunction and contributing to the development of mood disorders.

    View details for DOI 10.1016/j.smrv.2008.07.004

    View details for Web of Science ID 000266641300002

    View details for PubMedID 18848476

  • Melanopsin as a Sleep Modulator: Circadian Gating of the Direct Effects of Light on Sleep and Altered Sleep Homeostasis in Opn4(-/-) Mice PLOS BIOLOGY Tsai, J. W., Hannibal, J., Hagiwara, G., Colas, D., Ruppert, E., Ruby, N. F., Heller, H. C., Franken, P., Bourgin, P. 2009; 7 (6)

    Abstract

    Light influences sleep and alertness either indirectly through a well-characterized circadian pathway or directly through yet poorly understood mechanisms. Melanopsin (Opn4) is a retinal photopigment crucial for conveying nonvisual light information to the brain. Through extensive characterization of sleep and the electrocorticogram (ECoG) in melanopsin-deficient (Opn4(-/-)) mice under various light-dark (LD) schedules, we assessed the role of melanopsin in mediating the effects of light on sleep and ECoG activity. In control mice, a light pulse given during the habitual dark period readily induced sleep, whereas a dark pulse given during the habitual light period induced waking with pronounced theta (7-10 Hz) and gamma (40-70 Hz) activity, the ECoG correlates of alertness. In contrast, light failed to induce sleep in Opn4(-/-) mice, and the dark-pulse-induced increase in theta and gamma activity was delayed. A 24-h recording under a LD 1-hratio1-h schedule revealed that the failure to respond to light in Opn4(-/-) mice was restricted to the subjective dark period. Light induced c-Fos immunoreactivity in the suprachiasmatic nuclei (SCN) and in sleep-active ventrolateral preoptic (VLPO) neurons was importantly reduced in Opn4(-/-) mice, implicating both sleep-regulatory structures in the melanopsin-mediated effects of light. In addition to these acute light effects, Opn4(-/-) mice slept 1 h less during the 12-h light period of a LD 12ratio12 schedule owing to a lengthening of waking bouts. Despite this reduction in sleep time, ECoG delta power, a marker of sleep need, was decreased in Opn4(-/-) mice for most of the (subjective) dark period. Delta power reached after a 6-h sleep deprivation was similarly reduced in Opn4(-/-) mice. In mice, melanopsin's contribution to the direct effects of light on sleep is limited to the dark or active period, suggesting that at this circadian phase, melanopsin compensates for circadian variations in the photo sensitivity of other light-encoding pathways such as rod and cones. Our study, furthermore, demonstrates that lack of melanopsin alters sleep homeostasis. These findings call for a reevaluation of the role of light on mammalian physiology and behavior.

    View details for DOI 10.1371/journal.pbio.1000125

    View details for Web of Science ID 000268398600004

    View details for PubMedID 19513122

  • Long term repair of learning disability through short-term reduction of CNS inhibition. Augmented Cognition, HCII 2009. D.D. Schmorrow et al. (Eds.) Heller, H.C., Colas, D., Ruby, N.F., Fernandez, F., Chuluun, B., Blank, M., Garner, C.C. 2009: 818-825
  • Long Term Repair of Learning Disability through Short-Term Reduction of CNS Inhibition FOUNDATIONS OF AUGMENTED COGNITION, PROCEEDINGS Heller, H. C., Colas, D., Ruby, N. F., Fernandez, F., Chuluun, B., Blank, M., Garner, C. C. 2009; 5638: 818-825
  • VACUUM ENHANCED HEAT TRANSFER THROUGH MAMMALIAN RADIATOR STRUCTURES PROCEEDINGS OF THE ASME SUMMER BIOENGINEERING CONFERENCE 2008, PTS A AND B Grahn, D. A., Hall, C. L., Heller, H. C. 2009: 745-746
  • Hippocampal-dependent learning requires a functional circadian system PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ruby, N. F., Hwang, C. E., Wessells, C., Fernandez, F., Zhang, P., Sapolsky, R., Heller, H. C. 2008; 105 (40): 15593-15598

    Abstract

    Decades of studies have shown that eliminating circadian rhythms of mammals does not compromise their health or longevity in the laboratory in any obvious way. These observations have raised questions about the functional significance of the mammalian circadian system, but have been difficult to address for lack of an appropriate animal model. Surgical ablation of the suprachiasmatic nucleus (SCN) and clock gene knockouts eliminate rhythms, but also damage adjacent brain regions or cause developmental effects that may impair cognitive or other physiological functions. We developed a method that avoids these problems and eliminates rhythms by noninvasive means in Siberian hamsters (Phodopus sungorus). The present study evaluated cognitive function in arrhythmic animals by using a hippocampal-dependent learning task. Control hamsters exhibited normal circadian modulation of performance in a delayed novel-object recognition task. By contrast, arrhythmic animals could not discriminate a novel object from a familiar one only 20 or 60 min after training. Memory performance was not related to prior sleep history as sleep manipulations had no effect on performance. The GABA antagonist pentylenetetrazol restored learning without restoring circadian rhythms. We conclude that the circadian system is involved in memory function in a manner that is independent of sleep. Circadian influence on learning may be exerted via cyclic GABA output from the SCN to target sites involved in learning. Arrhythmic hamsters may have failed to perform this task because of chronic inhibitory signaling from the SCN that interfered with the plastic mechanisms that encode learning in the hippocampus.

    View details for DOI 10.1073/pnas.0808259105

    View details for Web of Science ID 000260360500068

    View details for PubMedID 18832172

  • Cooling via one hand improves physical performance in heat-sensitive individuals with Multiple Sclerosis: A preliminary study BMC NEUROLOGY Grahn, D. A., Murray, J. v., Heller, H. C. 2008; 8

    Abstract

    Many individuals afflicted with multiple sclerosis (MS) experience a transient worsening of symptoms when body temperature increases due to ambient conditions or physical activity. Resulting symptom exacerbations can limit performance. We hypothesized that extraction of heat from the body through the subcutaneous retia venosa that underlie the palmar surfaces of the hands would reduce exercise-related heat stress and thereby increase the physical performance capacity of heat-sensitive individuals with MS.Ten ambulatory MS patients completed one or more randomized paired trials of walking on a treadmill in a temperate environment with and without cooling. Stop criteria were symptom exacerbation and subjective fatigue. The cooling treatment entailed inserting one hand into a rigid chamber through an elastic sleeve that formed an airtight seal around the wrist. A small vacuum pump created a -40 mm Hg subatmospheric pressure enviinside the chamber where the palmar surface of the hand rested on a metal surface maintained at 18-22 degrees C. During the treatment trials, the device was suspended from above the treadmill on a bungee cord so the subjects could comfortably keep a hand in the device without having to bear its weight while walking on the treadmill.When the trials were grouped by treatment only, cooling treatment increased exercise durations by 33% (43.6 +/- 17.1 min with treatment vs. 32.8 +/- 10.9 min. without treatment, mean +/- SD, p < 5.0.10-6, paired t-test, n = 26). When the average values were calculated for the subjects who performed multiple trials before the treatment group results were compared, cooling treatment increased exercise duration by 35% (42.8 +/- 16.4 min with treatment vs. 31.7 +/- 9.8 min. without treatment, mean +/- SD, p < 0.003, paired t-test, n = 10).These preliminary results suggest that utilization of the heat transfer capacity of the non-hairy skin surfaces can enable temperature-sensitive individuals with MS to extend participation in day-to-day physical activities despite thermally stressful conditions. However, systematic longitudinal studies in larger cohorts of MS patients with specific deficits and levels of disability conducted under a variety of test conditions are needed to confirm these preliminary findings.

    View details for DOI 10.1186/1471-2377-8-14

    View details for Web of Science ID 000256222700001

    View details for PubMedID 18474113

  • A non-circadian role for clock-genes in sleep homeostasis: a strain comparison BMC NEUROSCIENCE Franken, P., Thomason, R., Heller, H. C., O'Hara, B. F. 2007; 8

    Abstract

    We have previously reported that the expression of circadian clock-genes increases in the cerebral cortex after sleep deprivation (SD) and that the sleep rebound following SD is attenuated in mice deficient for one or more clock-genes. We hypothesized that besides generating circadian rhythms, clock-genes also play a role in the homeostatic regulation of sleep. Here we follow the time course of the forebrain changes in the expression of the clock-genes period (per)-1, per2, and of the clock-controlled gene albumin D-binding protein (dbp) during a 6 h SD and subsequent recovery sleep in three inbred strains of mice for which the homeostatic sleep rebound following SD differs. We reasoned that if clock genes are functionally implicated in sleep homeostasis then the SD-induced changes in gene expression should vary according to the genotypic differences in the sleep rebound.In all three strains per expression was increased when animals were kept awake but the rate of increase during the SD as well as the relative increase in per after 6 h SD were highest in the strain for which the sleep rebound was smallest; i.e., DBA/2J (D2). Moreover, whereas in the other two strains per1 and per2 reverted to control levels with recovery sleep, per2 expression specifically, remained elevated in D2 mice. dbp expression increased during the light period both during baseline and during SD although levels were reduced during the latter condition compared to baseline. In contrast to per2, dbp expression reverted to control levels with recovery sleep in D2 only, whereas in the two other strains expression remained decreased.These findings support and extend our previous findings that clock genes in the forebrain are implicated in the homeostatic regulation of sleep and suggest that sustained, high levels of per2 expression may negatively impact recovery sleep.

    View details for DOI 10.1186/1471-2202-8-87

    View details for Web of Science ID 000252377200001

    View details for PubMedID 17945005

  • Pattern recognition of sleep in rodents using piezoelectric signals generated by gross body movements IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING Flores, A. E., Flores, J. E., Deshpande, H., Picazo, J. A., Xie, X. (., Franken, P., Heller, H. C., Grahn, D. A., O'Hara, B. F. 2007; 54 (2): 225-233

    Abstract

    Current research on sleep using experimental animals is limited by the expense and time-consuming nature of traditional EEG/EMG recordings. We present here an alternative, noninvasive approach utilizing piezoelectric films configured as highly sensitive motion detectors. These film strips attached to the floor of the rodent cage produce an electrical output in direct proportion to the distortion of the material. During sleep, movement associated with breathing is the predominant gross body movement and, thus, output from the piezoelectric transducer provided an accurate respiratory trace during sleep. During wake, respiratory movements are masked by other motor activities. An automatic pattern recognition system was developed to identify periods of sleep and wake using the piezoelectric generated signal. Due to the complex and highly variable waveforms that result from subtle postural adjustments in the animals, traditional signal analysis techniques were not sufficient for accurate classification of sleep versus wake. Therefore, a novel pattern recognition algorithm was developed that successfully distinguished sleep from wake in approximately 95% of all epochs. This algorithm may have general utility for a variety of signals in biomedical and engineering applications. This automated system for monitoring sleep is noninvasive, inexpensive, and may be useful for large-scale sleep studies including genetic approaches towards understanding sleep and sleep disorders, and the rapid screening of the efficacy of sleep or wake promoting drugs.

    View details for DOI 10.1109/TBME.2006.886938

    View details for Web of Science ID 000243952100004

    View details for PubMedID 17278579

  • Synaptic protein dynamics in hibernation JOURNAL OF NEUROSCIENCE von der Ohe, C. G., Garner, C. C., Darian-Smith, C., Heller, H. C. 2007; 27 (1): 84-92

    Abstract

    Neurons in hibernating mammals exhibit a dramatic form of plasticity during torpor, with dendritic arbors retracting as body temperature cools and then regrowing rapidly as body temperature rises. In this study, we used immunohistochemical imaging and Western blotting of several presynaptic and postsynaptic proteins to determine the synaptic changes that accompany torpor and to investigate the mechanisms behind these changes. We show torpor-related alterations in synaptic protein localization that occur rapidly and uniformly across several brain regions in a temperature-dependent manner. Entry into torpor is associated with a 50-65% loss of synapses, as indicated by changes in the extent of colocalization of presynaptic and postsynaptic markers. We also show that the loss of synaptic protein clustering occurring during entry into torpor is not attributable to protein loss. These findings suggest that torpor-related changes in synapses stem from dissociation of proteins from the cytoskeletal active zone and postsynaptic density, creating a reservoir of proteins that can be quickly mobilized for rapid rebuilding of dendritic spines and synapses during the return to euthermia. A mechanism of neural plasticity based on protein dissociation rather than protein breakdown could explain the hibernator's capacity for large, rapid, and repeated microstructural changes, providing a fascinating contrast to neuropathologies that are dominated by protein breakdown and cell death.

    View details for DOI 10.1523/JNEUROSCI.4385-06.2007

    View details for Web of Science ID 000243254500011

    View details for PubMedID 17202475

  • H. Craig Heller. Interviewed by Laura L. Mays Hoopes. CBE life sciences education Heller, H. C. 2007; 6 (4): 275-276

    View details for PubMedID 18056296

  • A global rather than local role for adenosine in sleep homeostasis SLEEP Heller, H. C. 2006; 29 (11): 1382-1383

    View details for Web of Science ID 000242181700007

    View details for PubMedID 17162982

  • Ubiquitous and temperature-dependent neural plasticity in hibernators JOURNAL OF NEUROSCIENCE von der Ohe, C. G., Darian-Smith, C., Garner, C. C., Heller, H. C. 2006; 26 (41): 10590-10598

    Abstract

    Hibernating mammals are remarkable for surviving near-freezing brain temperatures and near cessation of neural activity for a week or more at a time. This extreme physiological state is associated with dendritic and synaptic changes in hippocampal neurons. Here, we investigate whether these changes are a ubiquitous phenomenon throughout the brain that is driven by temperature. We iontophoretically injected Lucifer yellow into several types of neurons in fixed slices from hibernating ground squirrels. We analyzed neuronal microstructure from animals at several stages of torpor at two different ambient temperatures, and during the summer. We show that neuronal cell bodies, dendrites, and spines from several cell types in hibernating ground squirrels retract on entry into torpor, change little over the course of several days, and then regrow during the 2 h return to euthermia. Similar structural changes take place in neurons from the hippocampus, cortex, and thalamus, suggesting a global phenomenon. Investigation of neural microstructure from groups of animals hibernating at different ambient temperatures revealed that there is a linear relationship between neural retraction and minimum body temperature. Despite significant temperature-dependent differences in extent of retraction during torpor, recovery reaches the same final values of cell body area, dendritic arbor complexity, and spine density. This study demonstrates large-scale and seemingly ubiquitous neural plasticity in the ground squirrel brain during torpor. It also defines a temperature-driven model of dramatic neural plasticity, which provides a unique opportunity to explore mechanisms of large-scale regrowth in adult mammals, and the effects of remodeling on learning and memory.

    View details for DOI 10.1523/JNEUROSCI.2874-06.2006

    View details for Web of Science ID 000241192800033

    View details for PubMedID 17035545

  • Glycogen content in the cerebral cortex increases with sleep loss in C57BL/6J mice NEUROSCIENCE LETTERS Franken, P., Gip, P., Hagiwara, G., Ruby, N. F., Heller, H. C. 2006; 402 (1-2): 176-179

    Abstract

    We hypothesized that a function of sleep is to replenish brain glycogen stores that become depleted while awake. We have previously tested this hypothesis in three inbred strains of mice by measuring brain glycogen after a 6h sleep deprivation (SD). Unexpectedly, glycogen content in the cerebral cortex did not decrease with SD in two of the strains and was even found to increase in mice of the C57BL/6J (B6) strain. Manipulations that initially induce glycogenolysis can also induce subsequent glycogen synthesis thereby elevating glycogen content beyond baseline. It is thus possible that in B6 mice, cortical glycogen content decreased early during SD and became elevated later in SD. In the present study, we therefore measured changes in brain glycogen over the course of a 6 h SD and during recovery sleep in B6 mice. We found no evidence of a decrease at any time during the SD, instead, cortical glycogen content monotonically increased with time-spent-awake and, when sleep was allowed, started to revert to control levels. Such a time-course is opposite to the one predicted by our initial hypothesis. These results demonstrate that glycogen synthesis can be achieved during prolonged wakefulness to the extent that it outweighs glycogenolysis. Maintaining this energy store seems thus not to be functionally related to sleep in this strain.

    View details for DOI 10.1016/j.neulet.2006.03.072

    View details for Web of Science ID 000238434300037

    View details for PubMedID 16644123

  • Sleep restriction suppresses neurogenesis induced by hippocampus-dependent learning JOURNAL OF NEUROPHYSIOLOGY Hairston, I. S., Little, M. T., Scanlon, M. D., Barakat, M. T., Palmer, T. D., Sapolsky, R. M., Heller, H. C. 2005; 94 (6): 4224-4233

    Abstract

    Sleep deprivation impairs hippocampal-dependent learning, which, in turn, is associated with increased survival of newborn cells in the hippocampus. We tested whether the deleterious effects of sleep restriction on hippocampus-dependent memory were associated with reduced cell survival in the hippocampus. We show that sleep restriction impaired hippocampus-dependent learning and abolished learning-induced neurogenesis. Animals were trained in a water maze on either a spatial learning (hippocampus-dependent) task or a nonspatial (hippocampus-independent) task for 4 days. Sleep-restricted animals were kept awake for one-half of their rest phase on each of the training days. Consistent with previous reports, animals trained on the hippocampus-dependent task expressed increased survival of newborn cells in comparison with animals trained on the hippocampus-independent task. This increase was abolished by sleep restriction that caused overall reduced cell survival in all animals. Sleep restriction also selectively impaired spatial learning while performance in the nonspatial task was, surprisingly, improved. Further analysis showed that in both training groups fully rested animals applied a spatial strategy irrespective of task requirements; this strategy interfered with performance in the nonspatial task. Conversely, in sleep-restricted animals, this preferred spatial strategy was eliminated, favoring the use of nonspatial information, and hence improving performance in the nonspatial task. These findings suggest that sleep loss altered behavioral strategies to those that do not depend on the hippocampus, concomitantly reversing the neurogenic effects of hippocampus-dependent learning.

    View details for DOI 10.1152/jn.00218.2005

    View details for Web of Science ID 000233317100053

    View details for PubMedID 16014798

  • Light induces c-fos and per1 expression in the suprachiasmatic nucleus of arrhythmic hamsters AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Barakat, M. T., O'Hara, B. F., Cao, V. H., Heller, H. C., Ruby, N. F. 2005; 289 (5): R1381-R1386

    Abstract

    Locomotor activity rhythms in a significant proportion of Siberian hamsters (Phodopus sungorus sungorus) become arrhythmic after the light-dark (LD) cycle is phase-delayed by 5 h. Arrhythmia is apparent within a few days and persists indefinitely despite the presence of the photocycle. The failure of arrhythmic hamsters to regain rhythms while housed in the LD cycle, as well as the lack of any masking of activity, suggested that the circadian system of these animals had become insensitive to light. We tested this hypothesis by examining light-induced gene expression in the suprachiasmatic nucleus (SCN). Several weeks after the phase delay, arrhythmic and re-entrained hamsters were housed in constant darkness (DD) for 24 h and administered a 30-min light pulse 2 h after predicted dark onset because light induces c-fos and per1 genes at this time in entrained animals. Brains were then removed, and tissue sections containing the SCN were processed for in situ hybridization and probed with c-fos and per1 mRNA probes made from Siberian hamster cDNA. Contrary to our prediction, light pulses induced robust expression of both c-fos and per1 in all re-entrained and arrhythmic hamsters. A separate group of animals held in DD for 10 days after the light pulse remained arrhythmic. Thus, even though the SCN of these animals responded to light, neither the LD cycle nor DD restored rhythms, as it does in other species made arrhythmic by constant light (LL). These results suggest that different mechanisms underlie arrhythmicity induced by LL or by a phase delay of the LD cycle. Whereas LL induces arrhythmicity by desynchronizing SCN neurons, phase delay-induced arrhythmicity may be due to a loss of circadian rhythms at the level of individual SCN neurons.

    View details for DOI 10.1152/ajpregu.00695.2004

    View details for Web of Science ID 000232528200020

    View details for PubMedID 16002555

  • Heat extraction through the palm of one hand improves aerobic exercise endurance in a hot environment JOURNAL OF APPLIED PHYSIOLOGY Grahn, D. A., Cao, V. H., Heller, H. C. 2005; 99 (3): 972-978

    Abstract

    In situations where the accumulation of internal heat limits physical performance, enhanced heat extraction from the body should improve performance capacity. The combined application of local subatmospheric pressure (35-45 mmHg) to an entire hand (to increase blood volume) and a heat sink (18-22 degrees C) to the palmar surface were used to draw heat out of the circulating blood. Subjects walked uphill (5.63 km/h) on a treadmill in a 40 degree C environment. Slopes of the treadmill were held constant during paired experimental trials (with and without the device). Heat extraction attenuated the rate of esophageal temperature rise during exercise (2.1 +/- 0.4 degrees and 2.9 +/- 0.5 degrees C/h, mean +/- SE, with and without the device, respectively; n = 8) and increased exercise duration (46.1 +/- 3.4 and 32.3 +/- 1.7 min with and without the device, respectively; n = 18). Hand cooling alone had little effect on exercise duration (34.1 +/- 3.0, 38.0 +/- 3.5, and 57.0 +/- 6.4 min, for control, cooling only, and cooling, and subatmospheric pressure, respectively; n = 6). In a longer term study, nine subjects participated in two or four trials per week for 8 wk. The individual workloads (treadmill slope) were varied weekly. Use of the device had a beneficial effect on exercise endurance at all workloads, but the benefit proportionally decreased at higher workloads. It is concluded that heat can be efficiently removed from the body by using the described technology and that such treatment can provide a substantial performance benefit in thermally stressful conditions.

    View details for DOI 10.1152/japplphysiol.00093.2005

    View details for Web of Science ID 000231538000027

    View details for PubMedID 15879169

  • Lack of the alanine-serine-cysteine transporter 1 causes tremors, seizures, and early postnatal death in mice BRAIN RESEARCH Xie, X. M., Dumas, T., Tang, L., Brennan, T., Reeder, T., Thomas, W., Klein, R. D., Flores, J., O'Hara, B. F., Heller, H. C., Franken, P. 2005; 1052 (2): 212-221

    Abstract

    The Na(+)-independent alanine-serine-cysteine transporter 1 (Asc-1) is exclusively expressed in neuronal structures throughout the central nervous system (CNS). Asc-1 transports small neutral amino acids with high affinity especially for D-serine and glycine (K(i): 8-12 microM), two endogenous glutamate co-agonists that activate N-methyl-D-aspartate (NMDA) receptors through interacting with the strychnine-insensitive glycine binding-site. By regulating D-serine (and possibly glycine) levels in the synaptic cleft, Asc-1 may play an important role in controlling neuronal excitability. We generated asc-1 gene knockout (asc-1(-/-)) mice to test this hypothesis. Behavioral phenotyping combined with electroencephalogram (EEG) recordings revealed that asc-1(-/-) mice developed tremors, ataxia, and seizures that resulted in early postnatal death. Both tremors and seizures were reduced by the NMDA receptor antagonist MK-801. Extracellular recordings from asc-1(-/-) brain slices indicated that the spontaneous seizure activity did not originate in the hippocampus, although, in this region, a relative increase in evoked synaptic responses was observed under nominal Mg(2+)-free conditions. Taken together with the known neurochemistry and neuronal distribution of the Asc-1 transporter, these results indicate that the mechanism underlying the behavioral hyperexcitability in mutant mice is likely due to overactivation of NMDA receptors, presumably resulting from elevated extracellular D-serine. Our study provides the first evidence to support the notion that Asc-1 transporter plays a critical role in regulating neuronal excitability, and indicate that the transporter is vital for normal CNS function and essential to postnatal survival of mice.

