Gorman Circadian Research Lab

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- Gorman, M.R., Elliott, J.A. Enhanced phase and period control of mammalian circadian rhythms with manipulations of rhythm waveform. No Preview available

- Glickman, G.L., Harrison, E.M., Elliott, J.A., Gorman, M.R. Increased photic sensitivity for phase resetting but not melatonin suppression in Siberian hamsters under short photoperiods. Light regulates a variety of behavioral and physiological processes, including activity rhythms and hormone secretory patterns. Seasonal changes in the proportion of light in a day (photoperiod) further modulate those functions. Recently, short (SP) versus long days (LP) were found to markedly increase light sensitivity for phase shifting in Syrian hamsters. To our knowledge, photoperiod effects on light sensitivity have not been studied in other rodents, nor is it known if they generalize to other circadian responses. We tested whether photic phase shifting and melatonin suppression vary in Siberian hamsters maintained under LP or SP. Select irradiances of light were administered, and shifts in activity were determined. Photic sensitivity for melatonin suppression was examined in a separate group of animals via pulses of light across a 4 log-unit photon density range, with post-pulse plasma melatonin levels determined via RIA. Phase shifting and melatonin suppression were greater at higher irradiances for both LP and SP. The lower irradiance condition was below threshold for phase shifts in LP but not SP. Melatonin suppression did not vary by photoperiod, and the half saturation constant for fitted sigmoid curves was similar under LP and SP. Thus, the photoperiodic modulation of light sensitivity for phase shifting is conserved across two hamster genera. The dissociation of photoperiod effects on photic phase shifting and melatonin suppression suggests that the modulation of sensitivity occurs downstream of the common retinal input pathway. Understanding the mechanistic basis for this plasticity may yield therapeutic targets for optimizing light therapy practices.

- Raiewski, E.E., Elliott, J.A., Evans, J.A., Glickman, G.R., Gorman, M. R. Bimodal melatonin pattern in Siberian but not Syrian hamsters under exotic 8:4:8:4 photoperiod. Chronobiology International.No Preview available
- Harrison, E.M., Gorman, M.R. Changing the waveform of circadian rhythms: considerations for shiftwork. Frontiers in Sleep and Chronobiology, frontiers in Neurology. 2012.00072 Circadian disruption in shift-work is common and has deleterious effects on health and performance. Current efforts to mitigate these harms reasonably focus on the phase of the circadian pacemaker, which unfortunately in humans, shifts slowly and often incompletely. Temporal reorganization of the rhythmic waveform (i.e. the shape of its 24h oscillation), rather than its phase, however, may better match performance demands of shift-workers and can be quickly and feasibly implemented in animals. In fact, a bifurcated pacemaker waveform may permit stable entrainment of a bimodal sleep/wake rhythm promoting alertness in both night and daylight hours. Although bifurcation has yet to be formally assessed in humans, evidence of conserved properties of circadian organization and plasticity predict its occurence: humans respond to conventional manipulations of waveform (e.g. photoperiodism); behaviorally, the sleep/wake rhythm is adaptable; and finally, the human circadian system likely derives from the same multiple cellular oscillators that permit waveform flexibility in the rodent pacemaker. In short, investigation into untried manipulations of waveform in humans to facilitate adjustment to challenging schedules is justified.
- Evans, J.A., Carter S.N., Freeman, D.A., Gorman, M.R. Dim nighttime illumination alters photoperiodic responses of hamsters through the intergeniculate leaflet and other photic pathways, Neuroscience. 202:300-308. In mammals, light entrains the central pacemaker within the suprachiasmatic nucleus (SCN) through both a direct neuronal projection from the retina and an indirect projection from the intergeniculate leaflet (IGL) of the thalamus. Although light comparable in intensity to moonlight is minimally effective at resetting the phase of the circadian clock, dimly lit and completely dark nights are nevertheless perceived differentially by the circadian system, even when nighttime illumination is below putative thresholds for phase resetting. Under a variety of experimental paradigms, dim nighttime illumination exerts effects that may be characterized as enhancing the plasticity of circadian entrainment. For example, relative to completely dark nights, dimly lit nights accelerate development of photoperiodic responses of Siberian hamsters transferred from summer to winter day lengths. Here we assess the neural pathways underlying this response by testing whether IGL lesions eliminate the effects of dim nighttime illumination under short day lengths. Consistent with previous work, dimly lit nights facilitated the expansion of activity duration under short day lengths. Ablation of the IGL, moreover, did not influence photoperiodic responses in animals held under completely dark nights. However, among animals that were provided dimly lit nights, IGL lesions prevented the short-day typical expansion of activity duration as well as the seasonally appropriate gonadal regression and reduction in body weight. Thus, the present data indicate that the IGL plays a central role in mediating the facilitative effects of dim nighttime illumination under short day lengths, but in the absence of the IGL, dim light at night influences photoperiodic responses through residual photic pathways.
- Individual differences in circadian waveform of Siberian hamsters under multiple lighting conditions. Because the circadian clock in the mammalian brain derives from a network of interacting cellular oscillators, characterizing the nature and bases of circadian coupling is fundamental to understanding how the pacemaker operates. Various phenomena involving plasticity in circadian waveform have been theorized to reflect changes in oscillator coupling; however, it remains unclear whether these different behavioral paradigms reference a unitary underlying process. To test whether disparate coupling assays index a common mechanism, we examined whether there is covariation among behavioral responses to various lighting conditions that produce changes in circadian waveform. Siberian hamsters, Phodopus sungorus, were transferred from long to short photoperiods to distinguish short photoperiod responders (SP-R) from nonresponders (SP-NR). Short photoperiod chronotyped hamsters were subsequently transferred, along with unselected controls, to 24-h light:dark:light: dark cycles (LDLD) with dim nighttime illumination, a procedure that induces bifurcated entrainment. Under LDLD, SP-R hamsters were more likely to bifurcate their rhythms than were SP-NR hamsters or unselected controls. After transfer from LDLD to constant dim light, SP-R hamsters were also more likely to become arrhythmic compared to SP-NR hamsters and unselected controls. In contrast, short photoperiod chronotype did not influence more transient changes in circadian waveform. The present data reveal a clear relationship in the plasticity of circadian waveform across 3 distinct lighting conditions, suggesting a common mechanism wherein individual differences reflect variation in circadian coupling.
- Photic sensitivity for circadian response to light varies with photoperiod. The response of the circadian system to light varies markedly depending on photic history. Under short day lengths, hamsters exhibit larger maximal light-induced phase shifts as compared with those under longer photoperiods. However, effects of photoperiod length on sensitivity to subsaturating light remain unknown. Here, Syrian hamsters were entrained to long or short photoperiods and subsequently exposed to a 15-min light pulse across a range of irradiances (0-68.03 mW/cm2 ) to phase shift activity rhythms. Phase advances exhibited a dose response, with increasing irradiances eliciting greater phase resetting in both conditions. Photic sensitivity, as measured by the half-saturation constant, was increased 40-fold in the short photoperiod condition. In addition, irradiances that generated similar phase advances under short and long days produced equivalent phase delays, and equal photon doses produced larger delays in the short photoperiod condition. Mechanistically, equivalent light exposure induced greater pERK, PER1, and cFOS immunoreactivity in the suprachiasmatic nuclei of animals under shorter days. Patterns of immunoreactivity in all 3 proteins were related to the size of the phase shift rather than the intensity of the photic stimulus, suggesting that photoperiod modulation of light sensitivity lies upstream of these events within the signal transduction cascade. This modulation of light sensitivity by photoperiod means that considerably less light is necessary to elicit a circadian response under the relatively shorter days of winter, extending upon the known seasonal changes in sensitivity of sensory systems. Further characterizing the mechanisms by which photoperiod alters photic response may provide a potent tool for optimizing light treatment for circadian and affective disorders in humans.

- Harrison, E.M., Gorman, M.R. The effect of narrowband 500 nm light on daytime sleep in humans, Physiology and Behavior. 103:197-202. Naps frequently take place during the daytime under some ambient light. People are commonly advised to wear eyeshades, or use black-out curtains while sleeping, as light is thought to inhibit sleep. Little is known, however, about how light during daytime sleep may affect the quality or architecture of that sleep. The present withinsubjects design administered green narrowband light via light masks to 17 young adults (23.2±4.7 years) during four 90-minute afternoon naps. Subjects were exposed to each of four light conditions that approximate the intensity of 1) physiological darkness (~0 lx), 2) moonlight (~1 lx), 3) typical indoor lighting (~80 lx) and 4) indirect outdoor light (~6400 lx). All subjects were able to sleep in all lighting conditions, with no differences in sleep quality or architecture. Power analysis revealed sufficient power to detect meaningful differences. Sleep inertia measured upon waking showed a general effect of the nap, independent of condition. Although light has various alerting effects at night, 500 nm LED light presented via light mask does not appear to inhibit daytime sleep. The finding that this light had no effect on the ability of individuals to fall asleep or stay asleep during an afternoon nap may inform decisions regarding the use of the nap as a facilitator of schedule adjustment, and challenges the assumption of light as a barrier to napping.
- Evans, J.A., Elliott, J.A., Gorman, M.R. Dim nighttime illumination interacts with parametric effects of bright light to increase the stability of circadian rhythm bifurcation in hamsters, Chronobiology International. 28(6):488-496. The endogenous circadian pacemaker of mammals is synchronized to the environmental day by the ambient cycle of relative light and dark. The present studies assessed the actions of light in a novel circadian entrainment paradigm where activity rhythms are bifurcated following exposure to a 24-h light:dark:light:dark (LDLD) cycle. Bifurcated entrainment under LDLD reflects the temporal dissociation of component oscillators that comprise the circadian system and is facilitated when daily scotophases are dimly lit rather than completely dark. Although bifurcation can be stably maintained in LDLD, it is quickly reversed under constant conditions. Here the authors examine whether dim scotophase illumination acts to maintain bifurcated entrainment under LDLD through potential interactions with the parametric actions of bright light during the two daily photophases. In three experiments, wheel-running rhythms of Syrian hamsters were bifurcated under LDLD with dimly lit scotophases, and after several weeks, dim scotophase illumination was either retained or extinguished. Additionally, “full” and “skeleton” photophases were employed under LDLD cycles with dimly lit or completely dark scotophases to distinguish parametric from nonparametric effects of bright light. Rhythm bifurcation was more stable in full versus skeleton LDLD cycles. Dim light facilitated the maintenance of bifurcated entrainment under full LDLD cycles but did not prevent the loss of rhythm bifurcation in skeleton LDLD cycles. These studies indicate that parametric actions of bright light maintain the bifurcated entrainment state; that dim scotophase illumination increases the stability of the bifurcated state; and that dim light interacts with the parametric effects of bright light to increase the stability of rhythm bifurcation under full LDLD cycles. A further understanding of the novel actions of dim light may lead to new strategies for understanding, preventing, and treating chronobiological disturbances.
- Ethanol consumption in mice: relationships with circadian period and entrainment. A functional connection between the circadian timing system and alcohol consumption is suggested by multiple lines of converging evidence. Ethanol consumption perturbs physiological rhythms in hormone secretion, sleep, and body temperature; and conversely, genetic and environmental perturbations of the circadian system can alter alcohol intake. A fundamental property of the circadian pacemaker, the endogenous period of its cycle under free-running conditions, was previously shown to differ between selectively bred high- (HAP) and low- (LAP) alcohol preferring replicate 1 mice. To test whether there is a causal relationship between circadian period and ethanol intake, we induced experimental, rather than genetic, variations in free-running period. Male inbred C57Bl/6J mice and replicate 2 male and female HAP2 and LAP2 mice were entrained to light:dark cycles of 26 or 22 h or remained in a standard 24 h cycle. On discontinuation of the light:dark cycle, experimental animals exhibited longer and shorter free-running periods, respectively. Despite robust effects on circadian period and clear circadian rhythms in drinking, these manipulations failed to alter the daily ethanol intake of the inbred strain or selected lines. Likewise, driving the circadian system at long and short periods produced no change in alcohol intake. In contrast with replicate 1 HAP and LAP lines, there was no difference in free-running period between ethanol naı¨ve HAP2 and LAP2 mice. HAP2 mice, however, were significantly more active than LAP2 mice as measured by general homeecage movement and wheel running, a motivated behavior implicating a selection effect on reward systems. Despite a marked circadian regulation of drinking behavior, the free-running and entrained period of the circadian clock does not determine daily ethanol intake.