    View details for DOI 10.1016/j.brainres.2005.06.039

    View details for Web of Science ID 000231493000012

    View details for PubMedID 16026768

  • Unresolved issues in sleep ontogeny: a response to Blumberg et al. JOURNAL OF SLEEP RESEARCH Frank, M. G., Heller, H. C. 2005; 14 (1): 98-101

    View details for Web of Science ID 000227316500014

    View details for PubMedID 15743340

  • Phenotypic differences in reentrainment behavior and sensitivity to nighttime light pulses in Siberian hamsters JOURNAL OF BIOLOGICAL RHYTHMS Ruby, N. F., Barakat, M. T., Heller, H. C. 2004; 19 (6): 530-541

    Abstract

    Spontaneous reentrainment to phase shifts of the photocycle is a fundamental property of all circadian systems. Siberian hamsters are, however, unique in this regard because most fail to reentrain when the LD cycle (16-h light/day) is phase delayed by 5 h. In the present study, the authors compared reentrainment responses in hamsters from 2 colonies. One colony descended from animals trapped in the wild more than 30 years ago (designated "nonentrainers"), and the other colony was outbred as recently as 13 years ago (designated "entrainers"). As reported previously, only 10% of hamsters from the nonentrainer colony reentrained to a 5-h phase delay of the LD cycle. By contrast, 75% of animals from the entrainer colony reentrained to the phase shift. Another goal of this study was to test the hypothesis that failure to reentrain was a consequence of light exposure during the middle of the night on the day of the 5-h phase delay. This hypothesis was tested by exposing animals to 2 h of light during the early, middle, or late part of the night and then subjecting them on the next day to a 3-h phase delay of the photocycle, which is a phase shift to which all hamsters normally reentrain. All animals from both colonies reentrained when light pulses occurred early in the night, but more animals from the entrainer colony, compared to the nonentrainer colony, reentrained when the light pulse occurred in the middle or late part of the night. The phenotypic variation in reentrainment responses is similar to the variation in photoperiodic responsiveness previously reported for these 2 colonies. Phenotypic variation in both traits is due to underlying differences in circadian organization and suggests a common genetic basis for reentrainment responses and photoperiodic responsiveness.

    View details for DOI 10.1177/0748730404268055

    View details for Web of Science ID 000225093900008

    View details for PubMedID 15523114

  • Light pulses do not induce c-fos or per1 in the SCN of hamsters that fail to reentrain to the photocycle JOURNAL OF BIOLOGICAL RHYTHMS Barakat, M. I., O'Hara, B. E., Cao, V. H., Larkin, J. E., Heller, H. C., Ruby, N. F. 2004; 19 (4): 287-297

    Abstract

    Circadian activity rhythms of most Siberian hamsters (Phodopus sungorus sungorus) fail to reentrain to a 5-h phase shift of the light-dark (LD) cycle. Instead, their rhythms free-run at periods close to 25 h despite the continued presence of the LD cycle. This lack of behavioral reentrainment necessarily means that molecular oscillators in the master circadian pacemaker, the SCN, were unable to reentrain as well. The authors tested the hypothesis that a phase shift of the LD cycle rendered the SCN incapable of responding to photic input. Animals were exposed to a 5-h phase delay of the photocycle, and activity rhythms were monitored until a lack of reentrainment was confirmed. Hamsters were then housed in constant darkness for 24 h and administered a 30-min light pulse 2 circadian hours after activity onset. Brains were then removed, and tissue sections containing the SCN were processed for in situ hybridization. Sections were probed with Siberian hamster c-fos and per1 mRNA probes because light rapidly induces these 2 genes in the SCN during subjective night but not at other circadian phases. Light pulses induced robust expression of both genes in all animals that reentrained to the LD cycle, but no expression was observed in any animal that failed to reentrain. None of the animals exhibited an intermediate response. This finding is the first report of acute shift in a photocycle eliminating photosensitivity in the SCN and suggests that a specific pattern of light exposure may desensitize the SCN to subsequent photic input.

    View details for DOI 10.1177/0748730404266771

    View details for Web of Science ID 000222693400004

    View details for PubMedID 15245648

  • Homeostatic regulation of sleep in arrhythmic Siberian hamsters AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Larkin, J. E., Yokogawa, T., Heller, H. C., Franken, P., Ruby, N. F. 2004; 287 (1): R104-R111

    Abstract

    Sleep is regulated by independent yet interacting circadian and homeostatic processes. The present study used a novel approach to study sleep homeostasis in the absence of circadian influences by exposing Siberian hamsters to a simple phase delay of the photocycle to make them arrhythmic. Because these hamsters lacked any circadian organization, their sleep homeostasis could be studied in the absence of circadian interactions. Control animals retained circadian rhythmicity after the phase shift and re-entrained to the phase-shifted photocycle. These animals displayed robust daily sleep-wake rhythms with consolidated sleep during the light phase beginning about 1 h after light onset. This marked sleep-wake pattern was circadian in that it persisted in constant darkness. The distribution of sleep in the arrhythmic hamsters over 24 h was similar to that in the light phase of rhythmic animals. Therefore, daily sleep amounts were higher in arrhythmic animals compared with rhythmic ones. During 2- and 6-h sleep deprivations (SD), it was more difficult to keep arrhythmic hamsters awake than it was for rhythmic hamsters. Because the arrhythmic animals obtained more non-rapid eye movement sleep (NREMS) during the SD, they showed a diminished compensatory response in NREMS EEG slow-wave activity during recovery sleep. When amounts of sleep during the SD were taken into account, there were no differences in sleep homeostasis between experimental and control hamsters. Thus loss of circadian control did not alter the homeostatic response to SD. This supports the view that circadian and homeostatic influences on sleep regulation are independent processes.

    View details for DOI 10.1152/ajpregu.00676.2003

    View details for Web of Science ID 000221944000017

    View details for PubMedID 14962826

  • Glucocorticoids influence brain glycogen levels during sleep deprivation AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Gip, P., Hagiwara, G., Sapolsky, R. M., Cao, V. H., Heller, H. C., Ruby, N. F. 2004; 286 (6): R1057-R1062

    Abstract

    We investigated whether glucocorticoids [i.e., corticosterone (Cort) in rats] released during sleep deprivation (SD) affect regional brain glycogen stores in 34-day-old Long-Evans rats. Adrenalectomized (with Cort replacement; Adx+) and intact animals were sleep deprived for 6 h beginning at lights on and then immediately killed by microwave irradiation. Brain and liver glycogen and glucose and plasma glucose levels were measured. After SD in intact animals, glycogen levels decreased in the cerebellum and hippocampus but not in the cortex or brain stem. By contrast, glycogen levels in the cortex of Adx+ rats increased by 43% (P < 0.001) after SD, while other regions were unaffected. Also in Adx+ animals, glucose levels were decreased by an average of 28% throughout the brain after SD. Intact sleep-deprived rats had elevations of circulating Cort, blood, and liver glucose that were absent in intact control and Adx+ animals. Different responses between brain structures after SD may be due to regional variability in metabolic rate or glycogen metabolism. Our findings suggest that the elevated glucocorticoid secretion during SD causes brain glycogenolysis in response to energy demands.

    View details for DOI 10.1152/ajpregu.00528.2003

    View details for Web of Science ID 000221443600011

    View details for PubMedID 14962825

  • Sleep deprivation effects on growth factor expression in neonatal rats: A potential role for BDNF in the mediation of delta power JOURNAL OF NEUROPHYSIOLOGY Hairston, I. S., Peyron, C., Denning, D. P., Ruby, N. F., Flores, J., Sapolsky, R. M., Heller, H. C., O'Hara, B. F. 2004; 91 (4): 1586-1595

    Abstract

    The sleeping brain differs from the waking brain in its electrophysiological and molecular properties, including the expression of growth factors and immediate early genes (IEG). Sleep architecture and homeostatic regulation of sleep in neonates is distinct from that of adults. Hence, the present study addressed the question whether the unique homeostatic response to sleep deprivation in neonates is reflected in mRNA expression of the IEG cFos, brain-derived nerve growth factor (BDNF), and basic fibroblast growth factor (FGF2) in the cortex. As sleep deprivation is stressful to developing rats, we also investigated whether the increased levels of corticosterone would affect the expression of growth factors in the hippocampus, known to be sensitive to glucocorticoid levels. At postnatal days 16, 20, and 24, rats were subjected to sleep deprivation, maternal separation without sleep deprivation, sleep deprivation with 2 h recovery sleep, or no intervention. mRNA expression was quantified in the cortex and hippocampus. cFos was increased after sleep deprivation and was similar to control level after 2 h recovery sleep irrespective of age or brain region. BDNF was increased by sleep deprivation in the cortex at P20 and P24 and only at P24 in the hippocampus. FGF2 increased during recovery sleep at all ages in both brain regions. We conclude that cortical BDNF expression reflects the onset of adult sleep-homeostatic response, whereas the profile of expression of both growth factors suggests a trophic effect of mild sleep deprivation.

    View details for DOI 10.1152/jn.00894.2003

    View details for Web of Science ID 000220086100016

    View details for PubMedID 14668298

  • Sleep and circadian rhythms in mammalian torpor ANNUAL REVIEW OF PHYSIOLOGY Heller, H. C., Ruby, N. F. 2004; 66: 275-289

    Abstract

    Sleep and circadian rhythms are the primary determinants of arousal state, and torpor is the most extreme state change that occurs in mammals. The view that torpor is an evolutionary extension of sleep is supported by electrophysiological studies. However, comparisons of factors that influence the expression of sleep and torpor uncover significant differences. Deep sleep immediately following torpor suggests that torpor is functionally a period of sleep deprivation. Recent studies that employ post-torpor sleep deprivation, however, show that the post-torpor intense sleep is not homeostatically regulated, but might be a reflection of synaptic loss and replacement. The circadian system regulates sleep expression in euthermic mammals in such a way that would appear to preclude multiday bouts of torpor. Indeed, the circadian system is robust in animals that show shallow torpor, but its activity in hibernators is at least damped if not absent. There is good evidence from some species, however, that the circadian system plays important roles in the timing of bouts of torpor.

    View details for DOI 10.1146/annurev.physiol.66.032102.115313

    View details for Web of Science ID 000220827800012

    View details for PubMedID 14977404

  • Changes in brain glycogen after sleep deprivation vary with genotype AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Franken, P., Gip, P., Hagiwara, G., Ruby, N. F., Heller, H. C. 2003; 285 (2): R413-R419

    Abstract

    Sleep has been functionally implicated in brain energy homeostasis in that it could serve to replenish brain energy stores that become depleted while awake. Sleep deprivation (SD) should therefore lower brain glycogen content. We tested this hypothesis by sleep depriving mice of three inbred strains, i.e., AKR/J (AK), DBA/2J (D2), and C57BL/6J (B6), that differ greatly in their sleep regulation. After a 6-h SD, these mice and their controls were killed by microwave irradiation, and glycogen and glucose were quantified in the cerebral cortex, brain stem, and cerebellum. After SD, both measures significantly increased by approximately 40% in the cortex of B6 mice, while glycogen significantly decreased by 20-38% in brain stem and cerebellum of AK and D2 mice. In contrast, after SD, glucose content increased in all three structures in AK mice and did not change in D2 mice. The increase in glycogen after SD in B6 mice persisted under conditions of food deprivation that, by itself, lowered cortical glycogen. Furthermore, the strains that differ most in their compensatory response to sleep loss, i.e., AK and D2, did not differ in their glycogen response. Thus glycogen content per se is an unlikely end point of sleep's functional role in brain energy homeostasis.

    View details for DOI 10.1152/ajpregu.00668.2002

    View details for Web of Science ID 000184071000016

    View details for PubMedID 12730076

  • The ontogeny of mammalian sleep: a reappraisal of alternative hypotheses JOURNAL OF SLEEP RESEARCH Frank, M. G., Heller, H. C. 2003; 12 (1): 25-34

    Abstract

    Newborn mammals spend as much as 90% or more of their time in a sleep state characterized by frequent twitches, rapid eye movements (REMs), and irregular respiratory cycles. These motor and respiratory patterns resemble the phasic motor/respiratory components of adult REM sleep, and as a consequence, this sleep state is traditionally viewed as an immature form of REM sleep. An alternative view is that a significant portion of what has been called REM sleep in these species is a form of spontaneous activity typical of the immature nervous system. In this review, we compare and contrast these two opposing views about the ontogenetic origins of REM sleep, and review the evidence most often cited to support the idea that REM sleep is present in newborn altricial mammals. Critical review of this evidence indicates that REM sleep may not be present at birth in these species; rather, it appears that all mammals early in development exhibit spontaneous, dissociated activity that progressively becomes organized into the distinct states of REM and non-rapid eye movement sleep.

    View details for Web of Science ID 000181108800004

    View details for PubMedID 12603784

  • Region-specific expression in recovery sleep changes in immediate early gene response to sleep deprivation and in the mouse brain NEUROSCIENCE Terao, A., Greco, M. A., Davis, R. W., Heller, H. C., Kilduff, T. S. 2003; 120 (4): 1115-1124

    Abstract

    Previous studies have documented changes in expression of the immediate early gene (IEG) c-fos and Fos protein in the brain between sleep and wakefulness. Such expression differences implicate changes in transcriptional regulation across behavioral states and suggest that other transcription factors may also be affected. In the current study, we examined the expression of seven fos/jun family member mRNAs (c-fos, fosB, fos related antigen (fra)1, fra-2, junB, c-jun, and junD) and three other IEG mRNAs (egr-1, egr-3, and nur77) in mouse brain following short-term (6 h) sleep deprivation (SD) and 4 h recovery sleep (RS) after SD. Gene expression was quantified in seven brain regions by real-time reverse transcription-polymerase chain reaction (RT-PCR). Multivariate analysis of variance revealed statistically significant variation in cerebral cortex, basal forebrain, thalamus and cerebellum. Levels of c-fos and fosB mRNA were elevated during SD in all four of these brain regions. In the cerebral cortex, junB mRNA was also elevated during SD whereas, in the basal forebrain, fra-1 and fra-2 mRNA levels increased in this condition. During RS, the only IEG mRNA to undergo significant increase was fra-2 in the cortex. C-jun and junD mRNAs were invariant across experimental conditions. These results indicate that the expression of fos/jun family members is diverse during SD. Among other IEGs, nur77 mRNA expression across conditions was similar to c-fos and fosB, egr-1 mRNA was elevated during SD in the cortex and basal forebrain, and egr-3 mRNA was elevated in the cortex during both SD and RS. The similarity of fosB and nur77 expression to c-fos expression indicates that these genes might also be useful markers of functional activity. Along with our previous results, the increased levels of fra-2 and egr-3 mRNAs during RS reported here suggest that increased mRNA expression during sleep is rare and may be anatomically restricted.

    View details for DOI 10.1016/S0306-4522(03)00395-6

    View details for Web of Science ID 000187447900021

    View details for PubMedID 12927216

  • Differential increase in the expression of heat shock protein family members during sleep deprivation and during sleep NEUROSCIENCE Terao, A., Steininger, T. L., Hyder, K., Apte-Deshpande, A., Ding, J., Rishipathak, D., Davis, R. W., Heller, H. C., Kilduff, T. S. 2003; 116 (1): 187-200

    Abstract

    Although sleep is thought to be restorative from prior wakeful activities, it is not clear what is being restored. To determine whether the synthesis of macromolecules is increased in the cerebral cortex during sleep, we subjected C57BL/6 mice to 6 hours of sleep deprivation and then screened the expression of 1176 genes of known function by using cDNA arrays. The expression of the heat shock proteins (HSP), endoplasmic reticulum protein (ERp72) and glucose-regulated protein (GRp78), was among the genes whose expression was significantly elevated in the cortex during sleep deprivation, whereas GRp78 and GRp94 mRNAs were elevated in the cortex during recovery sleep after sleep deprivation, as confirmed by conventional and quantitative real-time polymerase chain reaction and/or Northern analyses. A systematic evaluation of the expression of six heat shock protein family members (ERP72, GRp78, GRp94, HSP27, HSP70-1, and HSP84) in seven brain regions revealed increased mRNA levels in cortex, basal forebrain, hypothalamus, cerebellum and medulla during sleep deprivation, whereas increased mRNA levels during recovery sleep were limited to the cortex and medulla. Immunohistochemical studies identified increased numbers of GRp78-, GRp94-, and ERp72-immunoreactive cells in the dorsal and lateral cortex during sleep deprivation but, during recovery sleep, elevated numbers of these cells were found only in the lateral cortex. In the medulla, increased numbers of GRp94-immunoreactive cells were observed in nucleus tractus solitarius, dorsal motor nucleus of the vagus and the rostroventrolateral medulla during recovery sleep. The widespread increase of heat shock protein family mRNAs in brain during sleep deprivation may be a neuroprotective response to prolonged wakefulness. In contrast, the relatively limited heat shock protein family mRNA expression during recovery sleep may be related to the role of heat shock proteins in protein biogenesis and thus to the restorative function of sleep.

    View details for Web of Science ID 000180738000023

    View details for PubMedID 12535952

  • Role of melanopsin in circadian responses to light SCIENCE Ruby, N. F., Brennan, T. J., Xie, X. M., Cao, V., Franken, P., Heller, H. C., O'Hara, B. F. 2002; 298 (5601): 2211-2213

    Abstract

    Melanopsin has been proposed as an important photoreceptive molecule for the mammalian circadian system. Its importance in this role was tested in melanopsin knockout mice. These mice entrained to a light/dark cycle, phase-shifted after a light pulse, and increased circadian period when light intensity increased. Induction of the immediate-early gene c-fos was observed after a nighttime light pulse in both wild-type and knockout mice. However, the magnitude of these behavioral responses in knockout mice was 40% lower than in wild-type mice. Although melanopsin is not essential for the circadian clock to receive photic input, it contributes significantly to the magnitude of photic responses.

    View details for Web of Science ID 000179773700054

    View details for PubMedID 12481140

  • Constant darkness restores entrainment to phase-delayed Siberian hamsters AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Ruby, N. F., Joshi, N., Heller, H. C. 2002; 283 (6): R1314-R1320

    Abstract

    Over 90% of Siberian hamsters (Phodopus sungorus) fail to reentrain to a 5-h phase delay of a 16:8-h photocycle. Because constant darkness (DD) restores rhythms disrupted by constant light, we tested whether DD could also restore entrainment. DD began 0, 5, or 14 days after a 5-h phase delay, and the light-dark cycle was reinstated 14 days later. All hamsters exposed to DD on day 0 reentrained, whereas 42% reentrained irrespective of whether DD began 5 or 14 days later. For these latter two groups, tau (tau) and alpha (alpha) in DD predicted reentrainment; animals that reentrained had a mean tau and alpha of 24.1 and 8.9 h, respectively, whereas those that failed to reentrain maintained a mean tau and alpha of 25.0 and of 7.1 h, respectively. Restoration of entrainment by DD is somewhat paradoxical because it suggests that reentrainment to the photocycle was prevented by continued exposure to that same photocycle. The dichotomy of circadian responses to DD suggests "entrainment" phenotypes that are similar to those of photoperiodic responders and nonresponders.

    View details for DOI 10.1152/ajpregu.00362.2002

    View details for Web of Science ID 000179169300004

    View details for PubMedID 12388431

  • Sleep deprivation decreases glycogen in the cerebellum but not in the cortex of young rats AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Gip, P., Hagiwara, G., Ruby, N. F., Heller, H. C. 2002; 283 (1): R54-R59

    Abstract

    We tested whether brain glycogen reserves were depleted by sleep deprivation (SD) in Long-Evans rats 20-59 days old. Animals were sleep deprived beginning at lights on and then immediately killed by microwave irradiation. Glycogen and glucose levels were measured by a fluorescence enzymatic assay. In all age groups, SD reduced cerebellar glycogen levels by an average of 26% after 6 h of SD. No changes were observed in the cortex after 6 h of SD, but in the oldest animals, 12 h of SD increased cortical glycogen levels. There was a developmental increase in basal glycogen levels in both the cortex and cerebellum that peaked at 34 days and declined thereafter. Robust differences in cortical and cerebellar glycogen levels in response to enforced waking may reflect regional differences in energy utilization and regulation during wakefulness. These results show that brain glycogen reserves are sensitive to SD.

    View details for DOI 10.1152/ajpregu.00735.2001

    View details for Web of Science ID 000176257500005

    View details for PubMedID 12069930

  • Loss of circadian organization of sleep and wakefulness during hibernation AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Larkin, J. E., Franken, P., Heller, H. C. 2002; 282 (4): R1086-R1095

    Abstract

    We investigated circadian and homeostatic regulation of nonrapid eye movement (NREM) sleep in golden-mantled ground squirrels during euthermic intervals between torpor bouts. Slow-wave activity (SWA; 1-4 Hz) and sigma activity (10-15 Hz) represent the two dominant electroencephalographic (EEG) frequency components of NREM sleep. EEG sigma activity has a strong circadian component in addition to a sleep homeostatic component, whereas SWA mainly reflects sleep homeostasis [Dijk DJ and Czeisler CA. J Neurosci 15: 3526-3538, 1995; Dijk DJ, Shanahan TL, Duffy JF, Ronda JM, and Czeisler CA. J Physiol (Lond) 505: 851-858, 1997]. Animals maintained under constant conditions continued to display circadian rhythms in both sigma activity and brain temperature throughout euthermic intervals, whereas sleep and wakefulness showed no circadian organization. Instead, sleep and wakefulness were distributed according to a 6-h ultradian rhythm. SWA, NREM sleep bout length, and sigma activity responded homeostatically to the ultradian sleep-wake pattern. We suggest that the loss of sleep-wake consolidation in ground squirrels during the hibernation season may be related to the greatly decreased locomotor activity during the hibernation season and may be necessary for maintenance of multiday torpor bouts characteristic of hibernating species.

    View details for DOI 10.1152/ajpregu.00771.2000

    View details for Web of Science ID 000174364900019

    View details for PubMedID 11893613

  • The suprachiasmatic nucleus is essential for circadian body temperature rhythms in hibernating ground squirrels JOURNAL OF NEUROSCIENCE Ruby, N. F., Dark, J., Burns, D. E., Heller, H. C., Zucker, I. 2002; 22 (1): 357-364

    Abstract

    Body temperature (T(b)) was recorded at 10 min intervals over 2.5 years in female golden-mantled ground squirrels that sustained complete ablation of the suprachiasmatic nucleus (SCNx). Animals housed at an ambient temperature (T(a)) of 6.5 degrees C were housed in a 12 hr light/dark cycle for 19 months followed by 11 months in constant light. The circadian rhythm of T(b) was permanently eliminated in euthermic and torpid SCNx squirrels, but not in those with partial destruction of the SCN or in neurologically intact control animals. Among control animals, some low-amplitude T(b) rhythms during torpor were driven by small (<0.1 degrees C) diurnal changes in T(a). During torpor bouts in which T(b) rhythms were unaffected by T(a), T(b) rhythm period ranged from 23.7 to 28.5 hr. Both SCNx and control squirrels were more likely to enter torpor at night and to arouse during the day in the presence of the light/dark cycle, whereas entry into and arousal from torpor occurred at random clock times in both SCNx and control animals housed in constant light. Absence of circadian rhythms 2.5 years after SCN ablation indicates that extra-SCN pacemakers are unable to mediate circadian organization in euthermic or torpid ground squirrels. The presence of diurnal rhythms of entry into and arousal from torpor in SCNx animals held under a light/dark cycle, and their absence in constant light, suggest that light can reach the retina of hibernating ground squirrels maintained in the laboratory and affect hibernation via an SCN-independent mechanism.

    View details for Web of Science ID 000172905700044

    View details for PubMedID 11756519

  • Sleep deprivation elevates plasma corticosterone levels in neonatal rats NEUROSCIENCE LETTERS Hairston, I. S., Ruby, N. F., Brooke, S., Peyron, C., Denning, D. P., Heller, H. C., Sapolsky, R. M. 2001; 315 (1-2): 29-32

    Abstract

    Plasma corticosterone (CORT) levels were measured after short periods of sleep deprivation in rats at postnatal days 12, 16, 20, and 24. There was an age-dependent increase in basal CORT levels and sleep deprivation significantly elevated CORT at all ages compared to non-sleep deprived controls. The levels of CORT after sleep deprivation in P16, P20 and P24 animals were similar, resulting in an age-dependent decrease of the magnitude of the response. Sleep deprived P12 animals had lower levels of CORT. However, the observed response to sleep deprivation suggests that sleep loss is a significant stressor at this age. These observations suggest that younger animals are more sensitive to the effects of mild sleep deprivation than older ones.