- Glickman, G. Circadian rhythms and sleep in children with autism, Neuroscience and Biobehavioral Reviews 34(2010) 755-768. A growing body of research has identified significant sleep problems in children with autism. Disturbed sleep–wake patterns and abnormal hormone profiles in children with autism suggest an underlying impairment of the circadian timing system. Reviewing normal and dysfunctional relationships between sleep and circadian rhythms will enable comparisons to sleep problems in children with autism, prompt a reexamination of existing literature and offer suggestions for future inquiry. In addition, sleep and circadian rhythms continue to change over the course of development even in typical, healthy humans. Therefore, exploring the dynamic relationship between circadian rhythms and sleep throughout development provides valuable insight into those sleep problems associated with autism. Ultimately, a better understanding of sleep and circadian rhythms in children with autism may help guide appropriate treatment strategies and minimize the negative impact of these disturbances on both the children and their families.
- Frank, D.W., Evans, J.A., Gorman, M.R. Time-dependent effects of dim light at night on re-entrainment and masking of hamster activity, Journal of Biological Rhythms. 25:103-113. Bright light has been established as the most ubiquitous environmental cue that entrains circadian timing systems under natural conditions. Light equivalent in intensity to moonlight (<1 lux), however, also strongly modulates circadian function in a number of entrainment paradigms. For example, compared to completely dark nights, dim nighttime illumination accelerated reentrainment of hamster activity rhythms to 4-hour phase advances and delays of an otherwise standard laboratory photocycle. The purpose of this study was to determine if a sensitive period existed in the night during which dim illumination had a robust influence on speed of re-entrainment. Male Siberian hamsters were either exposed to dim light throughout the night, for half of the night, or not at all. Compared to dark nights, dim illumination throughout the entire night decreased by 29% the time for the midpoint of the active phase to re-entrain to a 4-hour phase advance and by 26% for a 4-hour delay.Acceleration of advances and delays were also achieved with 5 hours of dim light per night, but effects depended on whether dim light was present in the first half, second half, or first and last quarters of the night. Both during phase shifting and steady-state entrainment, partially lit nights also produced strong positive and negative masking effects, as well as entrainment aftereffects in constant darkness. Thus, even in the presence of a strong zeitgeber, light that might be encountered under a natural nighttime sky potently modulates the circadian timing system of hamsters.
- Yan, L., Silver, R., Gorman, M.R. Reorganization of suprachiasmatic nucleus networks under 24-h LDLD conditions, Journal of Biological Rhythms. 25:19-28. The suprachiasmatic nucleus (SCN), locus of the master circadian clock in the brain, is comprised of multioscillator neural networks that are highly plastic in responding to environmental lighting conditions. Under a 24-h light:dark:light:dark (LDLD) cycle, hamsters bifurcate their circadian locomotor activity such that wheel running occurs in each of the 2 daily dark periods with complete inactivity in between. In the present study, we explored the neural underpinning of this behavioral bifurcation. Using calbindin (CalB)– containing cells of the SCN as a regional marker, we characterized PER1 and c-FOS expression in the core and shell SCN subregions. In LD-housed animals, it is known that PER1 and c-FOS in the core and shell region are in phase with each other. In contrast, in behaviorally bifurcated animals housed in LDLD, the core and shell SCN exhibit antiphase rhythms of PER1. Furthermore, cells in the core show high FOS expression in each photophase of the LDLD cycle. The activation of FOS in the core is light driven and disappears rapidly when the photophase is replaced by darkness. The results suggest that bifurcated activity bouts in daytime and nighttime are associated with oscillating groups of cells in the core and shell subregions, respectively, and support the notion that reorganization of SCN networks underlies changes in behavioral responses under different environmental lighting conditions.
- Butler, M.P, Turner, K.W., Park, J.H., Schoomer, E.E., Zucker, I., Gorman, M.R. Seasonal regulation of reproduction: altered role of melatonin under naturalistic conditions in hamsters, Proc. R. Soc. 277:2867–2874. The seasonal reproductive cycle of photoperiodic rodents is conceptualized as a series of discrete melatonin-dependent neuroendocrine transitions. Least understood is the springtime restoration of responsiveness to winter-like melatonin signals (breaking of refractoriness) that enables animals to once again respond appropriately to winter photoperiods the following year. This has been posited to require many weeks of long days based on studies employing static photoperiods instead of the annual pattern of continually changing photoperiods under which these mechanisms evolved. Maintaining Siberian hamsters under simulated natural photoperiods, we demonstrate that winter refractoriness is broken within six weeks after the spring equinox. We then test whether a history of natural photoperiod exposure can eliminate the requirement for long-day melatonin signalling. Hamsters pinealectomized at the spring equinox and challenged 10 weeks later with winter melatonin infusions exhibited gonadal regression, indicating that refractoriness was broken. A photostimulatory effect on body weight is first observed in the last four weeks of winter. Thus, the seasonal transition to the summer photosensitive phenotype is triggered prior to the equinox without exposure to long days and is thereafter melatonin-independent. Distinctions between photoperiodic and circannual seasonal organization erode with the incorporation in the laboratory of ecologically relevant day length conditions.
- Evans, J.A., Elliott, J.A., Gorman, M.R. Dynamic interactions between coupled oscillators within the hamster circadian pacemaker, Behavioral Neuroscience. 124(1):87-96. Within the mammalian suprachiasmatic nucleus, multiple oscillators interact to coordinate circadian rhythms in behavior and physiology. We have developed a behavioral assay that disassociates central oscillators and allows rigorous study of their formal properties and interactions. Rodents held under 24h light:dark:light:dark (LDLD) cycles display “split” activity rhythms that reflect the reorganization of the central pacemaker into two oscillator groups cycling 12h apart. After transfer to constant conditions, the two activity components rejoin through a series of transients lasting 2–7 days. Here we analyze fusion dynamics, characterize the underlying oscillator interactions, and assess two influencing factors: phase of transfer and lighting conditions upon transfer. Syrian hamsters were split under LDLD with dimly lit nights and then transferred to constant dim illumination or complete darkness during one of the two daily scotophases. Fusion was influenced by phase of transfer, suggesting that the oscillators split under LDLD exert an asymmetric influence over one another. Transfer to constant dim and dark conditions produced similar overall patterns of fusion, but nevertheless differed in the rejoined state of the system. The present results are discussed within a model wherein oscillators influence one another in a phase-dependent manner.
- Lifespan daily locomotor activity rhythms in a mouse model of amyloid-induced neuropathy. Using a rodent model for neuropathology induced by human amyloid precursor protein, the present study tested the hypothesis that 24 h rest/activity rhythms deteriorate with age. A lifespan of rest/activity patterns was studied in transgenic Tg2576 mice and wild-type controls. Classic indices of circadian timekeeping, including onsets, offsets, and the duration of nighttime activity, were stable throughout the 96-week study. Analyses of ultradian bout activity revealed significant genotype and age-related changes in the duration and intensity of activity bouts, as well as amplitude of the 24 h rhythm. Tg2576 mice had more total activity counts, fewer bouts/24 h, more counts/bout, and longer bout time than wild-type controls. Amyloid deposits and plaques were solely found in specific cortex regions in aged postmortem Tg2576 mice, but were not evident in the hypothalamus or suprachiasmatic nucleus; this neuropathology was absent from brains of wild-type controls. These findings suggest that amyloidosis of the Tg2576 mouse exerts little influence on timing of locomotor activity in the circadian domain but significantly alters the temporal structure of ultradian activity.

- Evans, J.A., Elliott, J.A., Gorman, M.R. Dim nighttime illumination accelerates adjustment to timezone travel in an animal model, Current Biology. 19(4):R156. No Preview available
- Circadian timing of ethanol exposure exerts enduring effects on subsequent ad libitum consumption in C57 mice. Background: There is a daily rhythm in the voluntary intake of ethanol in mice, with greatest consumption in the early night and lowest intake during the day. The role of daily timing of ethanol exposure on the development and control of long-term ethanol self-administration has been neglected. The present study examines these issues using C57BL ⁄ 6J mice.
Methods: Mice were repeatedly exposed to 10% ethanol for 2 hours early in the night or day for several weeks. Subsequently, ethanol was available at the opposite time (Expt 1) or 24 hours daily (Expts 1 and 2). Lick sensors recorded the patterns of drinking activity in Experiment 2.
Results: Mice exposed to ethanol during the night drink more than mice exposed during the day. Prior history did not affect ethanol intake when the schedule was reversed. Under 24-hour exposure conditions, mice with a history of drinking during the night consumed significantly more than mice drinking during the day. The circadian patterns of drinking were not altered.
Conclusions: These results demonstrate that the daily timing of ethanol exposure exerts enduring effects of self-administration of ethanol in mice. Understanding how circadian rhythms regulate ethanol consumption may be valuable for modifying subsequent intake.

- Circadian effects of light no brighter than moonlight. In mammals, light entrains endogenous circadian pacemakers by inducing daily phase shifts via a photoreceptor mechanism recently discovered in retinal ganglion cells. Light that is comparable in intensity to moonlight is generally ineffective at inducing phase shifts or suppressing melatonin secretion, which has prompted the view that circadian photic sensitivity has been titrated so that the central pacemaker is unaffected by natural nighttime illumination. However, the authors have shown in several different entrainment paradigms that completely dark nights are not functionally equivalent to dimly lit nights, even when nighttime illumination is below putative thresholds for the circadian visual system. The present studies extend these findings. Dim illumination is shown here to be neither a strong zeitgeber, consistent with published fluence response curves, nor a potentiator of other zeitgebers. Nevertheless, dim light markedly alters the behavior of the free-running circadian pacemaker. Syrian hamsters were released from entrained conditions into constant darkness or dim narrowband green illumination (~0.01 lx, 1.3 × 10 -9 W/cm2 , peak λ = 560 nm). Relative to complete darkness, constant dim light lengthened the period by ~0.3 h and altered the waveform of circadian rhythmicity. Among animals transferred from long day lengths (14 L:10 D) into constant conditions, dim illumination increased the duration of the active phase (α) by ~3 h relative to complete darkness. Short day entrainment (8 L:16 D) produced initially long α that increased further under constant dim light but decreased under complete darkness. In contrast, dim light pulses 2 h or longer produced effects on circadian phase and melatonin secretion that were small in magnitude. Furthermore, the amplitude of phase resetting to bright light and nonphotic stimuli was similar against dimly lit and dark backgrounds, indicating that the former does not directly amplify circadian inputs. Dim illumination markedly alters circadian waveform through effects on α, suggesting that dim light influences the coupling between oscillators theorized to program the beginning and end of subjective night. Physiological mechanisms responsible for conveying dim light stimuli to the pacemaker and implications for chronotherapeutics warrant further study