    View details for Web of Science ID 000172434800008

    View details for PubMedID 11711207

  • Prenatal nicotine alters vigilance states and AchR gene expression in the neonatal rat: implications for SIDS AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Frank, M. G., Srere, H., Ledezma, C., O'Hara, B., Heller, H. C. 2001; 280 (4): R1134-R1140

    Abstract

    Maternal smoking is a major risk factor for sudden infant death syndrome (SIDS). The mechanisms by which cigarette smoke predisposes infants to SIDS are not known. We examined the effects of prenatal nicotine exposure on sleep/wake ontogenesis and central cholinergic receptor gene expression in the neonatal rat. Prenatal nicotine exposure transiently increased sleep continuity and accelerated sleep/wake ontogeny in the neonatal rat. Prenatal nicotine also upregulated nicotinic and muscarinic cholinergic receptor mRNAs in brain regions involved in regulating vigilance states. These findings suggest that the nicotine contained in cigarette smoke may predispose human infants to SIDS by interfering with the normal maturation of sleep and wake.

    View details for Web of Science ID 000167445600027

    View details for PubMedID 11247836

  • Prepro-hypocretin (prepro-orexin) expression is unaffected by short-term sleep deprivation in rats and mice SLEEP Terao, A., Peyron, C., Ding, J., Wurts, S. W., Edgar, D. M., Heller, H. C., Kilduff, T. S. 2000; 23 (7): 867-874

    Abstract

    The hypocretin/orexin ligand-receptor system has recently been implicated in the sleep disorder narcolepsy. During the dark (active) period, null mutants of the prepro-orexin (prepro-hypocretin) gene have cataplectic attacks and increased levels of both rapid eye movement (REM) and non-REM (NREM) sleep. Intracerebroventricular injection of one of the encoded neuropeptides, orexin-A, early in the light period increases wakefulness and reduces REM sleep in the rat, suggesting that this system may be involved in the normal regulation of sleep and wakefulness. To further test this hypothesis, we measured hypocretin (hcrt) mRNA levels by both Northern hybridization and Taqman analysis in mouse and rat hypothalamus after short-term (6 h) sleep deprivation (SD) and 2-4 hours after recovery from SD. Although our SD procedures effectively induced a sleep debt and increased c-fos mRNA expression in the cortex and hypothalamus as described by other investigators, we found that hcrt mRNA levels were not significantly changed in either species either after SD or after recovery from SD. If the hcrt system is involved in normal regulation of sleep and wakefulness, longer periods of SD may be necessary to affect hcrt mRNA levels or changes may occur at the protein rather than mRNA level. Alternatively, this system may also be involved in another function that counterbalances any SD-induced changes in hcrt mRNA levels.

    View details for Web of Science ID 000165175500003

    View details for PubMedID 11083595

  • Siberian hamsters that fail to reentrain to the photocycle have suppressed melatonin levels AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Ruby, N. F., Dubocovich, M. L., Heller, H. C. 2000; 278 (3): R757-R762

    Abstract

    Siberian hamsters readily reentrain to a 3-h phase delay of the photocycle (16 h light/day) but fail to reentrain to a 5-h phase delay. This study tested whether melatonin production was suppressed in animals that failed to reentrain. Melatonin was measured on the day before, day of, or several days after each phase shift. Melatonin levels measured 4 h after dark onset were approximately 83 microg/ml on the day before each phase delay and undetectable (<6 microg/ml) during the light phase on the day of the phase shift. Activity onsets regained their prior phase relationship to the photocycle 4 (3 h) or 5 (5 h) days after the phase shift; on that day, melatonin levels were measured 4 h after dark onset. Melatonin levels were unaffected by the 3-h phase delay (>57.6 microg/ml) but were undetectable after a 5-h phase delay (<8 microg/ml). Thus melatonin remained suppressed only after the phase delay to which hamsters also fail to reentrain. This relationship suggests that the propensity for reentrainment may be influenced by changes in melatonin production following a phase shift of the photocycle.

    View details for Web of Science ID 000085808000028

    View details for PubMedID 10712298

  • Implications of sleep deprivation experiments for our understanding of sleep homeostasis SLEEP Benington, J. H., Heller, H. C. 1999; 22 (8): 1033-1037

    View details for Web of Science ID 000084409000003

    View details for PubMedID 10617164

  • HSP70 expression is increased during the day in a diurnal animal, the golden-mantled ground squirrel Spermophilus lateralis MOLECULAR AND CELLULAR BIOCHEMISTRY Bitting, L., Watson, F. L., O'Hara, B. F., Kilduff, T. S., Heller, H. C. 1999; 199 (1-2): 25-34

    Abstract

    Heat shock protein 70 (HSP70) gene expression was studied in a seasonal hibernator, the diurnal ground squirrel, Spermophilus lateralis. RNA transcripts of 2.7 and 2.9 kb hybridizing to an HSP70 cDNA were expressed in both brain and peripheral tissues of pre-hibernation euthermic animals; higher levels of expression were observed during the day than during nighttime samples. A decline in the expression of both transcripts occurred in all tissues examined during hibernation that remained low throughout the hibernation season, including the interbout euthermic periods and regardless of time of day. Quantitative comparisons showed pre-hibernation nighttime HSP70 expression to be as low as that observed during hibernation, despite the drastic increase in metabolic state and nearly 30 degrees C difference in body temperature. In contrast to HSP70, some mRNAs, such as beta-actin and HSP60, remained relatively constant, while others, such as glyceraldehyde 3-phosphate dehydrogenase, increased in specific tissues during the hibernation season. These results indicate that the expression of a highly conserved gene involved in protection from cellular stress, HSP70, can vary with an animal's arousal state.

    View details for Web of Science ID 000082799600004

    View details for PubMedID 10544948

  • 8-OH-DPAT-sensitive neurons in the nucleus raphe magnus modulate thermoregulatory output in rats BRAIN RESEARCH Berner, N. J., Grahn, D. A., Heller, H. C. 1999; 831 (1-2): 155-164

    Abstract

    The nucleus raphe magnus (NRM) is purported to be a relay through which peripheral thermoafferent information is transmitted to thermointegrative centers located in the preoptic/anterior hypothalamus (POAH). Therefore, suppression of neural activity in the NRM should reduce thermoregulatory responses to peripheral thermal challenges, but not affect responses elicited by manipulation of POAH temperature. At low ambient temperatures lidocaine injections into the NRM of nonanesthetized rats resulted in decreases in POAH temperature, oxygen consumption, and electromyographic activity. At a warm ambient temperature, lidocaine injections into the NRM decreased the elevations in oxygen consumption and electromyographic activity elicited by cooling the POAH. The effects of lidocaine injections were duplicated by injection of a 5-HT(1A) agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) into the NRM. The effect of 8-OH-DPAT was eliminated by pre-treatment with a selective autoreceptor antagonist. These results suggest that NRM 5-HT neurons are modulating the relationship between output of thermointegrative centers and thermoregulatory effector responses rather than processing thermoafferent information.

    View details for Web of Science ID 000080939700018

    View details for PubMedID 10411995

  • Gene expression in the brain across the hibernation cycle JOURNAL OF NEUROSCIENCE O'Hara, B. F., Watson, F. L., Srere, H. K., Kumar, H., Wiler, S. W., Welch, S. K., Bitting, L., Heller, H. C., Kilduff, T. S. 1999; 19 (10): 3781-3790

    Abstract

    The purpose of this study was to characterize changes in gene expression in the brain of a seasonal hibernator, the golden-mantled ground squirrel, Spermophilus lateralis, during the hibernation season. Very little information is available on molecular changes that correlate with hibernation state, and what has been done focused mainly on seasonal changes in peripheral tissues. We produced over 4000 reverse transcription-PCR products from euthermic and hibernating brain and compared them using differential display. Twenty-nine of the most promising were examined by Northern analysis. Although some small differences were observed across hibernation states, none of the 29 had significant changes. However, a more direct approach, investigating expression of putative hibernation-responsive genes by Northern analysis, revealed an increase in expression of transcription factors c-fos, junB, and c-Jun, but not junD, commencing during late torpor and peaking during the arousal phase of individual hibernation bouts. In contrast, prostaglandin D2 synthase declined during late torpor and arousal but returned to a high level on return to euthermia. Other genes that have putative roles in mammalian sleep or specific brain functions, including somatostatin, enkephalin, growth-associated protein 43, glutamate acid decarboxylases 65/67, histidine decarboxylase, and a sleep-related transcript SD464 did not change significantly during individual hibernation bouts. We also observed no decline in total RNA or total mRNA during torpor; such a decline had been previously hypothesized. Therefore, it appears that the dramatic changes in body temperature and other physiological variables that accompany hibernation involve only modest reprogramming of gene expression or steady-state mRNA levels.

    View details for Web of Science ID 000080162400015

    View details for PubMedID 10234010

  • Developmental changes in nicotinic receptor mRNAs and responses to nicotine in the suprachiasmatic nucleus and other brain regions MOLECULAR BRAIN RESEARCH O'Hara, B. F., MacDonald, E., Clegg, D., Wiler, S. W., Andretic, R., Cao, V. H., Miller, J. D., Heller, H. C., Kilduff, T. S. 1999; 66 (1-2): 71-82

    Abstract

    Our previous studies demonstrated that nicotine induces c-fos expression in the suprachiasmatic nucleus (SCN) of the rat during a narrow developmental window occurring in the perinatal period. We have extended these observations by showing that c-fos cannot be induced in the adult SCN by nicotine even during the subjective night, when phase shifts do occur. In contrast to the SCN, significant induction of c-fos and NGFI-A was observed in the medial habenula and paraventricular nucleus at all circadian times. In the fetal rat SCN we show that NGFI-A and junB are also induced by nicotine, but not c-jun. To investigate whether changes in nicotinic acetylcholine receptor (nAChR) expression in the SCN may underlie this change in sensitivity during the perinatal period, we examined nAChR mRNAs across this developmental period. By Northern analyses, alpha2, alpha3 and alpha4 subunit mRNAs are relatively abundant in the fetal SCN but decline substantially in the adult. alpha7 mRNA increases substantially while beta2 mRNA is relatively abundant throughout development. We also examine expression in the whole mouse brain beginning at embryonic day 11. Many mRNA sizes for nAChR subunits in both the rat and mouse are characterized here for the first time by Northern analyses and some show very large changes in expression across development. In particular, a small 1.4 kb alpha2-related mRNA is highly expressed during early development, perhaps indicating an important novel function for this subunit.

    View details for Web of Science ID 000079389200008

    View details for PubMedID 10095079

  • The glutamate induced phase shift in the SCN slice: a two pulse study BRAIN RESEARCH Franken, P., Cao, V., Heller, H. C., Miller, J. D. 1999; 818 (1): 34-40

    Abstract

    The short-term dynamics of resetting the circadian 'clock' was assessed by a double-pulse paradigm in vitro. On day 1, single and double 1 h 'pulses' of 1 mM l-glutamate were applied to the rat suprachiamastic nuclei (SCN). On days 2 and 3, single unit activity (SUA) was recorded and time-of-peak SUA was used as a phase marker of the circadian rhythm. The time-of-peak in untreated slices at 'Zeitgeber' time (ZT; hours after lights-on) 6, was used to evaluate effects of glutamate on phase. In accordance with published data, a single glutamate pulse at ZT 14 resulted in a 3 h delay of peak SUA on days 2 and 3. A 2nd pulse, given 3 h after a 1st pulse, resulted in two distinct peaks on day 2: a 1st at ZT 7 and a 2nd at ZT 12, i. e., a 6 h phase delay and hence twice the delay obtained after a single pulse. On day 3, no peak in SUA was observed which indicates that a new steady state was not reached on day 2. The bimodal distribution of SUA on day 2 corroborates other findings which suggest that the SCN comprises two distinct neuronal populations with circadian firing patterns that are normally coupled but, possibly due to different sensitivities to glutamate, can desynchronize. The additive phase-shifting effect of two consecutive glutamate pulses suggests that, at least for one sub-population of SCN neurons, the phase shift is completed within 3 h.

    View details for Web of Science ID 000078381500004

    View details for PubMedID 9914435

  • Sleep after arousal from hibernation is not homeostatically regulated AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Larkin, J. E., Heller, H. C. 1999; 276 (2): R522-R529

    Abstract

    Electroencephalographic slow-wave activity (SWA) in non-rapid eye movement (NREM) sleep is directly related to prior sleep/wake history, with high levels of SWA following extended periods of wake. Therefore, SWA has been thought to reflect the level of accumulated sleep need. The discovery that euthermic intervals between hibernation bouts are spent primarily in sleep and that this sleep is characterized by high and monotonically declining SWA has led to speculation that sleep homeostasis may play a fundamental role in the regulation of the timing of bouts of hibernation and periodic arousals to euthermia. It was proposed that because the SWA profile seen after arousal from hibernation is strikingly similar to what is seen in nonhibernating mammals after extended periods of wakefulness, that hibernating mammals may arouse from hibernation with significant accumulated sleep need. This sleep need may accumulate during hibernation because the low brain temperatures during hibernation may not be compatible with sleep restorative processes. In the present study, golden-mantled ground squirrels were sleep deprived during the first 4 h of interbout euthermia by injection of caffeine (20 mg/kg ip). We predicted that if the SWA peaks after bouts of hibernation reflected a homeostatic response to an accumulated sleep need, sleep deprivation should simply have displaced and possibly augmented the SWA to subsequent recovery sleep. Instead we found that after caffeine-induced sleep deprivation of animals just aroused from hibernation, the anticipated high SWA typical of recovery sleep did not occur. Similar results were found in a study that induced sleep deprivation by gentle handling (19). These findings indicate that the SWA peak immediately after hibernation does not represent homeostatic regulation of NREM sleep, as it normally does after prolonged wakefulness during euthermia, but instead may reflect some other neurological process in the recovery of brain function from an extended period at low temperature.

    View details for Web of Science ID 000078473600031

    View details for PubMedID 9950933

  • Phase shift magnitude and direction determine whether Siberian hamsters reentrain to the photocycle JOURNAL OF BIOLOGICAL RHYTHMS Ruby, N. F., Joshi, N., Heller, H. C. 1998; 13 (6): 506-517

    Abstract

    Body temperature (Tb) or activity rhythms were monitored in male Siberian hamsters (Phodopus sungorus) housed in an LD cycle of 16 h light/day from birth. At 3 months of age, rhythms were monitored for 14 days, and then the LD cycle was phase delayed by 1, 3, or 5 h or phase advanced by 5 h in four separate groups of animals. Phase delays were accomplished via a 1- or 3-h extension of the light phase or via a 5-h extension of the dark phase. The phase advance was accomplished via a 5-h shortening of the light phase. After 2 to 3 weeks, hamsters that were phase delayed by 1 or 3 h were then phase advanced by 1 or 3 h, respectively, via a shortening of the light phase. All of the animals reentrained to phase delays of 1 or 3 h and to a 1-h phase advance; 79% reentrained to a 3-h phase advance. In contrast, only 13% of the animals reentrained to the 5-h phase advance, 13% became arrhythmic, and 74% free ran for several weeks. After the 5-h phase delay, however, reentrainment was observed in 50% of the animals although half of them required more than 21 days to reentrain. The response to a phase shift could not be predicted by any parameter of circadian rhythm organization assessed prior to the phase shift. These data demonstrate that a phase shift of the LD cycle can permanently disrupt entrainment mechanisms and eliminate circadian Tb and activity rhythms. Magnitude and direction of a phase shift of the LD cycle determine not only the rate but also the probability of reentrainment. Furthermore, the phase of the LD cycle at which the phase shift is made has a marked effect on the proportion of animals that reentrain. Light exposure during mid-subjective night combined with daily light exposure during the active phase may explain these phenomena.

    View details for Web of Science ID 000084036900007

    View details for PubMedID 9850011

  • Neurons containing hypocretin (orexin) project to multiple neuronal systems JOURNAL OF NEUROSCIENCE Peyron, C., Tighe, D. K., Van den Pol, A. N., De Lecea, L., Heller, H. C., Sutcliffe, J. G., Kilduff, T. S. 1998; 18 (23): 9996-10015

    Abstract

    The novel neuropeptides called hypocretins (orexins) have recently been identified as being localized exclusively in cell bodies in a subregion of the tuberal part of the hypothalamus. The structure of the hypocretins, their accumulation in vesicles of axon terminals, and their excitatory effect on cultured hypothalamic neurons suggest that the hypocretins function in intercellular communication. To characterize these peptides further and to help understand what physiological functions they may serve, we undertook an immunohistochemical study to examine the distribution of preprohypocretin-immunoreactive neurons and fibers in the rat brain. Preprohypocretin-positive neurons were found in the perifornical nucleus and in the dorsal and lateral hypothalamic areas. These cells were distinct from those that express melanin-concentrating hormone. Although they represent a restricted group of cells, their projections were widely distributed in the brain. We observed labeled fibers throughout the hypothalamus. The densest extrahypothalamic projection was found in the locus coeruleus. Fibers were also seen in the septal nuclei, the bed nucleus of the stria terminalis, the paraventricular and reuniens nuclei of the thalamus, the zona incerta, the subthalamic nucleus, the central gray, the substantia nigra, the raphe nuclei, the parabrachial area, the medullary reticular formation, and the nucleus of the solitary tract. Less prominent projections were found in cortical regions, central and anterior amygdaloid nuclei, and the olfactory bulb. These results suggest that hypocretins are likely to have a role in physiological functions in addition to food intake such as regulation of blood pressure, the neuroendocrine system, body temperature, and the sleep-waking cycle.

    View details for Web of Science ID 000077169800038

    View details for PubMedID 9822755

  • Recovery from mild hypothermia can be accelerated by mechanically distending blood vessels in the hand JOURNAL OF APPLIED PHYSIOLOGY Grahn, D., Brock-Utne, J. G., Watenpaugh, D. E., Heller, H. C. 1998; 85 (5): 1643-1648

    Abstract

    Peripheral vasoconstriction decreases thermal conductance of hypothermic individuals, making it difficult to transfer externally applied heat to the body core. We hypothesized that increasing blood flow to the skin of a hypothermic individual would enhance the transfer of exogenous heat to the body core, thereby increasing the rate of rewarming. External auditory meatus temperature (TEAM) was monitored in hypothermic subjects during recovery from general anesthesia. In 10 subjects, heat (45-46 degreesC, water-perfused blanket) was applied to a single forearm and hand that had been placed in a subatmospheric pressure environment (-30 to -40 mmHg) to distend the blood vessels. Heat alone was applied to control subjects (n = 6). The application of subatmospheric pressure resulted in a 10-fold increase in rewarming rates as determined by changes in TEAM [13.6 +/- 2.1 (SE) degreesC/h in the experimental group vs. 1.4 +/- 0.1 degreesC/h in the control group; P < 0.001]. In the experimental subjects, the rate of change of TEAM decreased sharply as TEAM neared the normothermic range.

    View details for Web of Science ID 000076875900008

    View details for PubMedID 9804564

  • Early synaptogenesis in vitro: Role of axon target distance JOURNAL OF COMPARATIVE NEUROLOGY van den Pol, A. N., Obrietan, K., Belousov, A. B., Yang, Y., Heller, H. C. 1998; 399 (4): 541-560

    Abstract

    In contrast to some previous reports suggesting a delay in synapse formation in vitro, we found that under ideal conditions, most hippocampal and hypothalamic rat neurons were synaptically coupled after 3 or 4 days in vitro. Synaptophysin immunocytochemistry revealed strongly stained presynaptic boutons by 3 days in vitro. Studies with time-lapse laser confocal imaging of FM1-43 revealed that axonal boutons were recycling their synaptic vesicles, an indication of synapse formation, as early as 3 days after plating. To test the hypothesis that neurite outgrowth was enhanced in high-density cultures, thereby increasing the probability of synapse formation, neurons were transfected with the jellyfish green fluorescent protein (GFP) gene. After 2 days in high-density cultures, green fluorescent neurites were about three times longer than in sister neurons plated in low-density cultures. Even in single dishes, GFP-transfected cells in contact with other neurons had neurites that were at least three times longer and grew faster than more isolated cells. Neurons grew longer neurites (+51%) when growing on surface membranes of heat-killed neurons than on polylysine, underlining the importance of plasma membrane contact. Calcium imaging with fura-2 and whole cell recording showed that both GABA and glutamate presynaptic release occurred after 3 or 4 days in vitro in high-density cultures but was absent in low-density cultures at this time. Together, these morphological, cytochemical, and physiological data suggest that the distance an axon must grow to find a postsynaptic partner plays a substantial role in the timing of synapse formation. Although other factors in vitro may also play a role, the distance to a postsynaptic target, which defines the interval during which an axon grows to its target, can probably account for much of the difference in timing of synapse formation previously reported in vitro. A short intercell distance may increase the concentration of limited amounts of trophic factors available to a nearby cell, and once contact is made, a neuronal membrane provides a superior substrate for neuritic elongation.

    View details for Web of Science ID 000075648000007

    View details for PubMedID 9741482

  • Characterization of the circadian system of NGFI-A and NGFI-A/NGFI-B deficient mice JOURNAL OF BIOLOGICAL RHYTHMS Kilduff, T. S., Vugrinic, C., Lee, S. L., Milbrandt, J. D., Mikkelsen, J. D., O'Hara, B. F., Heller, H. C. 1998; 13 (4): 347-357

    Abstract

    The genes NGFI-A (also known as EGR-1, zif/268, and Krox-24) and NGFI-B (nur/77) have previously been shown to be induced in the SCN of rats and hamsters by photic stimulation during the subjective night. The purpose of this study is to determine whether these genes are also induced in the SCN of mice and, if so, to characterize the circadian system of animals in which either NGFI-A or both NGFI-A and NGFI-B were eliminated by homologous recombination. In wildtype mice, NGFI-A mRNA was found to be induced in the SCN as in other rodent species. Therefore, wheel-running activity was recorded from null mutants and wildtype controls under LD 12:12 and DD conditions. Mice of all three strains appeared to entrain normally to LD 12:12 and could re-entrain to both phase advances and phase delays of the light cycle. The response of the circadian pacemaker of all three genotypes to acute light pulses appeared to be normal. The retinal innervation of the SCN in NGFI-A-/- mice and the photic induction of Fos in the SCN of both NGFI-A-/- and NGFI-A-/-/B-/- mice were indistinguishable from wildtype mice. These results indicate that induction of NGFI-A and NGFI-B is not required for photic entrainment or phase shifting of the mouse circadian system.

    View details for Web of Science ID 000075100100009

    View details for PubMedID 9711509

  • Circadian system of mice integrates brief light stimuli AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Van den Pol, A. N., Cao, V., HELLER, H. G. 1998; 275 (2): R654-R657

    Abstract

    Light is the primary sensory stimulus that synchronizes or entrains the internal circadian rhythms of animals to the solar day. In mammals photic entrainment of the circadian pacemaker residing in the suprachiasmatic nuclei is due to the fact that light at certain times of day can phase shift the pacemaker. In this study we show that the circadian system of mice can integrate extremely brief, repeated photic stimuli to produce large phase shifts. A train of 2-ms light pulses delivered as one pulse every 5 or 60 s, with a total light duration of 120 ms, can cause phase shifts of several hours that endure for weeks. Single 2-ms pulses of light were ineffective. Thus these data reveal a property of the mammalian circadian clock: it can integrate and store latent sensory information in such a way that a series of extremely brief photic stimuli, each too small to cause a phase shift individually, together can cause a large and long-lasting change in behavior.

    View details for Web of Science ID 000075249000041

    View details for PubMedID 9688706

  • Effects of sleep deprivation in neonatal rats AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Frank, M. G., Morrissette, R., Heller, H. C. 1998; 275 (1): R148-R157

    Abstract

    This investigation represents the first systematic study of sleep homeostasis in developing mammals that spans the preweaning and postweaning periods. Neonatal rats from 12 to 24 days of postnatal life (P12-P24) were anesthetized with Metofane (methoxyflurane) and implanted with miniaturized electroencephalographic (EEG) and electromyographic electrodes. After 48 h of recovery, neonatal rats were sleep deprived for 3 h by either gentle handling or forced locomotion. We find that 3-h sleep deprivation produces dramatically different compensatory responses at different stages of postnatal development. In striking contrast to adult rats, sleep deprivation does not increase slow-wave sleep EEG delta (0.5-4.0 Hz) activity in rats younger than P24. However, P12-P20 rats do show evidence of sleep regulation because they show compensatory increases in sleep time and sleep continuity during recovery. In P12 rats, approximately 90% of total slow wave sleep time lost during the sleep-deprivation period was recovered during subsequent sleep. A similar recovery of active sleep time was observed in P20-P24 rats. These findings suggest not only that sleep is regulated in neonatal rats but that the accumulation and/or discharge of sleep need changes dramatically between the third and fourth postnatal weeks.

    View details for Web of Science ID 000074512100021

    View details for PubMedID 9688973

  • Effects of temperature on sleep in the developing rat AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Morrissette, R. N., Heller, H. C. 1998; 274 (4): R1087-R1093

    Abstract

    In altricial species, such as humans and rats, much of the development of autonomic systems occurs postnatally. Consequently, vulnerabilities exist early in postnatal development when immature autonomic functions are challenged by external factors such as variations in ambient temperature (Ta). Ta profoundly influences sleep/wake state structure in adult animals and humans, and exposure to excessive warmth has been implicated as a risk factor in sudden infant death syndrome. To better understand the relationship between temperature and sleep during development, we investigated the effect of Ta variation on sleep/wake state structure and sleep intensity in developing rats. In this experiment, sleep intensity was measured by the intensity of slow-wave activity during slow-wave sleep. Neonatal Long-Evans hooded rat pups were surgically prepared for chronic sleep/wake state and brain temperature (Tbr) recording. Two-hour recordings of sleep/wake state and Tbr were obtained from rats on postnatal day 12 (P12), P14, P16, P18, and P20 at a Ta of either 28.0-30.0, 33.0-35.0, or 38.0-40.0 degrees C. Ta significantly influenced sleep/wake state structure but had little, if any, effect on sleep intensity in developing rats.

    View details for Web of Science ID 000072831000027

    View details for PubMedID 9575973

  • Nicotine and nicotinic receptors in the circadian system PSYCHONEUROENDOCRINOLOGY O'Hara, B. F., Edgar, D. M., Cao, V. H., Wiler, S. W., Heller, H. C., Kilduff, T. S., Miller, J. D. 1998; 23 (2): 161-173

    Abstract

    Considerable data support a role for cholinergic influences on the circadian system. The extent to which these influences are mediated by nicotinic acetylcholine receptors (nAChRs) has been controversial, as have the specific actions of nicotine and acetylcholine in the suprachiasmatic nucleus (SCN) of the hypothalamus. In this article we review the existing literature and present new data supporting an important role for nAChRs in both the developing and adult SCN. Specifically, we present data showing that nicotine is capable of causing phase shifts in the circadian rhythms of rats. Like light and carbachol, nicotine appears to cause phase delays in the early subjective night and phase advances in the late subjective night. In the isolated SCN slice, however, only phase advances are seen, and, surprisingly, nicotine appears to cause the inhibition rather than the excitation of neurons. Among nAChR subunit mRNAs, alpha 7 appears to be the most abundant subunit in the adult SCN, whereas in the perinatal period, the more typical nAChRs with higher affinity for nicotine predominate in the SCN. This developmental change in subunit expression may explain the dramatic sensitivity of the perinatal SCN to nicotine that we have previously observed. The effects of nicotine on the SCN may contribute to alterations caused by nicotine in other physiological systems. These effects might also contribute to the dependence properties of nicotine through influences on arousal.

    View details for Web of Science ID 000073659200006

    View details for PubMedID 9621396

  • Suprachiasmatic nucleus: role in circannual body mass and hibernation rhythms of ground squirrels BRAIN RESEARCH Ruby, N. F., Dark, J., Heller, H. C., Zucker, I. 1998; 782 (1-2): 63-72

    Abstract

    Female golden-mantled ground squirrels that sustained complete ablation of the suprachiasmatic nucleus (SCNx) were housed pre- and post-operatively at 23 degrees C and then at 6.5 degrees C for 5-7 yr. SCNx and control animals held at the higher temperature manifested circannual rhythms (CARs) in body mass. In contrast, body mass CARs were not expressed in 50% of SCNx squirrels during cold exposure; rhythm amplitude was reduced to 25-40% of pre-operative values and the interval between successive peaks in body mass fell outside the circannual range. Unlike normal squirrels that hibernate for about 6 months during each circannual cycle, these SCNx squirrels expressed bouts of torpor nearly continuously throughout 2.5 yr of cold exposure. Body mass increases were often observed during hibernation--a phenomenon never observed in control animals. The remaining SCNx squirrels that did not hibernate continuously displayed CARs in body mass within the normal range. The effects of SCN ablation on body mass rhythms presumably are related to disrupted patterns of hibernation, food intake, and metabolism. The SCN, which sustains neural and metabolic activity at low tissue temperatures, may exert greater influence on thermoregulation and metabolism during the hibernation season than at other times of year, thereby accounting for the greater effect of SCN ablation in squirrels maintained at low ambient temperatures.

    View details for Web of Science ID 000072484100008

    View details for PubMedID 9519250

  • Does the preoptic anterior hypothalamus receive thermoafferent information? AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Berner, N. J., Heller, H. C. 1998; 274 (1): R9-R18

    Abstract

    The preoptic anterior hypothalamus (POAH) is considered the thermointegrative center of the mammalian brain. Studies on anesthetized and unanesthetized animals have demonstrated neurons in the POAH that respond to changes in both POAH temperature (TPOAH) and skin temperature (Ts). In these studies, however, electroencephalographic (EEG) activity was not monitored. Recent work has revealed the potential for arousal state selectivity of neurons combined with thermal influences on arousal state to create the appearance that cells are thermosensitive or thermoresponsive when in fact they may not be responding directly to temperature or to thermoafferent input. It is therefore necessary to reexamine the influence of central and peripheral temperature on POAH cells. In the present study, 66 POAH cells were recorded from urethan-anesthetized rats while EEG, TPOAH, and Ts were monitored. Seventy-five percent (41 of 55) of the cells were EEG state responsive; 22% (6 of 27) were TPOAH sensitive; and 33% (19 of 58) appeared to be Ts responsive. However, when EEG state changes were taken into account, none of the cells that appeared to be Ts responsive were responding to Ts within any uniform EEG state. All changes in their firing rates were associated with EEG state changes. This study raises a question as to whether or not peripheral temperature information is integrated in the POAH. Consideration should be given to the possibility that Ts information is integrated lower in the neuroaxis. Monitoring EEG is essential in studies attempting to characterize the integrative properties of POAH neurons of anesthetized or unanesthetized animals. This caveat applies not just to thermoregulatory studies but to investigations of other integrative functions of the hypothalamus and many other brain regions as well.

    View details for Web of Science ID 000071573600003

    View details for PubMedID 9458892

  • The aged suprachiasmatic nucleus is phase-shifted by cAMP in vitro BRAIN RESEARCH Ruby, N. F., Edgar, D. M., Heller, H. C., Miller, J. D. 1998; 779 (1-2): 338-341

    Abstract

    The cyclic adenosine monophosphate (cAMP) analog, 8-bromo-cAMP, phase advanced circadian neuronal rhythms in both aged and adult rat suprachiasmatic nuclei (SCN) by approximately 2 h in vitro. Rhythm amplitude was 20% lower in aged compared to adult SCN. The diminished efficacy of serotonergic agonists to phase shift behavioral rhythms of aged animals may be due to decrements in signal transduction mechanisms proximal to cAMP.

    View details for Web of Science ID 000071324800044

    View details for PubMedID 9473717

  • The effects of REM sleep-inhibiting drugs in neonatal rats: evidence for a distinction between neonatal active sleep and REM sleep BRAIN RESEARCH Frank, M. G., Page, J., Heller, H. C. 1997; 778 (1): 64-72

    Abstract

    Neonatal active sleep (AS) has been considered to be homologous and continuous with rapid-eye-movement (REM) sleep in adult animals. We have recently proposed an alternative view that AS is an undifferentiated sleep state distinct from REM sleep. To test these opposing views on the relationship of AS and REM sleep, neonatal rats (P11, P14 and P20) were systemically injected with compounds that inhibit REM sleep in adults. Zimelidine (ZMI) and desipramine (DMI) are monoamine uptake inhibitors which increase synaptic concentrations of serotonin and norepinephrine, respectively. Serotonin and norepinephrine inhibit brainstem cholinergic neurons important in REM sleep generation. Atropine (ATR) is a muscarinic receptor antagonist that blocks the post-synaptic effects of cholinergic projections. Only DMI (5 mg/kg) suppressed AS at P11. ZMI (6 mg/kg) and ATR (6 mg/kg) did not suppress AS until P14. These data suggest that serotonergic and cholinergic regulation of AS are absent before P14. The fact that AS in P11 rats is not affected by cholinergic antagonists supports the hypothesis that AS and REM sleep represent different sleep states.

    View details for Web of Science ID 000071238100008

    View details for PubMedID 9462878

  • Melatonin attenuates photic disruption of circadian rhythms in Siberian hamsters AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Ruby, N. F., Kang, T., Heller, H. C. 1997; 273 (4): R1540-R1549

    Abstract

    Body temperature (Tb) was recorded via a biotelemetry system from 28 adult male Siberian hamsters maintained in a light-dark (LD) cycle of 16 h light/day for several months. After Tb was recorded for 3 wk, the LD cycle was phase delayed by extending the light phase by 5 h for 1 day; animals remained on a 16:8 LD cycle for the remainder of the experiment. Hamsters were injected daily with melatonin or vehicle solution for several weeks, beginning either 2 mo after (experiment 1) or on the day of (experiment 2) the phase shift; injections occurred within 30 min of dark onset. In experiment 1, 75% of animals free ran with circadian periods >24 h, beginning on the day of the phase shift, and never reentrained to the LD cycle; no hamsters unambiguously entrained to daily injections. In contrast, 78% of animals in experiment 2 entrained to melatonin injections, and 71% of those animals subsequently reentrained to the photocycle when the injection regimen ended. No vehicle-treated animals entrained to the injection schedule. Melatonin had no effect on daily mean Tb and Tb rhythm amplitude in either experiment; however, melatonin doubled the duration of a hyperthermic response that occurred after each injection. Thus melatonin can prevent loss of entrainment induced by a phase shift of the LD cycle but cannot restore entrainment to free-running animals. Failure to reentrain in the presence of two appropriately coordinated entraining agents also suggests that a phase shift of the photocycle can diminish the sensitivity of the circadian system to both photic and nonphotic input.

    View details for Web of Science ID A1997YA44700042

    View details for PubMedID 9362322

  • Neonatal treatments with the serotonin uptake inhibitors clomipramine and zimelidine, but not the noradrenaline uptake inhibitor desipramine, disrupt sleep patterns in adult rats BRAIN RESEARCH Frank, M. G., Heller, H. C. 1997; 768 (1-2): 287-293

    Abstract

    Chronic postnatal exposure to clomipramine (CMI), a monoamine uptake inhibitor, results in persistent alterations in adult rat REM sleep. These effects have been ascribed to CMI's ability to block neonatal active sleep (AS). However, these effects have not been obtained with other anti-depressants which also block neonatal AS. We compared the long-term effects on adult rat sleep after postnatal treatments (P8-P21) with either CMI or zimelidine (ZMI, a selective serotonin uptake inhibitor) or desipramine (DMI, a selective noradrenaline uptake inhibitor). ZMI and CMI increased the frequency and decreased the duration of REM sleep bouts, increased the number of nonREM-REM transitions, and increased sigma power in REM and nonREM sleep EEGs in adulthood. In contrast, DMI had no effect on any adult sleep parameters. Since ZMI, DMI and CMI all reduce AS to similar levels, these results suggest that neonatal AS suppression is not responsible for the sleep deficits following CMI or ZMI treatment. However, since ZMI and CMI, but not DMI, increase synaptic concentrations of serotonin, elevated serotonin levels during development may instead be responsible for the long-lasting sleep deficits.

    View details for Web of Science ID A1997YB44200034

    View details for PubMedID 9369327

  • Daily variation of CNS gene expression in nocturnal vs. diurnal rodents and in the developing rat brain MOLECULAR BRAIN RESEARCH OHARA, B. F., Watson, F. L., Andretic, R., Wiler, S. W., Young, K. A., Bitting, L., Heller, H. C., Kilduff, T. S. 1997; 48 (1): 73-86

    Abstract

    Expression of c-fos has been shown to vary throughout the brain over the course of the 24-h day. The magnitude of these changes appear to be similar in a light:dark (LD) cycle or in constant dark (DD). To further examine whether the diurnal and circadian changes in c-fos and other immediate-early gene (IEG) expression in brain are related to waking behaviors such as locomotor activity, we conducted three experiments using Northern analysis. First, we compared IEG expression in nocturnal vs. diurnally active species. Second, we investigated IEG expression in a hibernating species during its active and inactive phases. Third, we examined the development of IEG expression in the young post-natal rat. As a comparison to results obtained in extra-SCN brain regions, we also examined IEG and vasopressin expression in the SCN itself across the circadian cycle. Animals maintained under a 12:12-h LD cycle were sacrificed in the morning (10:00-11:00 h, ZT2-ZT3) or night (22:00-23:00 h, ZT14-ZT15) or at the corresponding circadian times (CT) when kept in DD. Rats sacrificed in the morning always showed lower c-fos expression than at night in all brain areas examined while the reverse pattern was seen in squirrels under both LD and DD conditions, suggesting a direct correlation between c-fos message and activity. The cerebellum displayed the greatest magnitude change between morning and night (often reaching 10-fold). Among other IEGs examined, the expression of NGFI-A and junB are similar to c-fos, but of lesser magnitude, whereas c-jun appears to be invariant in the rat but is increased during the active phase in squirrels. During the hibernation season, squirrels have lower levels of c-fos consistent with their low levels of activity even during their euthermic interbout periods. c-fos expression in the cerebellum and rest of brain of 1-week-old rats sacrificed at ZT3 and ZT15 showed low levels at both timepoints whereas 2- and 3-week-old animals had higher levels at night as do adults. Among other IEGs, junB and NGFI-A again were similar to c-fos while c-jun and junD were more constant. Our observations support the idea of a diurnal rhythm of IEG expression in the CNS that is related to waking behaviors. Among IEGs, c-fos exhibits the greatest daily variation in expression.

    View details for Web of Science ID A1997XM88500011

    View details for PubMedID 9379853

  • Development of diurnal organization of EEG slow-wave activity and slow-wave sleep in the rat AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Frank, M. G., Heller, H. C. 1997; 273 (2): R472-R478

    Abstract

    This study characterizes the development of diurnal patterns of slow-wave sleep (SWS) distribution and SWS electroencephalographic (EEG) delta-power (DP) density in 12- to 24-day-old rats (P12-P24). Diurnal organization in sleep-wake distribution was established by P20. A decline in SWS DP across the light phase did not appear until P24. Before P20, SWS DP increased across the light phase in a pattern inverse to that typically seen in adult rats. At P20, SWS DP was evenly distributed across the light phase, and at P24, SWS DP declined across the light phase. The transient dissociation between diurnal organization in sleep-wake cycles and SWS DP suggests that circadian and homeostatic sleep regulatory mechanisms develop at different rates in the postnatal period.

    View details for Web of Science ID A1997XP26900002

    View details for PubMedID 9277528

  • Development of REM and slow wave sleep in the rat AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Frank, M. G., Heller, H. C. 1997; 272 (6): R1792-R1799

    Abstract

    Active sleep (AS) in the neonate has been considered to be an immature form of rapid eye movement (REM) sleep. Quiet sleep (QS) has been thought to represent an immature form of slow wave sleep (SWS). To determine the relationship between the behaviorally determined states of AS and QS and electrographically determined REM sleep and SWS, we examined sleep ontogeny in the developing rat using an experimental routine that permitted long-term recordings and minimized the effects of maternal separation. Under these conditions, a transient state that included electroencephalographic slow wave activity and phasic motor activity was eventually replaced with the mature SWS pattern. Our work suggests that neonatal QS is not an immature form of SWS and that AS is best considered as an undifferentiated behavioral state from which both SWS and REM sleep develop.

    View details for Web of Science ID A1997XF47700014

    View details for PubMedID 9227592

  • Metabotropic glutamate receptor activation modulates kainate and serotonin calcium response in astrocytes JOURNAL OF NEUROSCIENCE Haak, L. L., Heller, H. C., VANDENPOL, A. N. 1997; 17 (5): 1825-1837

    Abstract

    Although metabotropic glutamate receptor (mGluR) modulation has been studied extensively in neurons, it has not been investigated in astrocytes. We studied modulation of glutamate-evoked calcium rises in primary astrocyte cultures using fura-2 ratiometric digital calcium imaging. Calcium plays a key role as a second messenger system in astrocytes, both in regulation of many subcellular processes and in long distance intercellular signaling. Suprachiasmatic nucleus (SCN) and cortical astrocytes showed striking differences in sensitivity to glutamate and to mGluR agonists, even after several weeks in culture. Kainate-evoked intracellular calcium rises were inhibited by concurrent application of the type I and II mGluR agonists quisqualate (10 micro;M), trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylate (100-500 micro;M), and (2S-1'S-2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I) (10 micro;M). Inhibition mediated by L-CCG-I had long-lasting effects (>45 min) in approximately 30% of the SCN astrocytes tested. The inhibition could be mimicked by the L-type calcium channel blocker nimodipine (1 micro;M) as well as by protein kinase C (PKC) activators phorbol 12,13-dibutyrate (10 micro;M) and phorbol 12-myristate 13-acetate (500 nM), and blocked by the PKC inactivator (+/-)-1-(5-isoquinolinesulfonyl)-2-methylpiperazine (200 micro;M), suggesting a mechanism involving PKC modulation of L-type calcium channels. In contrast, mGluRs modulated serotonin (5HT)-evoked calcium rises through a different mechanism. The type III mGluR agonist L-2-amino-4-phosphonobutyrate consistently inhibited 5HT-evoked calcium rises, whereas in a smaller number of cells quisqualate and L-CCG-I showed both inhibitory and additive effects. Unlike the mGluR-kainate interaction, which required a pretreatment with an mGluR agonist and was insensitive to pertussis toxin (PTx), the mGluR modulation of 5HT actions was rapid and was blocked by PTx. These data suggest that glutamate, acting at several metabotropic receptors expressed by astrocytes, could modulate glial activity evoked by neurotransmitters and thereby influence the ongoing modulation of neurons by astrocytes.

    View details for Web of Science ID A1997WJ08700029

    View details for PubMedID 9030641

  • Appropriate thermal manipulations eliminate tremors in rats recovering from halothane anesthesia JOURNAL OF APPLIED PHYSIOLOGY Grahn, D. A., Heller, M. C., Larkin, J. E., Heller, H. C. 1996; 81 (6): 2547-2554

    Abstract

    Tremors are common in mammals emerging from anesthesia. To determine whether appropriate thermal manipulations immediately before emergence from anesthesia are sufficient to eliminate these tremors, electroencephalographic (EEG) and electromyographic (EMG) activities, hypothalamic temperature (Thy), and O2 consumption were monitored in 12 rats recovering from halothane anesthesia under three thermal regimes. EEG and EMG activities were recorded throughout anesthesia and served as feedback signals for controlling anesthetic depth. During anesthesia, Thy was either 1) allowed to fall to 32-34 degrees C, 2) maintained at 37-39 degrees C, or 3) allowed to fall to 32-34 degrees C and then raised to 37-39 degrees C. When hypothermic on emergence from anesthesia, all of the animals exhibited postanesthetic tremors that persisted until Thy values returned to normothermia. None of the animals expressed postanesthetic tremors when normothermic on emergence from anesthesia. In addition, the time between emergence from anesthesia (as determined by EEG/EMG parameters) and the initiation of coordinated motor activities was significantly decreased in the normothermic animals.

    View details for Web of Science ID A1996WB34900030

    View details for PubMedID 9018505

  • Siberian hamsters free run or become arrhythmic after a phase delay of the photocycle AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Ruby, N. F., Saran, A., Kang, T., Franken, P., Heller, H. C. 1996; 271 (4): R881-R890

    Abstract

    Body temperature (Tb) and locomotor activity were recorded telemetrically from male Siberian hamsters (Phodopus sungorus sungorus) that were 3 or 12 mo of age and maintained in a light-dark (LD) cycle of 16 h light/day for 2-4 mo. After 3 wk of Tb recording, the LD cycle was phase delayed by extending the light phase by 5 h for 1 day; animals remained on a 16:8-h LD cycle for the remainder of the experiment. Tb and activity rhythms of all animals were stably entrained to the LD cycle before the phase shift. After the phase shift, > or = 80% of the animals in each age group failed to reentrain and expressed free-running Tb rhythms with stable periods that ranged from 24.33 to 26.33 h; one hamster in each age group reentrained within several days. Tb became arrhythmic in 10% of all animals immediately after, and in 28% of free running animals several weeks after, the phase shift. Changes in tau and phase of activity rhythms closely paralleled Tb rhythms in individual hamsters. Daily mean Tb was unchanged, but Tb rhythm amplitude decreased by 25-50% in individual animals after the phase shift. We believe this to be the first report of neurologically intact animals failing to reentrain to a phase shift of the LD cycle. These phenomena are not readily explained by current knowledge of circadian systems and suggest that the entrainment process in Siberian hamsters differs markedly from that in other rodent species.

    View details for Web of Science ID A1996VL79400008

    View details for PubMedID 8897977

  • Ablation of suprachiasmatic nucleus alters timing of hibernation in ground squirrels PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ruby, N. F., Dark, J., Heller, H. C., Zucker, I. 1996; 93 (18): 9864-9868

    Abstract

    Hibernation patterns were monitored continuously for 2.5 years in female squirrels that were neurologically intact or in which the hypothalamic suprachiasmatic nucleus (SCN) was completely ablated (SCNx). The number of hibernation bouts in SCNx squirrels increased by 159%, total hibernation time increased by 58%, and periodic arousals from hibernation were 47% longer in SCNx than in control squirrels; the duration of individual torpor bouts was 2 days shorter and far more variable in SCNx than in control animals. Some SCNx squirrels cycled through bouts of torpor continuously for nearly 2 years. The SCN appears to be part of the mechanism that controls the duration of the hibernation season and the temporal structure of individual torpor bouts.

    View details for Web of Science ID A1996VF61400098

    View details for PubMedID 8790422

  • Temperature sensitivity of the suprachiasmatic nucleus of ground squirrels and rats in vitro JOURNAL OF BIOLOGICAL RHYTHMS Ruby, N. F., Heller, H. C. 1996; 11 (2): 126-136

    Abstract

    Temperature compensation of circadian rhythms in neuronal firing rate was investigated in the suprachiasmatic nucleus (SCN) of ground squirrels and rats in vitro. A reduction in SCN temperature from 37 to 25 degrees C reduced peak firing rates by > 70% in rats but only by approximately 21% in squirrels; trough firing rates were marginally altered in both species. In the rat SCN at 25 degrees C, the peak in neuronal activity decreased progressively on successive days and circadian rhythms no longer were present by Day 3. There was a 37% reduction in the number of single units detected and an increase in the temporal variability of peak firing rates among individual rat SCN neurons at low temperature. By contrast, single units were readily detected and circadian rhythms were robust in squirrels at 37 and 25 degrees C; a Q10 of 0.927 was associated with a shortening of tau by 2 h and a 5-h phase change after only 48 h at low temperature. These results suggest that temperature can have a substantial impact on circadian organization in a mammalian pacemaker considered to be temperature compensated.