- Gorman, M.R. and Steele, N. Phase angle Difference alters coupling relations of functionally distinct circadian oscillators revealed by rhythm splitting, J Biol Rhythms. 21:195-205. The interactions (i.e., coupling) between multiple oscillators of a circadian system determine basic properties of the integrated pacemaker. Unfortunately, there are few experimental models to investigate the putative interactions of functionally defined oscillators comprising the mammalian circadian pacemaker. Here the authors induce in hamsters a novel circadian entrainment pattern that is characterized by the daily expression of robust wheel-running activity in each scotophase of a 24-h light:dark:light:dark cycle. The daily activity bouts are mediated by 2 circadian oscillators, here designated “daytime” and “nighttime,” that have been temporally dissociated under this light regime. To assess the phase dependence of interactions between oscillatory components, the phase relationship of the 2 daily scotophases was manipulated over a 4-h range, and the timing of activity of the daytime and nighttime components under entrained and probe conditions was examined. The average phase angle of entrainment and the day-to-day variability of activity onset of each activity component depended on the phase relationship of the respective scotophases and not on whether the component occurred in the daytime or the nighttime. Short-term denial of wheel access subsequently influenced amount and duration of wheel running but not timing of its onset, suggesting that only the former measures depend on a homeostatic mechanism sensitive to the time elapsed since prior intense running. Replacement of individual photophases with darkness revealed phase attraction between oscillators that was not dependent on the phase relationship of component oscillators but differed for daytime versus nighttime activity components. Entrainment patterns shown here cannot be accounted for by only nonparametric actions of light. Instead, the phase-dependent interactions of oscillators strongly influence entrainment properties, whereas intrinsic functional differences in dissociated oscillators apparently influence their attraction in darkness. This model system may be ideal for identifying genomic and physiological factors that mediate these interactions and thus contribute importantly to system properties of the mammalian circadian clock.
- Gorman, M.R., Evans, J.A. and Elliott, J.A. Potent circadian effects of dim illumination at night in hamsters. Chronobiol Int. 23:245-50. Conventional wisdom holds that the circadian pacemaker of rodents and humans is minimally responsive to light of the intensity provided by dim moonlight and starlight. However, dim illumination (,0.005 lux) provided during the daily dark periods markedly alters entrainment in hamsters. Under dimly lit scotophases, compared to completely dark ones phases, the upper range of entrainment is increased by 4 h, and re-entrainment is accelerated following transfer from long to short day lengths. Moreover, the incidence of bimodal entrainment to 24 h light:dark:light:dark cycles is increased fourfold. Notably, the nocturnal illumination inducing these pronounced effects is equivalent in photic energy to that of a 2 sec, 100 lux light pulse. These effects may be parsimoniously interpreted as an action of dim light on the phase relations between multiple oscillators comprising the circadian pacemaker. An action of dim light distinct from that underlying bright-light phase-resetting may promote more effective entrainment. Together, the present results refute the view that scotopic illumination is environmental “noise” and indicate that clock function is conspicuously altered by nighttime illumination like that experienced under dim moonlight and starlight. We interpret our results as evidence for a novel action of dim light on the coupling of multiple circadian oscillators.

- Rosenthal S.L., Vakili, M.M., Evans, J.A., Elliott, J.A. and Gorman M.R. Influence of photoperiod and running wheel access on the entrainment of split circadian rhythms in hamsters. BMC Neuroscience, 6:41. Background: In the laboratory, behavioral and physiological states of nocturnal rodents alternate, with a period near 24 h, between those appropriate for the night (e.g., elevated wheel-running activity and high melatonin secretion) and for the day (e.g., rest and low melatonin secretion). Under appropriate 24 h light:dark:light:dark conditions, however, rodents may be readily induced to express bimodal rest/activity cycles that reflect a global temporal reorganization of the central neural pacemaker in the hypothalamus. We examine here how the relative length of the light and dark phases of the environmental cycle influences this rhythm splitting and the necessity of a running wheel for expression of this entrainment condition.
Results: Rhythm splitting was observed in wheel-running and general locomotion of Siberian and Syrian hamsters. The latter also manifest split rhythms in body temperature. Access to a running wheel was necessary neither for the induction nor maintenance of this entrainment pattern. While rhythms were only transiently split in many animals with two 5 h nights, the incidence of splitting was greater with twice daily nights of shorter duration. Removal of running wheels altered the body temperature rhythm but did not eliminate its clear bimodality.
Conclusion: The expression of entrained, split circadian rhythms exhibits no strict dependence on access to a running wheel, but can be facilitated by manipulation of ambient lighting conditions. These circadian entrainment patterns may be of therapeutic value to human shift-workers and others facing chronobiological challenges.

- Evans, J.A., Elliott, J.A. and Gorman, M.R. Circadian Entrainment and Phase Resetting Differ Markedly under Dimly Illuminated versus Completely Dark Nights, Behavioral Brain Research, 162:116-126. An endogenous circadian pacemaker uses photic input to synchronize mammalian physiological and behavioral rhythms to the 24 h day. Sunlight during dusk and dawn is thought to entrain the pacemaker of nocturnal rodents, whereas moonlight and starlight are presumed to exert little influence. We show that, to the contrary, dim illumination (<0.005 lux), similar in intensity to starlight and dim moonlight, markedly alters entrainment of hamster activity rhythms. Under 24 h light:dark:light:dark cycles (LDLD), for example, activity rhythms can disassociate, or split, into two distinct components, and the incidence of split entrainment is increased when daily scotophases are dimly lit rather than completely dark. The three present studies examine whether dim illumination promotes LDLD-induced splitting (1) by increasing nonphotic feedback during novelty-induced activity bouts, (2) by potentiating nonphotic and/or photic resetting, or (3) by influencing phase jumping responses under skeleton photoperiods simulating increases in day length. Experiment 1 illustrates that dim-exposed animals display split rhythms, while animals without dim light do not, despite equivalent activity levels. In Experiments 2 and 3, dim illumination potentiated both nonphotic and photic resetting, and the specific nature of these interactions suggests mechanisms through which dim illumination may alter entrainment under LDLD. Dim light likely promotes LDLD-induced splitting by facilitating both nonphotic resetting and bright light-induced phase jumping in animals entrained to short nights. The actions of dim illumination may be distinct from canonical responses to bright light, and potentially influence the interactions between oscillators comprising the circadian pacemaker.