    View details for Web of Science ID A1996UM90500006

    View details for PubMedID 8744240

  • Temperature sensitivity of sleep homeostasis during hibernation in the golden-mantled ground squirrel AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Larkin, J. E., Heller, H. C. 1996; 270 (4): R777-R784

    Abstract

    Brain temperature (Tbr), vigilance state, and electroencephalograph slow-wave activity (EEG SWA, 1.0-4.0 Hz) were measured during hibernation and spontaneous arousals to euthermia in seven golden-mantled ground squirrels (Spermophilus lateralis). Animals were held at air temperatures (Ta) ranging from 6 to 21 degrees C. SWA was used as a measure of the intensity of non-rapid eye movement (NREM) sleep. Squirrels that had hibernated at high Ta had lower SWA in NREM sleep in the hours following arousal than when they hibernated at low Ta. SWA in NREM sleep during euthermia immediately following arousal was significantly correlated to minimum Tbr and SWA during hibernation. The duration of the preceding hibernation bout had no significant effect on SWA during euthermia. We hypothesize that the restorative process of sleep, reflected by SWA, is temperature sensitive and is compromised by the low temperatures in hibernation. The accumulation of a SWA debt during hibernation may be related to the temperature-dependent depression of SWA during hibernation.

    View details for Web of Science ID A1996UD26900012

    View details for PubMedID 8967407

  • ADENOSINE PRESYNAPTIC AND POSTSYNAPTIC MODULATION OF GLUTAMATE-DEPENDENT CALCIUM ACTIVITY IN HYPOTHALAMIC NEURONS JOURNAL OF NEUROPHYSIOLOGY Obrietan, K., Belousov, A. B., Heller, H. C., VANDENPOL, A. N. 1995; 74 (5): 2150-2162

    Abstract

    1. Within the hypothalamus, adenosine has been reported to influence temperature regulation, sleep homeostasis, and endocrine secretions. The effects of adenosine on hypothalamic neurons have not been studied at the cellular level. Adenosine (5 nM-30 microM) showed no influence on intracellular Ca2+ or electrical activity in the presence of glutamate receptor antagonists D-2-amino-5-phosphonovalerate and 6-cyano-7-nitroquinoxaline-2,3-dione; consequently, we examined the role of adenosine in modulating the activity of glutamate in cultured hypothalamic neurons (n > 1,700) with fura-2 Ca2+ digital imaging and whole cell patch-clamp electrophysiology in the absence of glutamate receptor block. 2. When glutamate receptors were not blocked, adenosine (1-30 microM) and the selective adenosine A1 receptor agonist N6-cyclopentyl adenosine (CPA; 5 nM-1 microM) caused a large reduction in intracellular Ca2+ and electrical activity, suggesting that glutamate neurotransmission was critical for an effect of adenosine to be detected. Neuronal Ca2+ levels were reversibly depressed by CPA (50 nM), with a maximum depression of 90%, and these effects were blocked by coadministration of the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). 3. Ca2+ levels in immature neurons before the time of synaptogenesis were not affected by adenosine. Adenosine A1 receptor activation suppressed glutamate-mediated Ca2+ activity in neurons in vitro 8 to 73 days. 4. Adenosine (1 or 10 microM) caused a hyperpolarization of membrane potential and a reduction of large postsynaptic potentials arising from endogenously released glutamate. The administration of low concentrations of CPA (5 nM) decreased the frequency of glutamate-mediated, neuronally synchronized Ca2+ transients and the frequency of postsynaptic potentials. 5. To compare the relative effects of adenosine on hypothalamic neurons with cells from other brain regions, we assayed the effects of CPA on glutamate-mediated Ca2+ in hippocampal and cortical cultures. CPA (50 nM) reversibly depressed glutamate-mediated Ca2+ rises in hypothalamic neurons by 35%, compared with 54% in hippocampal neurons and 46% in cortical neurons. 6. If it does play a functional role, adenosine should be released by hypothalamic cells. In some neurons the adenosine A1 receptor antagonists cyclopentyltheophylline or DPCPX caused an increase in intracellular Ca2+, suggesting that adenosine was secreted by hypothalamic cells, tonically depressing glutamate-enhanced neuronal Ca2+. 7. To determine whether adenosine could exert a postsynaptic effect, we coapplied it with glutamate agonists in the presence of tetrodotoxin. Within subpopulations of hypothalamic neurons, adenosine and CPA either inhibited (18% of total neurons) or potentiated (6% of total neurons) responses to glutamate, N-methyl-D-aspartate, and kainate by > or = 20%. 8. In contrast to the modest effects found in neurons, responses of hypothalamic astrocytes to the application of glutamate or the metabotropic glutamate receptor agonist (+/-)-trans-1-amino-1,3-cyclopentanedicarboxylic acid were strongly potentiated by adenosine (mean +225%) and CPA. 9. Together, these findings suggest that adenosine exerts a major presynaptic effect and a minor postsynaptic effect in the modulation of glutamate neurotransmission in the hypothalamus, where it can play a significant role in blocking a large part of the glutamate-induced Ca2+ rise. In the absence of glutamate transmission, adenosine has relatively little effect on either neuronal intracellular Ca2+ or electrical activity.

    View details for Web of Science ID A1995TD64000028

    View details for PubMedID 8592203

  • APAMIN, A SELECTIVE SK POTASSIUM CHANNEL BLOCKER, SUPPRESSES REM-SLEEP WITHOUT A COMPENSATORY REBOUND BRAIN RESEARCH Benington, J. H., WOUDENBERG, M. C., Heller, H. C. 1995; 692 (1-2): 86-92

    Abstract

    To determine the role of neuronal potassium conductance in rapid-eye-movement (REM)-sleep homeostasis, we have administered small doses of apamin (2-5 ng), a selective blocker of the calcium-dependent SK potassium channel, injected into the lateral ventricle in rats, and characterized the resultant effects on REM-sleep expression. Apamin produces a dose-dependent reduction in REM-sleep expression without an increase in the frequency of attempts to enter REM sleep, suggesting that accumulation of REM-sleep propensity is suppressed. The vast majority (84-95%) of lost REM sleep is not recovered 40 h after apamin administration. These findings suggest that accumulation of REM-sleep propensity is linked to the increased neuronal potassium conductance in nonREM sleep.

    View details for Web of Science ID A1995RW35800009

    View details for PubMedID 8548324

  • STIMULATION OF A(1) ADENOSINE RECEPTORS MIMICS THE ELECTROENCEPHALOGRAPHIC EFFECTS OF SLEEP-DEPRIVATION BRAIN RESEARCH Benington, J. H., Kodali, S. K., Heller, H. C. 1995; 692 (1-2): 79-85

    Abstract

    N6-Cyclopentyladenosine (CPA), an A1 adenosine receptor agonist, increased EEG slow-wave activity in nonREM sleep when administered either systemically (0.1-3 mg/kg) or intracerebroventricularly (3.5-10 micrograms) in the rat. The power spectrum of EEG changes (as calculated by Fourier analysis) matched that produced by total sleep deprivation in the rat. The effects of CPA on the nonREM-sleep EEG were dose-dependent. These findings suggest that adenosine is an endogenous mediator of sleep-deprivation induced increases in EEG slow-wave activity, and therefore that increased adenosine release is a concomitant of accumulation of sleep need and may be involved in homeostatic feedback control of sleep expression.

    View details for Web of Science ID A1995RW35800008

    View details for PubMedID 8548323

  • MONOAMINERGIC AND CHOLINERGIC MODULATION OF REM-SLEEP TIMING IN RATS BRAIN RESEARCH Benington, J. H., Heller, H. C. 1995; 681 (1-2): 141-146

    Abstract

    The effects on sleep structure of systemic administration of benchmark cholinergic, serotonergic, and noradrenergic antagonists (QNB, ritanserin, metergoline, and prazosin) were characterized in rats using a new technique for identifying transitions (NRTs) from non-REM (NREM) sleep to REM sleep. In agreement with previous studies, all agents tested reduced REM-sleep expression (by 36-86%). In addition, the serotonergic and noradrenergic antagonists reduced NRT frequency (by 58-81%). The cholinergic antagonist QNB had no effect on NRT frequency. These findings suggest that blockade of serotonergic or noradrenergic receptors increases the interval between REM-sleep episodes, perhaps reducing the rate of accumulation of REM-sleep propensity. Blockade of cholinergic receptors, by contrast, decreases REM-sleep expression by interfering with REM-sleep maintenance, not by modulating REM-sleep timing. These conclusions are contrary to the predictions of a number of published models of REM-sleep timing.

    View details for Web of Science ID A1995RD89500018

    View details for PubMedID 7552271

  • SEQUENCE AND TISSUE DISTRIBUTION OF A CANDIDATE G-COUPLED RECEPTOR CLONED FROM RAT HYPOTHALAMUS BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Welch, S. K., OHARA, B. F., Kilduff, T. S., Heller, H. C. 1995; 209 (2): 606-613

    Abstract

    We have used RT-PCR with degenerate transmembrane primers to clone members of the G-coupled protein receptor family from rat hypothalamic suprachiasmatic nuclei. We report here a novel clone, UHR-1, which encodes a candidate receptor that is most similar to the neuropeptide receptor family, including the tachykinins, somatostatins, and opioids. Message for this putative receptor is expressed in several brain regions, with the highest levels in pituitary, cerebellum, and hypothalamus. No message was detected in peripheral tissues. Southern blot analysis suggests that UHR-1 is likely a member of a multigene family. The natural ligand for this novel receptor is unknown, but based on sequence homology and structural features is likely to be a peptide.

    View details for Web of Science ID A1995QU10000029

    View details for PubMedID 7733930

  • NICOTINE PHASE-ADVANCES THE CIRCADIAN NEURONAL-ACTIVITY RHYTHM IN RAT SUPRACHIASMATIC NUCLEI EXPLANTS NEUROSCIENCE Trachsel, L., Heller, H. C., Miller, J. D. 1995; 65 (3): 797-803

    Abstract

    In vivo studies reported that cholinergic agents affect mammalian circadian rhythmicity. To study phase resetting properties of cholinergic compounds more directly, we carried out experiments in rat suprachiasmatic nuclei slices. Compounds were added to the perfusate for 1 h at specific phases of the circadian cycle. On the following day, the time of peak neuronal activity, a measure of the phase of the endogenous circadian pacemaker, was assessed by means of extracellular recording in the suprachiasmatic nuclei. The peak of neuronal activity occurred at circadian time 5.8 +/- 0.7 (mean +/- 95% confidence limits) in the control slice (circadian time 0: lights-on). Ten-micromolar carbachol had no effect on the phase of the circadian rhythm when given at circadian times 6 and 15, while at circadian time 21 a phase advance of one hour was observed. By contrast, 10 microM nicotine significantly phase advanced (> 1 h) the neuronal circadian rhythm at all but one experimental circadian phase. The circadian times of maximal nicotinic phase advances were 15 (+2.6 h) and 21 (+2.8 h). A concentration response curve for nicotine was generated and pharmacological blocking experiments were performed at circadian time 15. The estimated maximum response of nicotine was 3.4 h, and the estimated concentration for half maximal response was 5 microM. The Hill coefficient (= 1.08) indicated that the effects of nicotine may be explained by a single receptor occupancy model. Mecamylamine (20 microM) almost completely antagonized the nicotinic phase-advances, whereas tetrodotoxin (1 microM) or high Mg2+ (10 mM) did not significantly attenuate the nicotinic phase-advances.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1995QN86100014

    View details for PubMedID 7609878

  • RESTORATION OF BRAIN ENERGY-METABOLISM AS THE FUNCTION OF SLEEP PROGRESS IN NEUROBIOLOGY Benington, J. H., Heller, H. C. 1995; 45 (4): 347-360

    View details for Web of Science ID A1995QN92200003

    View details for PubMedID 7624482

  • GABA(A), GABA(C), AND NMDA RECEPTOR SUBUNIT EXPRESSION IN THE SUPRACHIASMATIC NUCLEUS AND OTHER BRAIN-REGIONS MOLECULAR BRAIN RESEARCH OHARA, B. F., Andretic, R., Heller, H. C., Carter, D. B., Kilduff, T. S. 1995; 28 (2): 239-250

    Abstract

    Identification of the neurotransmitter receptor subtypes within the suprachiasmatic nuclei (SCN) will further understanding of the mechanism of the biological clock and may provide targets to manipulate circadian rhythms pharmacologically. We have focused on the ionotropic GABA and glutamate receptors because these appear to account for the majority of synaptic communication in the SCN. Of the 15 genes known to code for GABA receptor subunits in mammals we have examined the expression of 12 in the SCN, neglecting only the alpha 6, gamma 3, and rho 2 subunits. Among glutamate receptors, we have focused on the five known genes coding for the NMDA receptor subunits, and two subunits which help comprise the kainate-selective receptors. Expression was characterized by Northern analysis with RNA purified from a large number of mouse SCN and compared to expression in the remaining hypothalamus, cortex and cerebellum. This approach provided a uniform source of RNA to generate many replicate blots, each of which was probed repeatedly. The most abundant GABA receptor subunit mRNAs in the SCN were alpha 2, alpha 5, beta 1, beta 3, gamma 1 and gamma 2. The rho 1 (rho 1) subunit, which produces GABAC pharmacology, was expressed primarily in the retina in three different species and was not detectable in the mouse SCN despite a common embryological origin with the retina. For several GABA subunits we detected additional mRNA species not previously described. High expression of both genes coding for glutamic acid decarboxylase (GAD65 and GAD67) was also found in the SCN. Among the NMDA receptor subunits, NR1 was most highly expressed in the SCN followed in order of abundance by NR2B, NR2A, NR2C and NR2D. In addition, both GluR5 and GluR6 show clear expression in the SCN, with GluR5 being the most SCN specific. This approach provides a simple measure of receptor subtype expression, complements in situ hybridization studies, and may suggest novel isoforms of known subunits.

    View details for Web of Science ID A1995QE61700008

    View details for PubMedID 7723623

  • NICOTINE ADMINISTRATION DIFFERENTIALLY AFFECTS GENE-EXPRESSION IN THE MATERNAL AND FETAL CIRCADIAN CLOCK DEVELOPMENTAL BRAIN RESEARCH CLEGG, D. A., OHARA, B. F., Heller, H. C., Kilduff, T. S. 1995; 84 (1): 46-54

    Abstract

    Exposure to nicotine by active and passive cigarette smoke is a common public health problem. Recent studies have demonstrated that human fetuses are also exposed to significant levels of nicotine and that there is a five-fold increase in the incidence of Sudden Infant Death Syndrome among infants born to smoking mothers. We examined the effect of nicotine administration and expression of the immediate early gene c-fos in the maternal and fetal rat brain by in situ hybridization. Nicotine injection (1 mg/kg s.c.) on embryonic day 20 (E20) induced detectable c-fos mRNA in the maternal habenula and hypothalamic paraventricular nucleus whereas, in the fetal brain, c-fos was induced in both these structures and also in the suprachiasmatic nucleus (SCN). Nicotine-induced c-fos expression in the fetal SCN was confirmed by Northern analysis and found to return to near basal levels by 3 h post-injection. These responses were blocked by pre-administration of mecamylamine, indicating that the effect of nicotine is mediated through the cholinergic system. Investigation of the development of this response revealed that nicotine failed to induce c-fos expression in the SCN on E16, caused minimal expression on E18, robust expression on E20 and postnatal day 0 (P0), and no expression on P2 or thereafter. These observations suggest that an alteration in the composition of the nicotinic receptors (nAChR), or the subsequent intracellular responses leading to c-fos expression, occurs in the SCN during the perinatal period. Induction of c-fos mRNA in the SCN by light has been associated with phase-shifts of the circadian system, however, the behavioral consequences of the transient sensitivity of the fetal and neonatal SCN to nicotine administration and the consequences for maternal-fetal entrainment remain to be directly determined.

    View details for Web of Science ID A1995QD52400005

    View details for PubMedID 7720216

  • ONTOGENY OF PHOTIC-INDUCED C-FOS MESSENGER-RNA EXPRESSION IN RAT SUPRACHIASMATIC NUCLEI NEUROREPORT Leard, L. E., Macdonald, E. S., Heller, H. C., Kilduff, T. S. 1994; 5 (18): 2683-2687

    Abstract

    The suprachiasmatic nucleus (SCN) of the hypothalamus contains a circadian pacemaker that controls a variety of physiological and behavioral rhythms. Photic induction of immediate early genes such as c-fos in the SCN occurs in a circadian-phase dependent manner, suggesting that c-fos may be part of the pathway for entrainment of circadian rhythms. The purpose of this study was to determine the point in development when photic stimuli can first activate c-fos mRNA expression in the rat SCN. The results indicate that photic stimulation can induce statistically significant c-fos mRNA expression at circadian time 22 (CT22) on postnatal day 1 (P1), although hybridization above background levels can be detected in the SCN of some rat pups earlier in the subjective night. We infer that a multi-step pathway between visual transduction by the retina and regulation of c-fos transcription in SCN cells must be mature by CT22 on P1.

    View details for Web of Science ID A1994QB54700069

    View details for PubMedID 7696632

  • DOES THE FUNCTION OF REM-SLEEP CONCERN NON-REM SLEEP OR WAKING PROGRESS IN NEUROBIOLOGY Benington, J. H., Heller, H. C. 1994; 44 (5): 433-449

    Abstract

    We have hypothesized that REM sleep is functionally and homeostatically related to NREM sleep rather than to waking. In other words, REM sleep rather than to waking. In other words, REM sleep occurs in response to NREM-sleep expression and compensates for some process that takes place during NREM sleep. Under normal conditions, the need for REM sleep does not accrue during waking. The primary basis for this hypothesis is the fact that REM-sleep expression is a function of prior NREM-sleep expression. That is, REM sleep follows NREM sleep within sleep periods, REM-sleep episodes occur at intervals determined by the amount of NREM-sleep time elapsed, and total time spent in REM sleep is consistently about 1/4 of prior NREM-sleep time, regardless of how much time is spent in NREM sleep. Our experimental tests of the hypothesis support it. (1) REM-sleep propensity accumulates quite rapidly during a 2-hr interval spent predominantly in NREM sleep. (2) The timing of individual REM-sleep episodes is controlled homeostatically, by accumulation within NREM sleep of a propensity for REM sleep. The NREM sleep-related model of REM-sleep regulation (Fig. 1) explains a number of phenomena of REM-sleep expression, including the frequent and periodic occurrence of REM-sleep episodes throughout sleep periods, that have been accommodated by the waking-related model but are not functionally accounted for by it. In our opinion, the NREM sleep-related model of REM-sleep regulation recommends itself partly by its simplicity. According to the waking-related model, two independent and competing sleep propensities accumulate during waking and are discharged in two distinct sleep states that perform different waking-related recovery processes. One behaviour, sleep, is thought to perform two independent and competing functions that alternate at regular intervals. In the NREM sleep-related model of REM-sleep regulation, sleep debt simply reflects a need for NREM sleep. That is, the cerebrally less activated state of NREM sleep enables some form of restoration made necessary by the cerebrally activated state of waking. Periodic occurrence of REM-sleep episodes is explained without postulating an oscillatory mechanism to gate expression of NREM sleep versus REM sleep. In assessing the comparative merits of the waking-related and NREM sleep-related models of REM-sleep regulation, one should consider the influence of time-worn habits of thought.(ABSTRACT TRUNCATED AT 400 WORDS)

    View details for Web of Science ID A1994QB25200001

    View details for PubMedID 7886233

  • REM-SLEEP PROPENSITY ACCUMULATES DURING 2-H REM-SLEEP DEPRIVATION IN THE REST PERIOD IN RATS NEUROSCIENCE LETTERS Benington, J. H., WOUDENBERG, M. C., Heller, H. C. 1994; 180 (1): 76-80

    Abstract

    Two-hour, highly-selective, rest-period, rapid-eye-movement (REM)-sleep deprivation (RD) was performed on rats to characterize the time-course of the homeostatic response to REM-sleep loss. RD caused a dramatic and progressive increase in the frequency of attempts to enter REM sleep, suppressed non-REM sleep EEG delta power, and (in late rest period trials) was followed by a rebound increase in REM-sleep expression.

    View details for Web of Science ID A1994PP95400019

    View details for PubMedID 7877767

  • C-FOS MESSENGER-RNA IN THE SUPRACHIASMATIC NUCLEI IN-VITRO SHOWS A CIRCADIAN-RHYTHM AND RESPONDS TO A SEROTONERGIC AGONIST MOLECULAR BRAIN RESEARCH Prosser, R. A., Macdonald, E. S., Heller, H. C. 1994; 25 (1-2): 151-156

    Abstract

    The mammalian suprachiasmatic nuclei (SCN) contain a circadian clock that produces approximately 24 h rhythms of physiology and behavior even during constant dark. Under such conditions, light stimuli applied during the subjective night induce phase shifts of circadian rhythms and increase immediate early gene expression (c-fos) in the SCN. In vitro preparations of the SCN continue to show circadian rhythms of metabolic rate and neuronal firing rates, which can be phase shifted by non-photic stimuli. This study was designed to investigate whether the SCN display a rhythm of c-fos mRNA levels in vitro and whether quipazine, which phase-shifts the SCN circadian clock, induces c-fos expression in vitro. Levels of c-fos mRNA were found to be significantly higher in the subjective day than subjective night in the SCN in vitro. This rhythm parallels other in vivo and in vitro rhythms in SCN metabolic and neuronal activity and is consistent with previous in vivo work showing higher daytime levels of Fos-like immunoreactivity in animals maintained under constant dark conditions. Quipazine treatment during the subjective day (which phase-advances the circadian rhythm of neuronal firing in the SCN) decreased c-fos mRNA levels in the dorsomedial but not ventrolateral SCN, but quipazine did not affect c-fos levels when administered at night. This effect is consistent with serotonergic agonists inhibiting SCN neuronal activity and is the first evidence that a non-photic phase-shifting stimulus alters c-fos in the SCN at a phase-appropriate time.

    View details for Web of Science ID A1994NZ98700021

    View details for PubMedID 7984042

  • REM-SLEEP TIMING IS CONTROLLED HOMEOSTATICALLY BY ACCUMULATION OF REM-SLEEP PROPENSITY IN NON-REM SLEEP AMERICAN JOURNAL OF PHYSIOLOGY Benington, J. H., Heller, H. C. 1994; 266 (6): R1992-R2000

    Abstract

    Sleep structure in the rat was characterized during uninterrupted full-day recordings using an analytic procedure that identifies rapid eye movement (REM) sleep episodes based on REM-sleep-onset electroencephalograph phenomena, hence independently of REM-sleep duration. The data were used to determine whether REM-sleep timing is controlled homeostatically or by an oscillatory mechanism. The findings and conclusions are that 1) non-REM (NREM) sleep episode duration is positively correlated with prior REM-sleep episode duration, suggesting that REM-sleep expression is permissive of NREM sleep; 2) mean NREM-sleep episode duration decreases after repeated brief REM-sleep episodes (< 30 s), also suggesting that discharge of REM-sleep propensity is essential for NREM-sleep expression; 3) REM-sleep episode duration is independent of prior sleep history, suggesting that REM-sleep maintenance is controlled by factors other than accumulated REM-sleep propensity; 4) brief REM-sleep episodes occur progressively more frequently over the course of the NREM-sleep interval between sustained REM-sleep episodes (> 30 s), suggesting that REM-sleep propensity increases progressively within episodes of NREM sleep; and 5) the diurnal cycle of REM-sleep expression primarily reflects modulation in the efficiency of REM-sleep maintenance. These findings support the hypothesis that REM-sleep timing is controlled by accumulation of REM-sleep propensity during NREM sleep.

    View details for Web of Science ID A1994NV81000091

    View details for PubMedID 8024056

  • SEROTONERGIC PHASE ADVANCES OF THE MAMMALIAN CIRCADIAN CLOCK INVOLVE PROTEIN-KINASE-A AND K+ CHANNEL OPENING BRAIN RESEARCH Prosser, R. A., Heller, H. C., Miller, J. D. 1994; 644 (1): 67-73

    Abstract

    The mammalian circadian clock located in the suprachiasmatic nuclei (SCN) continues to oscillate when isolated in a brain slice preparation, and can be phase shifted in vitro by a variety of serotonergic (5-HTergic) agents. We have previously shown that 5-HT and a 5-HT agonist, quipazine, induce phase advances in the daytime and phase delays at night; the phase advances are mimicked by the 5-HT1A-selective agonist 8-OH-DPAT, by analogs of cyclic AMP, and by treatments that increase endogenous levels of cyclic AMP. Here we investigated the intracellular pathway through which these daytime phase advances occur. We find that quipazine- and 8-OH-DPAT-induced phase advances are blocked by two inhibitors of the cyclic AMP-dependent protein kinase, PK-A (H8 and Rp-cAMPS) as well as by a variety of K+ channel blockers (BaCl2, apamin, and charybdotoxin). Furthermore, we confirm previous work showing that a cyclic AMP analog induces phase advances in the daytime, and show that these phase advances are also blocked by BaCl2 and apamin. Finally, we show that a K+ ionophore induces similar phase advances in the subjective day, and these phase advances are blocked by Rp-cAMPS. These results indicate that both activation of PK-A and opening of K+ channels are necessary for 5-HT-induced phase advances of the SCN circadian clock. We propose a model that can account for our results.

    View details for Web of Science ID A1994NK69900011

    View details for PubMedID 8032950

  • A POSSIBLE GLIAL ROLE IN THE MAMMALIAN CIRCADIAN CLOCK BRAIN RESEARCH Prosser, R. A., Edgar, D. M., Heller, H. C., Miller, J. D. 1994; 643 (1-2): 296-301

    Abstract

    The primary mammalian circadian clock is located within the suprachiasmatic nuclei (SCN), but the cellular organization of the clock is not yet known. We investigated the potential role of glial cells in the clock mechanism by determining whether disrupting glial activity affects the in vitro circadian rhythm of neuronal activity and the in vivo circadian activity rhythm in rats. We used two agents (octanol and halothane) that block gap junctions, and one (fluorocitrate) that inhibits glial metabolism. All three agents disrupted the circadian pattern of neuronal activity. Octanol flattened the rhythm at the highest concentration (200 microM) and induced a small phase delay at a lower concentration (66 microM). Halothane and fluorocitrate induced ultradian rhythmicity. Fluorocitrate injected into the SCN of an intact rat induced arrhythmicity for about 1 week, after which the rhythm reappeared with a 1.6 h delay. These results suggest that glia play an important role in the SCN circadian clock.

    View details for Web of Science ID A1994NG73600035

    View details for PubMedID 8032923

  • PERSISTENCE OF CIRCADIAN RHYTHMICITY IN HIBERNATING GROUND-SQUIRRELS AMERICAN JOURNAL OF PHYSIOLOGY Grahn, D. A., Miller, J. D., HOUNG, V. S., Heller, H. C. 1994; 266 (4): R1251-R1258

    Abstract

    The body temperatures (Tb) of golden-mantled ground squirrels maintained under constant dim light (< 20 1x red light) at an ambient temperature of 10 degrees C were monitored via telemetry throughout the hibernation season. During euthermia, when Tb ranged from 34 to 39 degrees C, these animals exhibited robust circadian Tb rhythms. During bouts of hibernation, when Tb rhythms persisted, although the amplitudes of the rhythms were considerably dampened compared with euthermia. The periods of the intrabout Tb rhythms were within the ranges observed during euthermia and were stable within an individual bout but varied between hibernation bouts. Arousals from hibernation occurred at a fixed phase angle of the Tb cycle. Once the period of an intrabout Tb rhythm was determined, it was possible to predict the timing of arousal from the hibernation bout to within 1 h of any 24-h period. This study confirms previous speculation about the persistence of circadian rhythms in golden-mantled ground squirrels during deep hibernation and demonstrates that the circadian system is involved in the timing of periodic arousals from hibernation.

    View details for Web of Science ID A1994NJ99600075

    View details for PubMedID 8184969

  • THERMAL EFFECTS ON NEURONAL-ACTIVITY IN SUPRACHIASMATIC NUCLEI OF HIBERNATORS AND NONHIBERNATORS AMERICAN JOURNAL OF PHYSIOLOGY Miller, J. D., Cao, V. H., Heller, H. C. 1994; 266 (4): R1259-R1266

    Abstract

    The temperature sensitivity of neuronal firing rates in the suprachiasmatic nuclei (SCN) of the hypothalami of rats and ground squirrels was studied in vitro. SCN from euthermic squirrels were studied during the hibernation season (winter) and during the summer. SCN from hibernating squirrels were also studied. Most properties of SCN cells from hibernators and nonhibernators were similar. Warm- and cold-sensitive neurons were observed in all groups, but cold-sensitive neurons were more common in SCN from hibernating squirrels. No evidence for temperature compensation of firing rate was accumulated; no cell was observed to fire below 16.6 degrees C. If the persistence of circadian rhythmicity is a function of action potential-dependent neurotransmission from the SCN, these results suggest that deep hibernation (5-17 degrees C) should be characterized by an absence of circadian fluctuation in temperature. Two possible adaptations for the shallow torpor seen at somewhat higher temperatures were observed in the SCN: 1) a relatively large population of cold-sensitive neurons and 2) a population of neurons with very high activation energies. Activation energy analysis suggested that most of the temperature-sensitive properties of these cells could be explained in terms of the thermal sensitivity of the sodium channel.

    View details for Web of Science ID A1994NJ99600076

    View details for PubMedID 8184970

  • SCORING TRANSITIONS TO REM-SLEEP IN RATS BASED ON THE EEG PHENOMENA OF PRE-REM SLEEP - AN IMPROVED ANALYSIS OF SLEEP STRUCTURE SLEEP Benington, J. H., Kodali, S. K., Heller, H. C. 1994; 17 (1): 28-36

    Abstract

    Algorithms for scoring sleep/waking states and transitions to REM sleep (NRTs) in rats are presented and validated. Both algorithms are based on electroencephalographic (EEG) power in delta (0.5-4.0 Hz), theta (6-9 Hz) and sigma (10-14 Hz) frequency bands, and electromyogram (EMG) intensity. Waking is scored when EMG intensity is high or (sigma power).(theta power) is low. Nonrapid eye movement (NREM) sleep is scored in nonwaking epochs having high (delta power)/(theta power). Rapid eye movement (REM) sleep is scored in nonwaking epochs having low (delta power)/(theta power). NRTs are identified by the EEG phenomena of the pre-REM sleep phase of NREM sleep. Algorithms are validated by comparison with records scored independently by two investigators based on visual examination of EEGs and EMGs. The sleep/waking-state scoring algorithm produces greater than 90% agreement with visual scoring. The NRT-scoring algorithm produces 88-92% agreement with visual scoring. Scoring NRTs based on the phenomena of the pre-REM sleep phase of NREM sleep, instead of relying solely on REM sleep expression for identification of REM sleep onset, reveals a significant population of brief REM sleep episodes that are ignored by most sleep cycle analyses and allows independent quantification of REM sleep timing and maintenance.

    View details for Web of Science ID A1994ND34500004

    View details for PubMedID 8191200

  • C-FOS MESSENGER-RNA INCREASES IS THE GROUND-SQUIRREL SUPRACHIASMATIC NUCLEUS DURING AROUSAL FROM HIBERNATION NEUROSCIENCE LETTERS Bitting, L., SUTIN, E. L., Watson, F. L., Leard, L. E., OHARA, B. F., Heller, H. C., Kilduff, T. S. 1994; 165 (1-2): 117-121

    Abstract

    During hibernation the body temperature of the golden-mantled ground squirrel, Spermophilus lateralis, may drop below 5 degrees C for a few hours to a week or more. Animals cycle between euthermia and deep hibernation many times over the course of the hibernation season. Expression of the transcription factor c-fos increased in the suprachiasmatic nucleus (SCN) of the hypothalamus, the mammalian circadian clock, during deep hibernation and peaked during the arousal from hibernation. The pattern of increase in c-fos messenger RNA seen in the SCN by in situ hybridization was similar to that seen by Northern blot analysis of total hypothalamic RNA. The induction of c-fos may reflect a wake-up signal, increasing transcription of genes required in the euthermic state.

    View details for Web of Science ID A1994MU61100029

    View details for PubMedID 8015710

  • CHLORIDE CHANNEL BLOCK PHASE ADVANCES THE SINGLE-UNIT ACTIVITY RHYTHM IN THE SCN BRAIN RESEARCH BULLETIN Rangarajan, R., Heller, H. C., Miller, J. D. 1994; 34 (1): 69-72

    Abstract

    The mammalian suprachiasmatic nuclei (SCN) contain a circadian pacemaker that exhibits a 24 h rhythm in single-unit activity in vivo and in vitro. Chloride channel block by a saturating concentration of picrotoxin at either CT6 or CT15 produces large phase advances in the SCN single-unit activity rhythm in vitro. These phase advances are not affected by simultaneous blockade of voltage-sensitive sodium and calcium channels by TTX and magnesium. Thus, the effects of picrotoxin appear to be mediated by direct blockade of the chloride channel, rather than subsequent membrane depolarization. GABA-A receptor-mediated chloride flux may be part of the mechanism of circadian timekeeping.

    View details for Web of Science ID A1994NA53200011

    View details for PubMedID 8193935

  • LIGHT-INDUCED GENE-EXPRESSION IN THE SUPRACHIASMATIC NUCLEUS OF YOUNG AND AGING RATS NEUROBIOLOGY OF AGING SUTIN, E. L., Dement, W. C., Heller, H. C., Kilduff, T. S. 1993; 14 (5): 441-446

    Abstract

    We investigated age-related changes in a molecular mechanism associated with synchronization of circadian rhythms to the environment. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus contains a circadian pacemaker that regulates a variety of physiological and behavioral rhythms. Recent studies have demonstrated photic induction of immediate early genes (IEGs) such as c-fos in the SCN in a circadian-phase dependent manner, suggesting that IEGs may be part of the pathway for entrainment of circadian rhythms. We find that there is a decreased response of the IEGs c-fos, and NGFI-A but not NGFI-B in the SCN of old animals after photic stimulation. Changes in gene transcription indicated by IEGs may provide insights into the molecular machinery of the biological clock and ultimately elucidate mechanisms underlying the age-dependent decay of circadian organization.

    View details for Web of Science ID A1993LW58900005

    View details for PubMedID 8247226

  • SEROTONIN AND THE MAMMALIAN CIRCADIAN SYSTEM .1. INVITRO PHASE-SHIFTS BY SEROTONERGIC AGONISTS AND ANTAGONISTS JOURNAL OF BIOLOGICAL RHYTHMS Prosser, R. A., Dean, R. R., Edgar, D. M., Heller, H. C., Miller, J. D. 1993; 8 (1): 1-16

    Abstract

    The primary mammalian circadian clock, located in the suprachiasmatic nuclei (SCN), receives a major input from the raphe nuclei. The role of this input is largely unknown, and is the focus of this research. The SCN clock survives in vitro, where it produces a 24-hr rhythm in spontaneous neuronal activity that is sustained for at least three cycles. The sensitivity of the SCN clock to drugs can therefore be tested in vitro by determining whether various compounds alter the phase of this rhythm. We have previously shown that the nonspecific serotonin (5-HT) agonist quipazine resets the SCN clock in vitro, inducing phase advances in the daytime and phase delays at night. These results suggest that the 5-HT-ergic input from the raphe nuclei can modulate the phase of the SCN circadian clock. In this study we began by using autoradiography to determine that the SCN contain abundant 5-HT1A and 5-HT1B receptors, very few 5-HT1C and 5-HT2 receptors, and no 5-HT3 receptors. Next we investigated the ability of 5-HT-ergic agonists and antagonists to reset the clock in vitro, in order to determine what type or types of 5-HT receptor(s) are functionally linked to the SCN clock. We began by providing further evidence of 5-HT-ergic effects in the SCN. We found that 5-HT mimicked the effects of quipazine, whereas the nonspecific 5-HT antagonist metergoline blocked these effects, in both the day and night. Next we found that the 5-HT1A agonist 8-OH-DPAT, and to a lesser extent the 5-HT1A-1B agonist RU 24969, mimicked the effects of quipazine during the subjective daytime, whereas the 5-HT1A antagonist NAN-190 blocked quipazine's effects. None of the other specific agonists or antagonists we tried induced similar effects. This suggests that quipazine acts on 5-HT1A receptors in the daytime to advance the SCN clock. None of the specific agents we tried were able either to mimic or to block the actions of 5-HT or quipazine at circadian time 15. Thus, we were unable to determine the type of 5-HT receptor involved in nighttime phase delays by quipazine or 5-HT. However, since the dose-response curves for quipazine during the day and night are virtually identical, we hypothesize that the nighttime 5-HT receptor is a 5-HT1-like receptor.

    View details for Web of Science ID A1993KW38600001

    View details for PubMedID 8490207

  • IMMEDIATE EARLY GENE-EXPRESSION IN BRAIN DURING SLEEP-DEPRIVATION - PRELIMINARY-OBSERVATIONS SLEEP OHARA, B. F., Young, K. A., Watson, F. L., Heller, H. C., Kilduff, T. S. 1993; 16 (1): 1-7

    Abstract

    The two-process model of sleep regulation posits that a homeostatic drive to sleep, referred to as Process S, increases with time spent awake. The purpose of this study was to evaluate whether immediate early gene (IEG) expression increases in the brain in proportion to time spent awake, when Process S would be expected to increase. Rats were deprived of sleep by cage tapping, cage rotation and gentle handling beginning at light onset for 45 minutes, 3 hours or 6 hours. At the end of the deprivation periods, deprived animals and an equal number of controls were decapitated, the brains dissected into subregions and frozen. Northern blots were prepared from cortex, thalamus, cerebellum, pons and hypothalamus and hybridized with cDNA probes to five IEG mRNAs; c-fos, c-jun, junB, NGFI-A and NGFI-B. Basal levels of c-fos mRNA were detectable in all brain regions from all animals. Sleep-deprived animals showed higher expression of c-fos mRNA than control animals following 45 minutes and 6 hours of sleep deprivation in all brain regions examined, with the greatest increases observed in the cerebellum. Surprisingly, only the pons and cerebellum showed clear increases at the 3-hour timepoint. In contrast to c-fos, c-jun mRNA was essentially invariant among the animals while junB mRNA was inconsistently elevated. The expression of NGFI-A and NGFI-B was similar to the c-fos pattern but of lesser magnitude.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1993KG28100001

    View details for PubMedID 8456228

  • MELATONIN INFLUENCES FOS EXPRESSION IN THE RAT SUPRACHIASMATIC NUCLEUS MOLECULAR BRAIN RESEARCH Kilduff, T. S., LANDEL, H. B., Nagy, G. S., SUTIN, E. L., Dement, W. C., Heller, H. C. 1992; 16 (1-2): 47-56

    Abstract

    Administration of the pineal hormone melatonin to rats induces expression of Fos, the protein product of the c-fos proto-oncogene, in the suprachiasmatic nucleus (SCN), the putative biological clock of mammals. Expression of the Fos protein is dependent on circadian phase: injections in the late subjective night (circadian time (CT) 22) induce Fos expression in cells within the ventral SCN whereas injections during the subjective day are ineffective. Since melatonin injections in the late subjective day have previously been shown to phase advance circadian rhythms, these results indicate that phase-advances of the circadian system can occur without increased expression of Fos protein in the SCN, at least at levels detectable by immunohistochemistry. In support of in situ hybridization histochemical evidence obtained previously, immunocytochemical data from vehicle-injected control rats suggest that the Fos protein undergoes an endogenous fluctuation with peak levels in the SCN occurring during the subjective night. These observations indicate that melatonin can affect immediate early gene expression within the SCN.

    View details for Web of Science ID A1992JW77400006

    View details for PubMedID 1334199

  • SLEEP HOMEOSTASIS IN SUPRACHIASMATIC NUCLEI-LESIONED RATS - EFFECTS OF SLEEP-DEPRIVATION AND TRIAZOLAM ADMINISTRATION BRAIN RESEARCH Trachsel, L., Edgar, D. M., Seidel, W. F., Heller, H. C., Dement, W. C. 1992; 589 (2): 253-261

    Abstract

    The electroencephalogram (EEG) and electromyogram of rats with lesions in the suprachiasmatic nuclei (SCNx) were recorded during two series of 24-h baseline, 6-h sleep deprivation (SD), and 24-h recovery. At recovery onset, rats were injected i.p. with vehicle (VEH) control solution or 0.4 mg/kg triazolam (TRZ) in a balanced crossover design. Consecutive 10-s epochs were scored for vigilance states and EEG power spectra were computed. Arousal states were uniformly distributed during 24-h baseline (wake 47% of recording time, non-rapid-eye movement sleep (nonREMS) 47%, REMS 7%), and EEG spectra (0-25 Hz) were devoid of significant trends. State-specific EEG power spectra profiles in SCNx rats were similar to those of intact animals reported previously. However, EEG delta power (0.5-3.5 Hz) of nonREMS was markedly lower in SCNx rats. Recovery from 6-h SD was characterised by a short-lasting reduction of REMS, and a long-lasting increase of nonREMS time at the cost of wakefulness. EEG delta power rebounded during the first 8 h in recovery, and fell below baseline level after 12 h in recovery. During 0-2 h TRZ recovery, rats spent more time in nonREMS with higher EEG slow wave activity as compared to the corresponding VEH recovery period. EEG slow wave activity fell below baseline levels 10 h after TRZ injection and termination of SD. We conclude that major features of homeostatic sleep EEG regulation are present in SCNx rats.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1992JN18200008

    View details for PubMedID 1393593

  • MONOAMINE AND METABOLITE LEVELS IN THE CEREBROSPINAL-FLUID OF HIBERNATING AND EUTHERMIC MARMOTS JOURNAL OF SLEEP RESEARCH Reid, M. S., Kilduff, T. S., Romero, L. M., Florant, G. L., Dement, W. C., Heller, H. C. 1992; 1 (1): 45-50
  • SEROTONERGIC PHASE-SHIFTS OF THE MAMMALIAN CIRCADIAN CLOCK - EFFECTS OF TETRODOTOXIN AND HIGH MG2+ BRAIN RESEARCH Prosser, R. A., Heller, H. C., Miller, J. D. 1992; 573 (2): 336-340

    Abstract

    The mammalian circadian clock in the suprachiasmatic nuclei (SCN) can be phase-shifted in vitro by the serotonin agonist quipazine. Here we show that quipazine resets the SCN clock in the presence of tetrodotoxin or 10 mM Mg2+, treatments that block Na+ action potentials and Ca2+ channels, respectively. These results support the hypothesis that quipazine resets the clock by stimulating receptors located on clock elements rather than on cells afferent to the clock.

    View details for Web of Science ID A1992HH57500024

    View details for PubMedID 1504770

  • Monoaminc and metabolite levels in the cerebrospinal fluid of hibernating and euthermic marmots. Journal of sleep research Reid, M. S., Kilduff, T. S., Romero, L. M., Florant, G. L., Dement, W. C., Heller, H. C. 1992; 1 (1): 45-50

    Abstract

    Cerebrospinal fluid from yellow-bellied marmots, Marmota flaviventris, was analysed for monoamine and monoamine metabolite content during euthermia and deep hibernation. Dopamine (DA) levels were decreased, while DA metabolite levels, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were dramatically increased in hibernating marmots. Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5HIAA) levels were also greatly enhanced during hibernation while norepinephrine (NE) levels were only moderately increased. These findings demonstrate that cerebrospinal monoamine levels are dynamically altered during hibernation, such that DA versus 5-HT and NE levels undergo opposite changes. Therefore, these data indicate that DA, 5-HT and NE neuronal systems are differentially altered during hibernation in mammals.

    View details for PubMedID 10607025

  • REGIONAL CHANGES IN CENTRAL MONOAMINE AND METABOLITE LEVELS DURING THE HIBERNATION CYCLE IN THE GOLDEN-MANTLED GROUND-SQUIRREL BRAIN RESEARCH Haak, L. L., Mignot, E., Kilduff, T. S., Dement, W. C., Heller, H. C. 1991; 563 (1-2): 215-220

    Abstract

    We assayed various brain regions for levels of monoamines and their metabolites throughout the hibernation cycle of the golden-mantled ground squirrel Spermophilus lateralis. The tissue concentrations of serotonin, dopamine, norepinephrine and their metabolites were determined in the parietal cortex, striatum, midbrain, hippocampus, hypothalamus, and pons. Telencephalic regions exhibited the most significant variations in biogenic amine content. Cortical serotonin (5-HT) levels increased significantly at entrance (P less than 0.0001) relative to other periods of the hibernation cycle, suggesting a role for 5-HT in the initiation of hibernation. Among striatal dopamine (DA) metabolites, 3-methoxytyramine was detectable only during euthermia and arousal; from entrance through arousal, homovanillic acid (HVA) levels were half that found during euthermia (P = 0.0001); and dihydroxyphenylacetic acid (DOPAC) levels increased during day 1 of hibernation (P less than 0.0005). Midbrain DA (P = 0.0295) and hippocampal HVA (P = 0.0194) levels also changed significantly across the hibernation bout. The absence of a consistent change in any monoamine or metabolite throughout the brain precludes the possibility of preferential temperature-dependent impairment of an enzyme involved in biogenic amine synthesis or degradation and suggests that the levels observed reflect changes in neural activity specific to each brain region. Together with previous studies of brain 2-deoxyglucose uptake throughout the hibernation cycle, these data indicate that a transient change in afferent monoaminergic metabolism and neurotransmission in the forebrain is a necessary component for the entrance to hibernation.

    View details for Web of Science ID A1991GR67200031

    View details for PubMedID 1786534

  • ARE GROUND-SQUIRRELS SLEEP-DEPRIVED DURING HIBERNATION AMERICAN JOURNAL OF PHYSIOLOGY Trachsel, L., Edgar, D. M., Heller, H. C. 1991; 260 (6): R1123-R1129

    Abstract

    Hibernation is an adaptation for energy conservation, which probably evolved as an extension of non-rapid-eye-movement sleep mechanisms. Yet, during periodic arousals from bouts of deep hibernation, ground squirrels (Spermophilus lateralis) spend most of their time asleep. Spectral analysis of the electroencephalogram revealed that cortical slow-wave intensity during sleep is high at the beginning of a euthermic period and declines thereafter. Sleep slow-wave intensity is greater after longer bouts of hibernation than after shorter bouts. We hypothesize that low body temperatures during hibernation are incompatible with the restorative function of sleep as reflected in cortical slow-wave activity. Animals must incur the energetic costs of periodic arousals from hibernation to receive the restorative benefits of euthermic slow-wave sleep. The timing of arousals from hibernation may be a function of accumulated sleep debt.

    View details for Web of Science ID A1991FU84500051

    View details for PubMedID 2058740

  • RETICULAR-FORMATION ACTIVITY DURING WAKEFULNESS AND SLEEP IN A HIBERNATOR (SPERMOPHILUS-LATERALIS) BRAIN RESEARCH Krilowicz, B. L., Edgar, D. M., Heller, H. C. 1991; 540 (1-2): 266-272

    Abstract

    This study examined ground squirrel reticular formation (RF) cell activity as a function of: (1) arousal state, and, (2) phasic alterations in neck muscle activity. A total of 37 neurons were recorded from 11 behaving squirrels (Spermophilus lateralis). Five cells were located in the midbrain RF, 15 were in the lateral pontine site implicated in inhibition of motor output, i.e. the subcoeruleus area, 11 were in the medial pontine RF, and 6 were in the medullary RF. Regardless of location, the majority of the cells (81%; 30 of 37) exhibited greatest activity when the animals were awake and/or in rapid-eye-movement (REM) sleep. However, the relationship between neuronal activity and phasic alterations in neck muscle activity differed as a function of location. The activity of 53% of cells (8 of 15) located in the subcoeruleus area increased with phasic decreases in electromyographic (EMG) activity, whereas the activity of cells (22 of 22) in other RF sites decreased or did not change with phasic decreases in EMG activity. The increased activity of subcoeruleus area cells during phasic decreases in neck muscle activity is further evidence suggesting that the lateral pontine RF is involved in promotion of muscle atonia during REM sleep and possibly wakefulness.