- Gorman, M.R., Kendall, M. and Elliott, J.A. Scotopic illumination enhances entrainment of circadian rhythms to lengthening light:dark cycles, Journal of Biological Rhythms, 20:38-48. No Preview available
- Gorman, M.R. and Elliott, J. A. Dim nocturnal illumination alters coupling of circadian oscillators in Siberian hamsters, Phodopus sungorus. Journal of Comparative Physiology A, 190:631-9. The circadian pacemaker of mammals comprises multiple oscillators that may adopt different phase relationships to determine properties of the coupled system. The effect of nocturnal illumination comparable to dim moonlight was assessed in male Siberian hamsters exposed to two re-entrainment paradigms believed to require changes in the phase relationship of underlying component oscillators. In experiment 1, hamsters were exposed to a 24-h light-dark-light-dark cycle previously shown to split circadian rhythms into two components such that activity is divided between the two daily dark periods. Hamsters exposed to dim illumination (<0.020 lx) during each scotophase were more likely to exhibit split rhythms compared to hamsters exposed to completely dark scotophases. In experiment 2, hamsters were transferred to winter photoperiods (10 h light, 14 h dark) from two different longer daylengths (14 h or 18 h light daily) in the presence or absence of dim nighttime lighting. Dim nocturnal illumination markedly accelerated adoption of the winter phenotype as reflected in the expansion of activity duration, gonadal regression and weight loss. The two experiments demonstrate substantial efficacy of light intensities generally viewed as below the threshold of circadian systems. Light may act on oscillator coupling through rod-dependent mechanisms.
- Evans, J.A., Elliott, J.A. and Gorman, M.R. Photoperiod Differentially Modulates Photic and Nonphotic Phase Response Curves of Hamsters. American Journal of Physiology, 286:R539-46. Photoperiod differentially modulates photic and nonphotic phase response curves of hamsters. Am J Physiol Regul Integr Comp Physiol 286: R539–R546, 2004. First published November 26, 2003; 10.1152/ ajpregu.00456.2003.—Circadian pacemakers respond to light pulses with phase adjustments that allow for daily synchronization to 24-h light-dark cycles. In Syrian hamsters, Mesocricetus auratus, lightinduced phase shifts are larger after entrainment to short daylengths (e.g., 10 h light:14 h dark) vs. long daylengths (e.g., 14 h light:10 h dark). The present study assessed whether photoperiodic modulation of phase resetting magnitude extends to nonphotic perturbations of the circadian rhythm and, if so, whether the relationship parallels that of photic responses. Male Syrian hamsters, entrained for 31 days to either short or long daylengths, were transferred to novel wheel running cages for 2 h at times spanning the entire circadian cycle. Phase shifts induced by this stimulus varied with the circadian time of exposure, but the amplitude of the resulting phase response curve was not markedly influenced by photoperiod. Previously reported photoperiodic effects on photic phase resetting were verified under the current paradigm using 15-min light pulses. Photoperiodic modulation of phase resetting magnitude is input specific and may reflect alterations in the transmission of photic stimuli.

- Gorman, M.R. and Elliott, J.A. Entrainment of two subjective nights by daily light:dark:light:dark cycles in three rodent species. Journal of Biological Rhythms, 18:502-12. Recent work with exotic 24-h light:dark:light:dark (LDLD) cycles indicates surprising flexibility in the entrainment patterns of Syrian hamsters. Following exposure to an LDLD cycle, hamsters may adopt a form of rhythm splitting in which markers of subjective night (e.g., activity, melatonin) are expressed in each of the twice daily scotophases. This pattern contrasts markedly with that of conventionally entrained hamsters in which markers of subjective night are expressed once daily in only 1 of the 2 dark periods. The “split” entrainment pattern was examined further here in Syrian and Siberian hamsters and in mice exposed to LDLD 7:5:7:5, a condition that reliably induces split activity rhythms in all 3 species. The phase angle of entrainment and activity duration were generally similar comparing the 2 daily activity bouts in each species. The stability of this split entrainment state was assessed by deletions of photophases on individual days, by exposure to skeleton photoperiods, and by transfer to constant darkness. As in Syrian hamsters, the one-time substitution of darkness for one 7-h photophase did not grossly alter activity patterns of Siberian hamsters but acutely disrupted the split rhythms of mice. Skeleton light pulses of progressively shorter duration did not significantly alter split entrainment patterns of either Syrian or Siberian hamsters. Both species continued to exhibit stable entrainment with activity expressed in alternate scotophases of an LD 1:5 cycle presented 4 times daily. In contrast, the split activity rhythms of mice were not maintained under skeleton pulses. In constant darkness, rhythms of Siberian hamsters remained distinctly split for a minimum of 2 cycles. Split entrainment to these novel LDLD and 4-pulse skeleton lighting regimes demonstrates a marked degree of plasticity common to the circadian systems of several rodent species and identifies novel entrainment patterns that may be reliably elicited with simple environmental manipulations. Inter- and intraspecific differences in the stability of split activity rhythms likely reflect differences in coupling interactions between the component circadian oscillators, which, adopting separate phase relations to these novel LD cycles, yield a split entrainment pattern.
- Gorman, M.R. Independence of circadian entrainment state and responses to melatonin in male Siberian hamsters. BMC Physiology. No Preview available
- Gorman, M.R. Melatonin implants disrupt developmental synchrony regulated by flexible interval timers. J Neuroendocrinology, 15:1084-94. No Preview available
- Piatkowska,J.M., Prendergast, B.J., and Gorman, M.R. Temporal integration of melatonin infusion duration: signal averaging versus frequency dependence. J Pineal Res, 35:91-97. No Preview available
- Gorman, M.R., Evans, J.A., and Elliott, J.A. Plasticity of hamster circadian entrainment patterns depends on light intensity. Chronobiol Intl, 20:233-248. The multiple oscillatory basis of the mammalian circadian pacemaker is adduced by, among other phenomena, the occurrence of split locomotor activity rhythms in rodents after prolonged exposure to constant light. More recently, split rhythms entrained to a 24h light:dark:light:dark cycle have been documented following scheduled access of hamsters to a novel running wheel or by photoperiod manipulations alone. Because the incidence of constant light-induced splitting depends on light intensity, the role of this variable was assessed in this new splitting paradigm. Male Syrian hamsters, entrained to a 14h light:10h dark cycle, were transferred to individual running wheel cages 7h after light onset. Transfer coincided with the beginning of the scotophase of a new photocycle alternating between 5h of relative dark and 7h of light. For four weeks bright photophases (,350 lux) were alternated with either dim (,0.1 lux) or completely dark (0 lux) scotophases. An additional group received moderate intensity photophases (,45 lux) paired with dim scotophase illumination. For an additional four weeks, all hamsters were exposed to the same bright:dim light:dark cycle. Dim light in the scotophase significantly increased the incidence of split activity rhythms relative to that observed with completely dark scotophases. Overall wheel-running rates and activity induced by a cage change were also increased in dim light-exposed animals. Group differences largely disappeared four weeks later when hamsters previously maintained in completely dark scotophases were exposed to dim scotophases. Photophase light intensity did not affect the overall incidence of splitting, but influenced the timing of activity in the afternoon scotophase. The effects of dim illumination may be mediated in part via enhanced locomotor responses to transfer to a new cage or by changes in coupling interactions between component oscillators.
- Gorman, M.R., and Lee, T.M. Hormones and Biological Rhythms. In: Behavioral Endocrinology, ed. by J.B. Becker, S.M. Breedlove, M.M. McCarthy and D. Crews. MIT Press, pp.451-494.
- Photoperiod differentially modulates PRC in hamsters Photoperiod differentially modulates photic and nonphotic phase response curves of hamsters. Am J Physiol Regul Integr Comp Physiol 286: R539–R546, 2004. First published November 26, 2003; 10.1152/ ajpregu.00456.2003.—Circadian pacemakers respond to light pulses with phase adjustments that allow for daily synchronization to 24-h light-dark cycles. In Syrian hamsters, Mesocricetus auratus, lightinduced phase shifts are larger after entrainment to short daylengths (e.g., 10 h light:14 h dark) vs. long daylengths (e.g., 14 h light:10 h dark). The present study assessed whether photoperiodic modulation of phase resetting magnitude extends to nonphotic perturbations of the circadian rhythm and, if so, whether the relationship parallels that of photic responses. Male Syrian hamsters, entrained for 31 days to either short or long daylengths, were transferred to novel wheel running cages for 2 h at times spanning the entire circadian cycle. Phase shifts induced by this stimulus varied with the circadian time of exposure, but the amplitude of the resulting phase response curve was not markedly influenced by photoperiod. Previously reported photoperiodic effects on photic phase resetting were verified under the current paradigm using 15-min light pulses. Photoperiodic modulation of phase resetting magnitude is input specific and may reflect alterations in the transmission of photic stimuli.