    View details for Web of Science ID A1991EY79400031

    View details for PubMedID 2054617

  • A SEROTONIN AGONIST PHASE-SHIFTS THE CIRCADIAN CLOCK IN THE SUPRACHIASMATIC NUCLEI INVITRO BRAIN RESEARCH Prosser, R. A., Miller, J. D., Heller, H. C. 1990; 534 (1-2): 336-339

    Abstract

    The mammalian circadian pacemaker in the suprachiasmatic nuclei (SCN) receives a large serotonergic (5-HTergic) projection from the raphe nuclei. Whether the SCN pacemaker can be modulated by this afferent projection is a question of considerable theoretical and practical interest. In this study we investigated whether the 5-HT agonist, quipazine, can reset the phase of the SCN clock when it is isolated in vitro. Our results show that 1 h treatments with quipazine induce robust phase shifts in vitro, and that this effect depends upon the circadian time of treatment. We further show that the ability of quipazine to induce phase shifts is dose-dependent. These results suggest that the SCN circadian pacemaker is sensitive to 5-HTergic stimulation, and therefore that the 5-HTergic projection to the SCN may play a role in modulating the phase of the SCN clock in the intact animal.

    View details for Web of Science ID A1990EL64300049

    View details for PubMedID 2073598

  • C-14 2-DEOXYGLUCOSE UPTAKE IN THE GROUND-SQUIRREL BRAIN DURING ENTRANCE TO AND AROUSAL FROM HIBERNATION JOURNAL OF NEUROSCIENCE Kilduff, T. S., Miller, J. D., Radeke, C. M., Sharp, F. R., Heller, H. C. 1990; 10 (7): 2463-2475

    Abstract

    Neuronal activity underlying various phases of the mammalian hibernation cycle was investigated using the 14C-2-deoxyglucose (2DG) method. Relative 2DG uptake (R2DGU) values were computed for 96 brain regions across 7 phases of the hibernation cycle: euthermia, 3 body temperature (Tb) intervals during entrance into hibernation, stable deep hibernation, and 2 Tb intervals during arousal from hibernation. Multivariate statistical techniques were employed to identify objectively groups of brain regions whose R2DGU values showed a similar pattern across all phases of hibernation. Factor analysis revealed that most of the variability in R2DGU values for the 96 brain regions across the entire cycle could be accounted for by 3 principal factors. These factors could accurately discriminate the various phases of hibernation on the basis of the R2DGU values alone. Three hypothalamic and 3 cortical regions were identified as possibly mediating the entrance into hibernation because they underwent a change in R2DGU early in entrance into hibernation and loaded strongly on one of the principal factors. Another 4 hypothalamic regions were similarly identified as possibly causally involved in the arousal from hibernation. These results, coupled with characteristic changes in ordinal rank of the 96 brain regions in each phase of hibernation, support the concept that mammalian hibernation is an active, integrated orchestration of neurophysiological events rather than a state entered through a passive process.

    View details for Web of Science ID A1990DQ70000036

    View details for PubMedID 2376782

  • SUPRACHIASMATIC NUCLEI INFLUENCE HIBERNATION RHYTHMS OF GOLDEN-MANTLED GROUND-SQUIRRELS BRAIN RESEARCH Dark, J., Kilduff, T. S., Heller, H. C., Licht, P., Zucker, I. 1990; 509 (1): 111-118

    Abstract

    Hibernation and body mass rhythms were studied in 13 golden-mantled ground squirrels maintained in an LD 12:12 photoperiod at 5 degrees C. Complete or partial ablation of the suprachiasmatic nuclei (SCN) disrupted normal hibernation rhythms. Over the course of 2 years, several animals progressed through 4 hibernation cycles, one squirrel manifested two abnormally long hibernation seasons, and another failed to hibernate. Squirrels with intact SCN exhibited normal circannual hibernation rhythms at intervals of 11.5 +/- 0.3 months. Hibernation coincided with the weight loss phase of the body mass cycle in control squirrels, but these two rhythms were dissociated in animals with lesions of the SCN. The annual plasma testosterone rhythm was normal or slightly phase-delayed in squirrels with SCN lesions maintained at 23 degrees C. The SCN may be part of a neural circuit that mediates circannual organization of hibernation rhythms.

    View details for Web of Science ID A1990CP93100016

    View details for PubMedID 2306628

  • ACTIVITY OF MOST ROSTRAL VENTROMEDIAL MEDULLA NEURONS REFLECT EEG EMG PATTERN CHANGES AMERICAN JOURNAL OF PHYSIOLOGY Grahn, D. A., Heller, H. C. 1989; 257 (6): R1496-R1505

    Abstract

    Studies in lightly anesthetized animals have demonstrated neurons in the rostral ventromedial medulla (RVM) that respond to specific modalities of peripheral stimulation. We initiated this study to investigate putative thermoafferent processing in such RVM neurons. Our results indicate that most RVM neuronal responses are not specific for the applied stimulus but reflect changes in cortical activation. Electroencephalogram/electromyogram (EEG/EMG) and RVM single unit activity was recorded in lightly urethan-anesthetized rats. Five distinct EEG/EMG patterns were observed. Their expression was a function of skin and core temperatures. Pinches and strong thermal manipulations caused a desynchronization of a synchronized EEG pattern and an increase in EMG activity. The activity of 38 of the 51 RVM neurons sampled correlated with changes in EEG/EMG activity. Thirteen neurons were not affected by changes in EEG/EMG activity. One unit responded to temperature manipulations within an EEG/EMG state, suggesting that a small portion of RVM neurons may transmit thermoafferent information.

    View details for Web of Science ID A1989CG26500075

    View details for PubMedID 2690651

  • ACTION-POTENTIAL DURATION INCREASES AS BODY-TEMPERATURE DECREASES DURING HIBERNATION BRAIN RESEARCH Krilowicz, B. L., Edgar, D. M., Heller, H. C. 1989; 498 (1): 73-80

    Abstract

    The effect of temperature on the duration of both population spikes and action potentials of single neurons has been investigated in a variety of in vitro preparations. A few studies have examined the influence of temperature on spike potentials from spinal motoneurons of intact, anesthetized mammals. In all cases, the duration of the action potential or population spike increased as temperature decreased. A similar increase in the duration of action potentials accompanied hibernation in the ground squirrel (Spermophilus lateralis). Oscilloscope traces of 2 brainstem reticular formations, and 8 posterior thalamic single units were photographed at a body temperature (Tb) of 34-36 degrees C during euthermia prior to entrance into hibernation and at Tb's ranging from 10 to 27 degrees C during hibernation. There was a significant increase in the duration of the second component of the diphasic action potential at the lower Tb (P less than 0.01). This temperature effect was reversible, i.e. action potential durations returned to preentrance euthermic values following arousal from hibernation (Tb = 34-36 degrees C). This study is the first to use behaving animals to demonstrate that changes in biophysical characteristics of central nervous system neurons occur at low Tb. These changes in membrane characteristics probably result in alterations in neuronal functioning and information processing during hibernation.

    View details for Web of Science ID A1989AR15800007

    View details for PubMedID 2790478

  • SUPRACHIASMATIC NUCLEUS - PHASE-DEPENDENT ACTIVATION DURING THE HIBERNATION CYCLE AMERICAN JOURNAL OF PHYSIOLOGY Kilduff, T. S., Radeke, C. M., RANDALL, T. L., Sharp, F. R., Heller, H. C. 1989; 257 (3): R605-R612

    Abstract

    The suprachiasmatic nucleus (SCN) of the golden-mantled ground squirrel undergoes a phase-dependent change in its accumulation of 2-[14C]deoxy-D-glucose (2-DG) relative to other brain structures during the hibernation cycle. The greatest relative 2-DG uptake (R2DGU) is observed in the SCN during entrance into and during deep hibernation. A circadian fluctuation in R2DGU of the SCN is not evident in the euthermic ground squirrel but can be increased during the subjective day by photic stimulation. An increase in R2DGU by the paraventricular nucleus (PVN) correlates with the increase in R2DGU by the SCN during entrance to hibernation but not with the increase in SCN R2DGU evoked by photic stimulation during euthermia. The periventricular nuclei of the hypothalamus (PEV) also have high levels of R2DGU during the latter phase of the entrance. These observations support the hypothesis that the SCN, PEV, and PVN may play important roles in hibernation and suggest progressive activation of synaptic input to and within the SCN during entrance into this state.

    View details for Web of Science ID A1989AQ39200065

    View details for PubMedID 2782463

  • AROUSAL STATE VS TEMPERATURE EFFECTS ON NEURONAL-ACTIVITY IN SUBCOERULEUS AREA AMERICAN JOURNAL OF PHYSIOLOGY Grahn, D. A., Radeke, C. M., Heller, H. C. 1989; 256 (4): R840-R849

    Abstract

    It is believed that thermoafferent neurons synapse in the subcoeruleus area (SC). To assess the effect of arousal state on thermoafferent information processing, we recorded SC unit activity in unanesthetized rats. No responses to changes in ambient temperature were observed within an arousal state, but 85% of the units dramatically altered their firing rates as the arousal state changed. We replicated previous experiments on anesthetized animals which were the basis for ascribing thermoafferent function to the SC. Additionally, we monitored electroencephalographic (EEG) activity. In lightly anesthetized rats, five distinct EEG states could be defined, and the temperature profile of the animal was a primary determinant of the EEG state. No thermoresponses were observed within an EEG state, but 78% of the units dramatically altered their firing rates in synchrony with EEG pattern changes. Transient responses to noxious stimuli were also reflected in both the EEG patterns and single-unit activity. We conclude that SC single-unit activity is not specific for processing of thermal information but is correlated with EEG activity, which in turn is determined by a variety of factors including thermal stimuli.

    View details for Web of Science ID A1989U216100047

    View details for PubMedID 2539757

  • REGULATED NOCTURNAL HYPOTHERMIA INDUCED IN PIGEONS BY FOOD-DEPRIVATION AMERICAN JOURNAL OF PHYSIOLOGY Graf, R., Krishna, S., Heller, H. C. 1989; 256 (3): R733-R738

    Abstract

    The daily body temperature (Tb) cycle of pigeons is altered by food deprivation in that Tb falls to lower and lower levels on consecutive nights after the onset of deprivation, whereas the Tb levels during corresponding days remain nearly unchanged. Manipulations of spinal cord temperature, a major feedback parameter in the avian thermoregulatory system, reveal that episodes of nocturnal hypothermia are regulated. The spinal cord threshold temperature for inducing increases in metabolic heat production falls to progressively lower levels each night and returns to normal euthermic levels during the day.

    View details for Web of Science ID A1989T693900067

    View details for PubMedID 2923260

  • NEURONAL-ACTIVITY DURING SLEEP AND COMPLETE BOUTS OF HIBERNATION AMERICAN JOURNAL OF PHYSIOLOGY Krilowicz, B. L., GLOTZBACH, S. F., Heller, H. C. 1988; 255 (6): R1008-R1019

    Abstract

    Changes in arousal state in a euthermic mammal exert powerful influences on major neural regulatory systems. Changes in behavioral state occur at body temperature (Tb) greater than 25 degrees C during hibernation. However, no information exists regarding alterations in arousal states during deep torpor. In this study we used a combination of electroencephalographic, electromyographic, and posterior thalamic neuronal activity in ground squirrels (Spermophilus lateralis) to evaluate arousal states during deep hibernation. No state homologous to rapid-eye-movement sleep was observed below Tb = 21 degrees C during hibernation. However, the animals did continue to cycle through states homologous to electrophysiologically defined wakefulness (AW) and non-rapid-eye-movement (NREM) sleep at all temperatures examined (Tb = 14-36 degrees C). These results extend previous observations that hibernation is not a homogeneous state. Instead, deep torpor consists primarily of a state similar to NREM sleep, interrupted periodically by short intervals of a form of AW. These periodic alterations in state should be accompanied by changes in the properties of many regulatory systems and must be accounted for in any theory of the neural control of hibernation.

    View details for Web of Science ID A1988R495800063

    View details for PubMedID 3202216

  • PROGRESSIVE ACTIVATION OF PARATRIGEMINAL NUCLEUS DURING ENTRANCE TO HIBERNATION AMERICAN JOURNAL OF PHYSIOLOGY Kilduff, T. S., Sharp, F. R., Heller, H. C. 1988; 255 (1): R178-R181

    Abstract

    The paratrigeminal nucleus (Pa5) undergoes a progressive increase in its uptake of 2-[14C]deoxyglucose (2DG) relative to other brain structures during entrance to hibernation in the ground squirrel. This highly significant increase results in the Pa5 becoming the most highly labeled brain region during hibernation, even though it exhibits one of the lowest levels of 2DG uptake in the brain during the nonhibernating state. The progressive activation of the Pa5 observed during entrance is reversed during arousal from hibernation. These observations and the neuroanatomical projections of the Pa5 implicate this nucleus as playing a role in the entrance and maintenance of the hibernating state.

    View details for Web of Science ID A1988P300200056

    View details for PubMedID 3394841

  • MODULATION OF ACTIVITY OF THE STRIATAL DOPAMINERGIC SYSTEM DURING THE HIBERNATION CYCLE JOURNAL OF NEUROSCIENCE Kilduff, T. S., Bowersox, S. S., Faull, K. F., ZELLERDEAMICIS, L., Radeke, C. M., CIARANELLO, R. D., Heller, H. C., BARCHAS, J. D., Dement, W. C. 1987; 7 (9): 2732-2736

    Abstract

    To evaluate how the activity of a well-established neurotransmitter pathway is modulated by a behavioral state, 3H-spiperone binding sites and dopamine (DA) and DA metabolite concentrations were measured in the striata of ground squirrels in 5 phases of the hibernation cycle. Whereas levels of striatal DA and its deaminated metabolite DOPAC did not change significantly, the concentrations of the O-methylated-deaminated metabolite, homovanillic acid (HVA), decreased in all phases of hibernation relative to euthermia. Striatal 3H-spiperone binding sites declined across the hibernation cycle in parallel with the reduction of HVA concentration; receptor binding affinity was unchanged by arousal state. In conjunction with previously reported findings, these results are consistent with the hypothesis that hibernation is associated with a down-regulation of the postsynaptic D2 receptors secondary to increased extracellular DA concentration and reduced DA degradation.

    View details for Web of Science ID A1987J969800013

    View details for PubMedID 3625271

  • ACTIVITY OF SUPRACHIASMATIC AND HYPOTHALAMIC NEURONS DURING SLEEP AND WAKEFULNESS IN THE RAT BRAIN RESEARCH GLOTZBACH, S. F., CORNETT, C. M., Heller, H. C. 1987; 419 (1-2): 279-286

    Abstract

    Single unit activity was recorded from the suprachiasmatic nucleus (SCN) and preoptic/anterior hypothalamus (POAH) of unrestrained Wistar rats during sleep and wakefulness. Regularly firing cells, which are abundant in in vitro SCN preparations and have been considered the basis of a central neuronal oscillator, were conspicuously absent in this preparation and in other in vivo studies. Most of the 55 cells recorded in the SCN and POAH were characterized by spontaneous firing rates below 12 Hz and with heterogeneous patterns of changes in frequency with arousal states. In vivo neurophysiological studies of the SCN in which the anesthetic agent urethane is used should consider the effect of different levels of arousal, as indicated by the cortical EEG, in evaluating the relationship between sensory stimulation and single unit activity.

    View details for Web of Science ID A1987J901100033

    View details for PubMedID 3676731

  • ABSENCE OF A CIRCADIAN-RHYTHM OF PROTEIN-SYNTHESIS IN THE RAT SUPRACHIASMATIC NUCLEUS NEUROSCIENCE LETTERS GLOTZBACH, S. F., RANDALL, T. L., Radeke, C. M., Heller, H. C. 1987; 76 (1): 113-118

    Abstract

    Male Wistar rats chronically catheterized in the jugular vein were entrained to a 12 L:12 D (lights on at 07.00 h) photoperiod. [1-14C]Leucine was administered in behaving rats at either 10.00 (day) or 22.00 (night) h. After 45 min of incubation animals were sacrificed, brains frozen, sectioned, and autoradiographed. The relative amount of label in the hypothalamic suprachiasmatic nucleus (SCN) was measured as the ratio of the optical density (OD) of the image of the SCN on the autoradiograph to the OD of white matter. The relative incorporation of labelled leucine into protein did not differ in the SCN of day vs night animals. This finding is in contrast to the prominent circadian rhythm of glucose utilization which has been seen in the rat SCN at identical points in the circadian cycle.

    View details for Web of Science ID A1987G959300021

    View details for PubMedID 3587742

  • INFLUENCE OF SPINAL AND HYPOTHALAMIC WARMING ON METABOLISM AND SLEEP IN PIGEONS AMERICAN JOURNAL OF PHYSIOLOGY Graf, R., Heller, H. C., Sakaguchi, S., Krishna, S. 1987; 252 (4): R661-R667

    Abstract

    Animals were prepared with electrooculogram (EOG), cortical electroencephalogram (EEG), and electromyogram (EMG) electrodes and with spinal and/or hypothalamic thermodes. Experiments were run at a cold and a neutral ambient temperature (Ta) during the dark portion of a 24-h light-dark cycle. Metabolic rate, temperatures, EEG, EMG, and EOG were measured continuously for 4-h periods with hypothalamic or spinal temperature unmanipulated or warmed to the level measured during the light. The cold Ta increased metabolic rate over the neutral Ta, but did not influence total sleep time (TST) or rapid-eye-movement sleep (REM) as percent TST. At the cold Ta, spinal warming resulted in reduction in REM as a percent TST. Spinal warming frequently caused a fall in body temperature (Ta). A plot of REM as a percent TST vs. the fall in Tb, including data for all animals and all conditions, revealed a clear correlation between fall in Tb and reduction in REM. Hypothalamic warming had no influence on metabolic rate, Tb, or distributions of arousal states. Cold thermal stimuli caused by a fall in Tb can inhibit REM in birds as it can in mammals independently of thermoregulatory drive.

    View details for Web of Science ID A1987G841700029

    View details for PubMedID 3565598

  • CHANGES IN THE THERMAL-CHARACTERISTICS OF HYPOTHALAMIC NEURONS DURING SLEEP AND WAKEFULNESS BRAIN RESEARCH GLOTZBACH, S. F., Heller, H. C. 1984; 309 (1): 17-26

    Abstract

    The characteristics of the mammalian thermoregulatory system are dependent upon arousal state. During NREM sleep thermoregulatory mechanisms are intact but body temperature is regulated at a lower level than during wakefulness. In REM sleep thermoregulatory effector mechanisms are inhibited and thermal homeostasis is severely disrupted. Thermosensitivity of neurons in the preoptic/anterior hypothalamus (POAH) was determined for behaving kangaroo rats (Dipodomys deserti) during electrophysiologically defined wakefulness, NREM sleep and REM sleep to elucidate possible neural mechanisms for previous findings of state-dependent changes in thermoregulation. Thirty cells were tested during at least two arousal states. During wakefulness, 70% of the recorded cells were sensitive to changes in local temperature, with the number of warm-sensitive (W) cells outnumbering cold-sensitive (C) cells by 1.6:1. In NREM sleep, 43% of the cells were thermally sensitive, with the ratio of W:C remaining the same as in wakefulness. In REM sleep only two cells were thermosensitive (both W). The decrease in neuronal thermosensitivity of POAH cells during REM sleep parallels findings of inhibition of thermoregulatory effector responses during REM, although further work is necessary to determine the source and nature of the inhibition.

    View details for Web of Science ID A1984TH18200002

    View details for PubMedID 6488008

  • The physiology of hibernation. Science Heller, H. C. 1983; 220 (4597): 599-600

    View details for PubMedID 17749535

  • RELATIVE 2-DEOXYGLUCOSE UPTAKE OF THE PARATRIGEMINAL NUCLEUS INCREASES DURING HIBERNATION BRAIN RESEARCH Kilduff, T. S., Sharp, F. R., Heller, H. C. 1983; 262 (1): 117-123

    Abstract

    The paratrigeminal nucleus, a little-studied cell group of the medulla, is the only structure of the brain to significantly increase its relative [14C]2-deoxyglucose accumulation during hibernation in the ground squirrel. The zone of increased activity on the auto-radiographs is continuous between this structure and the marginal zone of the spinal trigeminal nucleus. Because of the known thermoafferent function of the latter structure, a similar function is suggested for the paratrigeminal nucleus.

    View details for Web of Science ID A1983QE67700012

    View details for PubMedID 6831223

  • METABOLIC-ACTIVATION OF THE BRACHIUM CONJUNCTIVUM DURING INDUCED HYPOTHERMIA BRAIN RESEARCH Kilduff, T. S., George, C. P., Sharp, F. R., Heller, H. C. 1983; 269 (1): 168-171

    Abstract

    During hypothermia induced in ground squirrels by the halothane-heliox method, 2-deoxyglucose uptake of a white matter structure, the brachium conjunctivum, increased relative to the surrounding gray matter structures. The possibility of 2-deoxyglucose uptake by glial as well as neuronal elements in the brachium conjunctivum and the implications of this observation for the use of optical density ratios is discussed.

    View details for Web of Science ID A1983QV70200020

    View details for PubMedID 6871697

  • CIRCADIAN AND AROUSAL STATE INFLUENCES ON THERMOREGULATION IN THE PIGEON AMERICAN JOURNAL OF PHYSIOLOGY Heller, H. C., Graf, R., Rautenberg, W. 1983; 245 (3): R321-R328

    Abstract

    We report here the characteristics of spinal thermosensitivity in pigeons as a function of arousal state and time of day. At any time in the light-dark (LD) cycle, the thresholds for shivering and panting were lower during non-rapid-eye-movement (NREM) sleep than during wakefulness. These thresholds in both awake and sleeping animals were lower during D than during L. The gain of the metabolic response to spinal cooling was nearly the same in wakefulness and NREM sleep. Shivering and panting responses to spinal thermal stimulations were impaired during REM sleep compared with wakefulness and NREM sleep. The results support the idea that central nervous system mechanisms controlling arousal states and circadian rhythmicity have separate and additive influences on temperature regulation in the pigeon.

    View details for Web of Science ID A1983RH38800076

    View details for PubMedID 6614203

  • THE RELATIONSHIP OF LOCAL CEREBRAL GLUCOSE-UTILIZATION TO OPTICAL-DENSITY RATIOS BRAIN RESEARCH Sharp, F. R., Kilduff, T. S., BZORGCHAMI, S., Heller, H. C., Ryan, A. F. 1983; 263 (1): 97-103

    Abstract

    The validity of optical density ratios used in [14C]2-deoxyglucose neuroanatomical mapping experiments is evaluated by comparing local cerebral glucose utilization (LCGU) and optical density (OD) ratios in the same animals. OD ratios are calculated by dividing the optical density of different gray matter structures by the optical density of a single white matter structure in each animal. OD ratios are linearly related to LCGU within a given animal including stimulated, highly activated regions. Anesthesia profoundly affects the relationship between LCGU and OD ratios, however, showing that OD ratios do not provide an accurate index of LCGU between animals in different physiological states. Anesthesia had only a slight effect on OD ratios, however, indicating that OD ratios may be helpful in assessing whether structures are functionally activated between animals in different physiological states.

    View details for Web of Science ID A1983QH02000010

    View details for PubMedID 6839171

  • AUTORADIOGRAPHIC PATTERNS OF HIPPOCAMPAL METABOLISM DURING INDUCED HYPOTHERMIA NEUROSCIENCE LETTERS George, C. P., Kilduff, T. S., Sharp, F. R., Heller, H. C. 1982; 34 (3): 233-239

    Abstract

    [14C]2-Deoxyglucose (2-DG) uptake in the hippocampal formation was studied in the ground squirrel subjected to induced hypothermia. Whereas the stratum lacunosum-molecular has the highest 2-DG uptake in the dorsal hippocampus during euthermia, 2-DG uptake in the stratum lacunosum-molecular and stratum radiatum are similar during hypothermia. This may indicate activation of a cholinergic input to the hippocampus during hypothermia.

    View details for Web of Science ID A1982QA76300005

    View details for PubMedID 7162705

  • [C-14]-LABELED 2-DEOXYGLUCOSE UPTAKE IN GROUND-SQUIRREL BRAIN DURING HIBERNATION JOURNAL OF NEUROSCIENCE Kilduff, T. S., Sharp, F. R., Heller, H. C. 1982; 2 (2): 143-157

    Abstract

    Autoradiographic patterns of [14C]2-deoxyglucose uptake are described throughout the brains of hibernating and euthermic ground squirrels. Autoradiographs of the brains of hibernating animals are generally homogeneous in comparison to euthermic animals; hence, the relative 2-deoxyglucose uptake (R2DGU) of gray to white matter for the majority of the 85 neural structures examined decreases during hibernation. Two categories of structures are identified as potentially important in hibernation: (1) structures that have the highest R2DGU during hibernation (cochlear nucleus, paratrigeminal nucleus, and superior colliculus) and (2) structures that undergo the least reduction in R2DGU in the transition from euthermia to hibernation (suprachiasmatic nucleus and lateral septal nucleus). The percentage of reduction in R2DGU that a structure undergoes in the transition from euthermia to hibernation is proportional to the R2DGU of that structure during euthermia. The suprachiasmatic, paratrigeminal, and cochlear nuclei undergo less of a reduction than would be predicted from this relationship and may be particularly important during hibernation. Sensory nuclei that receive primary afferent projections are among the structures with the highest R2DGU during hibernation. These metabolically active structures may be responsible for the sensitivity of the hibernator to environmental stimuli.

    View details for Web of Science ID A1982NQ80600002

    View details for PubMedID 6278102

  • HIBERNATION AT MODERATE TEMPERATURES - A CONTINUATION OF SLOW-WAVE SLEEP EXPERIENTIA Walker, J. M., Haskell, E. H., Berger, R. J., Heller, H. C. 1981; 37 (7): 726-728

    Abstract

    Golden-mantled ground squirrels (Citellus lateralis) displayed virtually continuous electrophysiological states of sleep when hibernating at moderate ambient temperatures (22 degrees C). Rapid-eye-movement sleep progressively diminished with the fall in body temperature so that at a body temperature of 23 degrees C it was completely absent. At this temperature hibernation was characterized by slow wave sleep isomorphic with slow wave sleep episodes at non-hibernating (euthermic) body temperatures.

    View details for Web of Science ID A1981LX54700032

    View details for PubMedID 7274382

  • THE EFFECTS OF HIGH AND LOW AMBIENT-TEMPERATURES ON HUMAN SLEEP STAGES ELECTROENCEPHALOGRAPHY AND CLINICAL NEUROPHYSIOLOGY Haskell, E. H., PALCA, J. W., Walker, J. M., Berger, R. J., Heller, H. C. 1981; 51 (5): 494-501

    Abstract

    Six male subjects slept nude except for shorts on a bed made from nylon webbing at 5 different ambient temperatures (TaS): 21, 24, 29 (thermoneutrality), 34 and 37 degrees C. Standard electrophysiological recordings were obtained and analyzed for sleep stages. Temperature displayed a significant quadratic trends for nearly every sleep variable, such that TaS above or below thermoneutrality had similar effects on sleep patterns. Multiple comparisons showed that 21 degrees C was the most disruptive condition, and that cold TaS were generally more disruptive to sleep than warm TaS. There were marked individual differences in sensitivity of sleep to cold. Decreases in REM sleep in humans produced by heat or cold probably result from a general disruption of sleep processes rather than being specifically related to the status of the thermoregulatory system during REM sleep.

    View details for Web of Science ID A1981LT02700006

    View details for PubMedID 6165549

  • METABOLISM AND THERMOREGULATION DURING STAGES OF SLEEP IN HUMANS EXPOSED TO HEAT AND COLD JOURNAL OF APPLIED PHYSIOLOGY Haskell, E. H., PALCA, J. W., Walker, J. M., Berger, R. J., Heller, H. C. 1981; 51 (4): 948-954

    Abstract

    Electrophysiological stages of sleep, oxygen consumption (VO2), and skin (Tsk) and rectal (Tre) temperatures were recorded from six virtually naked male subjects exposed to ambient temperatures (Ta) of 21, 24, 29, 34, and 37 degrees C. VO2 increased during sleep as a whole as Ta departed from thermoneutrality (29 degrees C) and was significantly greater during rapid-eye-movement (REM) sleep than during adjacent nonrapid-eye-movement (NREM) periods at low and high Ta but not at 29 degrees C. Tsk showed small but significant increases during REM sleep at 29, 34, and 37 degrees C, but Tre did not change during REM sleep at any Ta. Shivering was present during wakefulness at 21 and 24 degrees C but occurred only occasionally during stages 1 and 2 sleep at 21 degrees C. The increases in VO2 and the absence of marked changes in vasomotor tone during REM sleep in the cold were unexpected and possibly indicate that REM sleep is not as thermally disruptive in humans as in other mammals.

    View details for Web of Science ID A1981MJ83400027

    View details for PubMedID 7298439

  • HIBERNATION - NEURAL ASPECTS ANNUAL REVIEW OF PHYSIOLOGY Heller, H. C. 1979; 41: 305-321

    View details for Web of Science ID A1979GN03000024

    View details for PubMedID 373593

  • INFLUENCE OF HYPOTHALAMIC AND AMBIENT-TEMPERATURES ON SLEEP IN KANGAROO RATS AMERICAN JOURNAL OF PHYSIOLOGY Sakaguchi, S., GLOTZBACH, S. F., Heller, H. C. 1979; 237 (1): R80-R88

    Abstract

    Unanesthetized, unrestrained kangaroo rats (Dipodomys) were studied to examine the changes in the frequency and duration of sleep states caused by long-term manipulations of hypothalamic temperature (Thy) at a thermoneutral (30 degrees C) and a low (20 degrees C) ambient temperature (Ta). A cold stimulus present in either the hypothalamus or the skin decreased both the total sleep time (TST) and the ratio of paradoxical sleep (PS) to TST. At a low Ta, TST, but not the PS-to-TST ratio, was increased by raising Thy, indicating that a cold peripheral stimulus could differentially inhibit PS. At a thermoneutral Ta, cooling Thy decreased both TST and the PS/TST. Changes in the amount of PS were due largely to changes in the frequency, but not the duration, of individual episodes of PS, suggesting that the transition to PS is partially dependent on the thermoregulatory conditions existing during slow-wave sleep (SWS). These results are consistent with the recent findings that the thermoregulatory system is functional during SWS but is inhibited or inactivated during PS.

    View details for Web of Science ID A1979HE11700062

    View details for PubMedID 223451

  • SLEEP AND ESTIVATION (SHALLOW TORPOR) - CONTINUOUS PROCESSES OF ENERGY-CONSERVATION SCIENCE Walker, J. M., Garber, A., Berger, R. J., Heller, H. C. 1979; 204 (4397): 1098-1100

    Abstract

    Estivation (shallow torpor) in the round-tailed ground squirrel (Citellus tereticaudus) is entered through electrophysiologically defined states of sleep. Rapid-eye-movement sleep diminishes as body temperature falls in such a way that, at a body temperature of 26 degrees to 28 degrees C, torpor is characterized by almost continuous slow-wave sleep isomorphic with that observed at euthermic body temperatures.

    View details for Web of Science ID A1979GX22300028

    View details for PubMedID 221974

  • THERMOSTAT OF VERTEBRATE ANIMALS SCIENTIFIC AMERICAN Heller, H. C., Crawshaw, L. I., Hammel, H. T. 1978; 239 (2): 102-?

    View details for Web of Science ID A1978FH00500006

    View details for PubMedID 684402

  • Hypothalamic thermosensitivity in mammals. Experientia. Supplementum Heller, H. C. 1978; 32: 267-276

    Abstract

    Hypothalamic thermosensitivities of 21 species of mammals ranging in body size from 15 g to 34 Kg are surveyed. It is concluded that hypothalamic thermosensitivity as measured by the proportionality constant relating rate of metabolic heat production to hypothalamic temperature at a thermoneutral ambient temperature is inversely related to body size according to the relationship alphaMHP = -1.46 Wt-.37.

    View details for PubMedID 348488

  • TEMPERATURE REGULATION DURING WAKEFULNESS, SLEEP, AND HIBERNATION IN MARMOTS AMERICAN JOURNAL OF PHYSIOLOGY Florant, G. L., Turner, B. M., Heller, H. C. 1978; 235 (1): R82-R88

    View details for Web of Science ID A1978FH99200053

    View details for PubMedID 677343

  • CNS REGULATION OF BODY-TEMPERATURE IN EUTHERMIC AND HIBERNATING MARMOTS (MARMOTA-FLAVIVENTRIS) AMERICAN JOURNAL OF PHYSIOLOGY Florant, G. L., Heller, H. C. 1977; 232 (5): R203-R208

    Abstract

    Hypothalamic thermosensitivity of marmots was characterized during euthermia and hibernation. Hypothalamic temperature (Thy) was manipulated with chronically implanted, water-perfused thermodes while the animal's rate of oxygen consumption was continuously measured. The threshold Thy for eliciting an increase in metabolic heat production (MHP) and the proportionality constant (alphaMHP) relating rate of MHP to Thy were determined. In four euthermic marmots alphaMHP averaged -1.1 W-kg-1-degrees C-1. During the entrance into hibernation, as body temperature (Tb) declined from 36 to 8 degrees C, the threshold Thy for the MHP response progressively declined and was demonstrable at all times. The Thy of marmots in deep hibernation at an ambient temperature (Ta) of 5 degrees C plateaued near 7.5 degrees C, but threshold Thy for MHP showed a continuous slow decline of 0.2-0.4 degrees C a day, until one day prior to arousal. Proportional regulation of Tb was demonstrable at all times during deep hibernation. The average proportionality constant for the MHP response to hypothalamic cooling during deep hibernation in three marmots was -0.08 W-kg-1-degrees C-1. These results demonstrate that the hypothalamic regulator of Tb is active throughout hibernation and that there are progressive changes in its thermosensitivity.

    View details for Web of Science ID A1977DG48700047

    View details for PubMedID 871176

  • SLEEP AND HIBERNATION IN GROUND SQUIRRELS (CITELLUS SPP) - ELECTROPHYSIOLOGICAL OBSERVATIONS AMERICAN JOURNAL OF PHYSIOLOGY Walker, J. M., GLOTZBACH, S. F., Berger, R. J., Heller, H. C. 1977; 233 (5): R213-R221

    Abstract

    Electroencephalogram (EEG), electrooculogram, electromyogram, and electrocardiogram were recorded from ground squirrels (Citellus beldingi and C. lateralis) during the summer and also during the hibernation season. Summer recordings revealed that the animals spent an average of 66% of the 24-h period asleep (49% of the 12-h light period and 84% of the 12-h dark period); 19% of the total sleep time (TST) consisted of rapid-eye-movement (REM) sleep, and 81% of TST consisted of slow-wave sleep (SWS). Recordings obtained during the hibernation season showed that hibernation was entered through sleep, but the distribution of sleep states was different than in euthermic sleep. During the early entrance when brain temperature (Tbr) was between 35 and 25 degrees C, the animals were asleep 88% of the time, but only 10% of the TST was spent in REM sleep. The EEG amplitude declined with decreased Tbr so that classical sleep stages could not be identified below a Tbr of 25 degrees C. The frequency of the EEG increased as Tbr decreased; but activity in the 0-4 cycles/s band occupied the majority of the record even at a Tbr of 10 degrees C. Below a Tbr of 10 degrees C the EEG was isoelectric except for intermittent bursts of spindles. It was concluded from these and other results that the entrance into hibernation represents an extension of the thermoregulatory adjustments that occur during SWS.

    View details for Web of Science ID A1977EC66300046

    View details for PubMedID 200149

  • THERMOREGULATION DURING ENTRANCE INTO HIBERNATION PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY Heller, H. C., COLLIVER, G. W., Beard, J. 1977; 369 (1): 55-59

    Abstract

    The hypothalamic temperature (Thy) and the rate of oxygen consumption of golden-mantled ground squirrels were continuously measured as they entered hibernation. Thy was manipulated with chronically implanted, water-perfused thermodes. A threshold Thy for eliciting an increase in metabolic heat production was demonstrable at all times during entry. During smooth entries this threshold Thy showed a progressive decline so that it was below actual Thy at all times. These results are interpreted to mean that the normal mammalian central nervous regulator of body temperature is functional throughout the entrance into hibernation, and it can be reset to any level over the 35 degrees C range body temperatures experienced by the hibernator.

    View details for Web of Science ID A1977DG17400009

    View details for PubMedID 560008

  • THERMOREGULATORY RESPONSES TO ALTERING HYPOTHALAMIC TEMPERATURE IN HARBOR SEAL AMERICAN JOURNAL OF PHYSIOLOGY Hammel, H. T., Elsner, R. W., Heller, H. C., MAGGERT, J. A., Bainton, C. R. 1977; 232 (1): R18-R26

    Abstract

    The rostral brainstem of the harbor seal Phoca vitulina was cooled and heated 33-41 degrees C while oxygen consumption and rectal, hypothalamic, flipper and dorsal skin temperatures were measured. These experiments were made on restrained seals at ambient temperatures -15 to 30 degrees C. Cooling the preoptic and hypothalamic (POH) tissue increased oxygen consumption in a way that could be approximated by a linear regression line with slope and threshold temperature at which the metabolic rate was minimal. The slope of the regression line was a function of ambient temperature and rectal temperature. At each ambient temperature, the slope was significantly higher for lower rectal temperature. At all rectal temperatures, the slope was significantly higher for lower ambient temperature. The threshold hypothalamic temperatures did not very consistently or significantly with either rectal temperature or ambient temperature. These results on the harbor seal are explicable by suggesting that the thermal-sensitive and reference neurons in the POH which regulate body temperature are inhibited equally by extrahypothalamic cold transducing neural elements.

    View details for Web of Science ID A1977CU33900049

    View details for PubMedID 835725

  • Thermoregulation during sleep and hibernation. International review of physiology Heller, H. C., GLOTZBACH, S. F. 1977; 15: 147-188

    View details for PubMedID 328435

  • HYPOTHALAMIC THERMOSENSITIVITY AND REGULATION OF HEAT STORAGE BEHAVIOR IN A DIURNAL DESERT GROUND-SQUIRREL (AMMOSPERMOPHILUS-NELSONI) ISRAEL JOURNAL OF MEDICAL SCIENCES Henderson, J. A., Heller, H. C. 1976; 12 (9): 1029-1032

    View details for Web of Science ID A1976CK69900016

    View details for PubMedID 1002427

  • CENTRAL NERVOUS REGULATION OF BODY-TEMPERATURE DURING SLEEP SCIENCE GLOTZBACH, S. F., Heller, H. C. 1976; 194 (4264): 537-539

    Abstract

    The relationship between hypothalamic temperature and metabolic heat production was measured during wakefulness, slow-wave sleep, and paradoxical sleep in unrestrained kangaroo rats (Dipodomys). Hypothalamic temperature was manipulated with chronically implanted, water-perfused thermodes while cortical electroencephalogram, electromyogram, metabolic rate, and body movement were continuously recorded. During slow-wave sleep, in comparison to wakefulness, there is a lowered threshold hypothalamic temperature for the metabolic heat production response and a lowered proportionality constant relating rate of metabolic heat production to hypothalamic temperature. During paradoxical sleep no increase in metabolic heat production could be elicited by lowering hypothalamic temperature, which indicates that the thermoregulatory system is inoperative. These results provide a basis for explaining the changes in various body temperatures, metabolic rate, and other thermoregulatory responses during sleep in a variety of mammals.

    View details for Web of Science ID A1976CH19700023

    View details for PubMedID 973138

  • ELEVATED BLOOD-GLUCOSE LEVELS AND SATIETY IN RAT PHYSIOLOGY & BEHAVIOR Wilson, W. H., Heller, H. C. 1975; 15 (2): 137-143

    Abstract

    Thirteen rats were placed on a feeding schedule of two 3 hr periods of food availability daily. blood glucose levels of the experimental animals were altered by intraperitoneal injection of 8 ml of 2, 5, 8, 12, 16, 20 and 25 percent glucose solutions and by intragastric loading of 8 ml of 25, 50 and 65 percent glucose solutions in 10 different feeding experiments. In 4 additional experiments, experimental animals received intraperitoneal injections of 8 ml of 12, 16, 20 and 25 percent solutions of mannitol, a non-metabolizable sugar-alcohol. Controls always received identical quantities of mammalian Ringer's solution administered via the same route as in the experimentals. Another set of 20 rats was used to determine glucose tolerance curves for each concentration of glucose and mannitol administered. No food intake depression occurred following intraperitoneal injections of 2, 5, 8 and 12 percent glucose, 12 percent mannitol and following intragastric loading of 25, 50 and 65 percent glucose. However, intraperitoneal injections of 16, 20 and 25 percent glucose and mannitol caused depression of food intake. No depression of food intake occurred following intragastric loading of 50 and 65 percent glucose solutions which raised blood glucose levels a minimum of 43 mg percent and 55 mg percent above basal, respectively, for the duration of the 3 hr feeding period. These minimum blood glucose levels greatly exceed normal values following a meal. It was concluded that blood glucose level per se is not an important feedback parameter in the long-term control of food intake, and the depression in food intake following intraperitoneal injections of 16, 20 and 25 percent glucose and mannitol solutions was due to an abnormal physiological condition.

    View details for Web of Science ID A1975AU85900001

    View details for PubMedID 1187848

  • CNS REGULATION OF METABOLIC-RATE IN KANGAROO RAT DIPODOMYS-INGENS AMERICAN JOURNAL OF PHYSIOLOGY GLOTZBACH, S. F., Heller, H. C. 1975; 228 (6): 1880-1886

    Abstract

    Water-perfused thermodes were chronically implanted around the preoptic nuclei and hypothalamus (POH) of kangaroo rats (Dipodomys ingens). Responses in rate of metabolic heat production to manipulations of POH temperature (Thy) were measured in unanesthetized, unrestrained animals at ambient temperatures of 10, 20, 25, and 30 degreeC. The threshold Thy and the proportionally constant (alpha) for this response consistently decreased as ambient temperature increased, but alpha was not significantly different between any two Ta's. Average values of alpha for the three animals studied ranged between -.0024 W.g minus 1.degree C minus 1 and -.0034 W.g minus1.degree C minus 1. No influence of extrahypothalamic core temperature on the characteristics of the central nervous system regulatory mechanism was observed. Ahypothesis accounting for high POH and low peripheral thermosensitivities in small mammals is presented. An additional finding was that during sleep there is a profound depression or elimination of POH thermosensitivity in this species.

    View details for Web of Science ID A1975AJ22300040

    View details for PubMedID 168786

  • CNS REGULATION OF BODY-TEMPERATURE DURING HIBERNATION AMERICAN JOURNAL OF PHYSIOLOGY Heller, H. C., COLLIVER, G. W. 1974; 227 (3): 583-589

    View details for Web of Science ID A1974U350300012

    View details for PubMedID 4412700

  • CNS REGULATION OF BODY-TEMPERATURE IN EUTHERMIC HIBERNATORS AMERICAN JOURNAL OF PHYSIOLOGY Heller, H. C., COLLIVER, G. W., Anand, P. 1974; 227 (3): 576-582

    View details for Web of Science ID A1974U350300011

    View details for PubMedID 4412701

  • PROBING ROSTRAL BRAIN-STEM OF ANESTHETIZED, UNANESTHETIZED, AND EXERCISING DOGS AND OF HIBERNATING AND EUTHERMIC GROUND SQUIRRELS FEDERATION PROCEEDINGS Hammel, H. T., Heller, H. C., Sharp, F. R. 1973; 32 (5): 1588-1597

    View details for Web of Science ID A1973P707200014

    View details for PubMedID 4705205

  • CNS control of body temperature during hibernation. Comparative biochemistry and physiology. A, Comparative physiology Heller, H. C., Hammel, H. T. 1972; 41 (2): 349-359

    View details for PubMedID 4404314

  • CNS regulation of body temperature in the hibernator Citellus lateralis. International journal of biometeorology Heller, H. C., Hammel, H. T. 1971; 15 (2): 231-235

    View details for PubMedID 5146814

Conference Proceedings


  • No Rescue of the Impaired Homeostasic Sleep Rebound in DBA/2J Mice with Attentuation of the Stress Response Mongrain, V., Curie, T., Gip, P., Heller, H. C., Franken, P. KARGER. 2009: 247-247
  • Neural plasticity in hibernation Von Der Ohe, C. G., Darian-Smith, C., Heller, H. C. OXFORD UNIV PRESS INC. 2005: 1090-1090
  • Stress response to sleep deprivation varies with genotype: Implications for sleep regulation Franken, P., Gip, P. T., Hagiwara, G., Heller, H. AMER ACAD SLEEP MEDICINE. 2004: 168-168
  • Glucocorticoids mediate the effects of sleep deprivation on brain glycogen and glucose levels Ruby, N. F., Gip, P., Hagiwara, G., Sapolsky, R., Cao, V., Franken, P., Heller, H. C. AMER ACAD SLEEP MEDICINE. 2003: A14-A15
  • Clock-related gene expression in non-SCN brain regions following sleep deprivation in wildtype and cryptochrome knockout mice: Relevance to sleep homeostasis O'Hara, B. F., Terao, A., Cao, V., Gip, P., Wisor, J. P., Heller, H. C., Franken, P., Kilduff, T. S. AMER ACAD SLEEP MEDICINE. 2003: A419-A419
  • Gene expression profiling of the response to sleep deprivation in mouse and rat cortex using affymetrix DNA chips Terao, A., Peyron, C., Apte-Deshpande, A., Brown, B., Wurts, S. W., Edgar, D. M., Davis, R. W., Heller, H. C., Kilduff, T. S. AMER ACAD SLEEP MEDICINE. 2001: A138-A138
  • Circadian rhythms in the suprachiasmatic nucleus are temperature-compensated and phase-shifted by heat pulses in vitro Ruby, N. F., Burns, D. E., Heller, H. C. SOC NEUROSCIENCE. 1999: 8630-8636

    Abstract

    Temperature compensation and the effects of heat pulses on rhythm phase were assessed in the suprachiasmatic nucleus (SCN). Circadian neuronal rhythms were recorded from the rat SCN at 37 and 31 degrees C in vitro. Rhythm period was 23.9 +/- 0.1 and 23.7 +/- 0.1 hr at 37 and 31 degrees C, respectively; the Q(10) for tau was 0.99. Heat pulses were administered at various circadian times (CTs) by increasing SCN temperature from 34 to 37 degrees C for 2 hr. Phase delays and advances were observed during early and late subjective night, respectively, and no phase shifts were obtained during midsubjective day. Maximum phase delays of 2.2 +/- 0.3 hr were obtained at CT 14, and maximum phase advances of 3.5 +/- 0.2 hr were obtained at CT 20. Phase delays were not blocked by a combination of NMDA [AP-5 (100 microM)] and non-NMDA [CNQX (10 microM)] receptor antagonists or by tetrodotoxin (TTX) at concentrations of 1 or 3 microM. The phase response curve for heat pulses is similar to ones obtained with light pulses for behavioral rhythms. These data demonstrate that circadian pacemaker period in the rat SCN is temperature-compensated over a physiological range of temperatures. Phase delays were not caused by activation of ionotropic glutamate receptors, release of other neurotransmitters, or temperature-dependent increases in metabolism associated with action potentials. Heat pulses may have phase-shifted rhythms by directly altering transcriptional or translational events in SCN pacemaker cells.

    View details for Web of Science ID 000082805400050

    View details for PubMedID 10493763

  • FUNCTIONAL MAPPING OF BRAIN ACTIVITY DURING AROUSAL STATES - MAMMALIAN HIBERNATION AS A MODEL SYSTEM Kilduff, T. S., Dement, W. C., Heller, H. C. S P B ACADEMIC PUBL. 1990: 229-239
  • A REEVALUATION OF PURPORTED THERMOAFFERENT FUNCTION OF CELLS IN THE SUBCOERULEUS AREA AND THE NUCLEUS RAPHE MAGNUS Grahn, D. A., Heller, H. C. ELSEVIER SCIENCE PUBL B V. 1989: 95-100
  • CNS REGULATION OF BODY-TEMPERATURE DURING SLEEP AND HIBERNATION Heller, H. C., Walker, J., Florant, G., GLOTZBACH, S., Berger PERGAMON-ELSEVIER SCIENCE LTD. 1978: 91-91
  • TEMPERATURE REGULATION IN MARMOTS (MARMOTA-FLAVIVENTRIS) DURING ENTRANCE INTO HIBERNATION Florant, G. L., Turner, B. M., Heller, H. C. PERGAMON-ELSEVIER SCIENCE LTD. 1978: 92-92

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