- Split circadian rhythms of female Syrian hamsters and their offspring. In several mammalian species, circadian pacemakers of breeding females synchronize the developing clocks of offspring by as of yet unspecified mechanisms. The present study assessed whether maternal communication of circadian rhythms extends beyond setting pacemaker phase to include transfer of a fundamental reorganization of component circadian oscillators from dams to pups. In Experiment 1, a regimen of daily novel wheelrunning previously demonstrated to split activity rhythms of adult male hamsters into two discrete components was shown to similarly reorganize female hamster rhythms. In Experiment 2, females split by this method and unsplit controls exposed to similar light environments were mated with males. Split and unsplit females were equally fecund, but the former weaned pups of lower body weight. After weaning into running wheel cages, offspring of split dams were more likely to exhibit split activity rhythms than were offspring of unsplit females. Among pups not categorized as split, moreover, maternal entrainment nonetheless influenced distribution of pup activity across the 24-h cycle. Entrainment patterns of split and unsplit pups resembled those of adults. Thus, split and unsplit hamster dams provide different entraining signals to their developing offspring. The influence of maternal rhythms extends beyond entraining phase to alter interactions between component circadian oscillators that underlie split activity bouts. Maternal effects did not persist beyond the second week postweaning in split or unsplit hamsters, however, and rhythms of many split pups later joined. Thus, the maternal influence on the pup’s circadian pacemaker may be transient.
- Hormones and Biological Rhythms. No Preview available

- Gorman, M. R., and Lee, T. M. Daily novel Wheel Running Reorganizes and Splits Hamster Circadian Activity Rhythms. J Biol Rhythms, 16:541-551. The phenomenon of splitting of locomotor activity rhythms in constant light has implied that the mammalian circadian pacemaker is composed of multiple interacting circadian oscillators. Exposure of male Syrian hamsters to novel running wheels also induces splitting in some reports, although novel wheel running (NWR) is better known for its effects on altering circadian phase and the length of the free-running period. In three experiments, the authors confirm and extend earlier reports of split rhythms induced by NWR. Male Syrian hamsters, entrained to LD 14:10, were transferred for 6 to 11 consecutive days to darkened novel Wahmann wheels at ZT 4 and were returned to their home cages at ZT 9. All hamsters ran robustly in the novel wheels. NWR caused a marked reorganization of home cage wheel-running behavior: Activity onsets delayed progressively with each additional day of NWR. After 11 days, activity onset in the nighttime scotophase was delayed by 7 h and disappeared completely in 2 hamsters (Experiment 1). After 6 to 7 days of NWR (Experiment 2), activity onset delayed by 5 h. Transfer of hamsters to constant darkness (DD) after 7 days of NWR revealed clearly split activity rhythms: The delayed nighttime activity bout was clearly identifiable and characterized by a short duration. A second bout associated with the former time of NWR was equally distinct and exhibited a similarly short duration. These components rejoined after 3 to 5 days in DD accomplished via delays and advances of the nighttime and afternoon components, respectively. The final experiment established that rejoining of activity components could be prevented by perpetuating the light-dark:light-dark cycle used to induce split rhythms. The data suggest that NWR causes selective phase shifting of some circadian oscillators and that component oscillators interact strongly in constant darkness.
- Gorman, M. R. Exotic photoperiods induce and entrain split circadian activity rhythms in hamsters. J Comp Physiol A, 187:793-800. The split circadian activity rhythm that emerges in hamsters after prolonged exposure to constant light has been a theoretical cornerstone of a multi-oscillator view of the circadian mammalian pacemaker. The present study demonstrates a novel method for splitting hamster rhythms and entraining them to exotic light:dark cycles. Male Syrian hamsters previously maintained on a 14-h day and 10-h night were exposed to a second 5-h dark phase in the afternoon. The 10-h night was progressively shortened until animals experienced two 5-h dark phases beginning 10-h apart. Most hamsters responded by splitting their activity rhythms into two components associated with the afternoon and nighttime dark phases, respectively. Each activity component was entrained to this light:dark:light:dark cycle. Transfer of split hamsters to constant darkness resulted in rapid joining of the two activity components with the afternoon component associated with onset of the fused rhythm. In constant light, the nighttime component corresponded to activity onset of the fused rhythm, but splitting emerged again at an interval characteristic of this species. The results place constraints on multi-oscillator models of circadian rhythms and offer opportunities to characterize the properties of constituent circadian oscillators and their interactions.
- Gorman, M. R., Yellon, S.M., and Lee, T. M. Temporal Reorganization of the Suprachiasmatic Nuclei in Hamsters with Split circadian Rhythms. J Biol Rhythms, 16:552-563. No Preview available
- Gorman, M.R. A Plastic Interval Timer Synchronizes Springtime Pubertal Development of Summer- and Fall-born Siberian Hamsters. Am J Physiol Regul Integrative Comp Physiol, 281(5):R1613-RNo Preview available
- Gorman MR, Goldman BD, and Zucker I. Mammalian photoperiodism. In: Circadian Clocks, edited by J. S. Takahashi, F. W. Turek and R. Y. Moore. New York: Plenum Press, 2001, p. 481-508. No Preview available

- Lee, T.M. and Gorman, M.R. Timing of reproduction by the integration of photoperiod and other seasonal signals. In: Reproduction in Context, ed. by K. Wallen and J. Schneider, MIT Press, 2000, pg. 191-218.
- Prendergast, B. J., Gorman, M. R., and Zucker, I. (2000). Establishment and persistence of photoperiodic memory in hamsters. Proc Natl Acad Sci U S A 97(10), 5586-91.

- Gorman, M.R. and Zucker, I. "Mammalian photoperiodism: new perspectives from the use of simulated natural photoperiods." In: Biological Clocks. Mechanisms and Applications, ed. by Y. Touitou, Excerpta Medica International Congress Series Volume 1152, Elsevier Science B.V. Amsterdam. 1998 (pp. 195-204).
- Prendergast BJ, Zucker I, Yellon SM, Ringold DA, Gorman MR. Melatonin chimeras alter reproductive development and photorefractoriness in Siberian hamsters. J Biol Rhythms 1998 Dec;13(6):518-31.

- Gorman MR, Freeman DA, Zucker I. Photoperiodism in hamsters: abrupt versus gradual changes in day length differentially entrain morning and evening circadian oscillators. J Biol Rhythms 1997 Apr;12(2):122-35.
- Gorman MR, Zucker I. Environmental induction of photononresponsiveness in the Siberian hamster, Phodopus sungorus. Am J Physiol 1997 Mar;272(3 Pt 2):R887-95.
- Gorman MR, Zucker I. Pattern of change in melatonin duration determines testicular responses in Siberian hamsters, Phodopus sungorus. Biol Reprod 1997 Mar;56(3):668-73.

- Prendergast BJ, Kelly KK, Zucker I, Gorman MR. Enhanced reproductive responses to melatonin in juvenile Siberian hamsters. Am J Physiol 1996 Oct;271(4 Pt 2):R1041-6.
- Gorman MR, Yellon SM. Three daily melatonin infusions alter gonadal development but not GnRH neuron number in the medial preoptic area or diagonal band of Broca in Siberian hamsters. Neurosci Lett 1996 Jun 7;210(3):165-8.

- Gorman MR, Zucker I. Testicular regression and recrudescence without subsequent photorefractoriness in Siberian hamsters. Am J Physiol 1995 Oct;269(4 Pt 2):R800-6 .
- Gorman MR, Zucker I. Seasonal adaptations of Siberian hamsters. II. Pattern of change in daylength controls annual testicular and body weight rhythms. Biol Reprod 1995 Jul;53(1):116-25.
- Gorman MR. Seasonal adaptations of Siberian hamsters. I. Accelerated gonadal and somatic development in increasing versus static long day lengths. Biol Reprod 1995 Jul;53(1):110-5.
- Finley CM, Gorman MR, Tuthill CR, Zucker I. Long-term reproductive effects of a single long day in the Siberian hamster (Phodopus sungorus). J Biol Rhythms 1995 Mar;10(1):33-41.

- Gorman MR, Ferkin MH, Dark J. Melatonin influences sex-specific prenatal mortality in meadow voles. Biol Reprod 1994 Nov;51(5):873-8.

- Gorman, M.R., Ferkin, M.H., Nelson, R.J. and Zucker, I. "Reproductive status influences odor preferences of the meadow vole, Microtus pennsylvanicus, in winter day lengths." Canadian Journal of Zoology, 71, 1993. (pp. 1748-1754)

- Ferkin MH, Gorman MR, Zucker I. Influence of gonadal hormones on odours emitted by male meadow voles (Microtus pennsylvanicus). J Reprod Fertil 1992 Aug;95(3):729-36.
- Ferkin MH, Gorman MR. Photoperiod and gonadal hormones influence odor preferences of the male meadow vole, Microtus pennsylvanicus. Physiol Behav 1992 May;51(5):1087-91.

- Ferkin MH, Gorman MR, Zucker I. Ovarian hormones influence odor cues emitted by female meadow voles, Microtus pennsylvanicus. Horm Behav 1991 Dec;25(4):572-81.

Human Sexuality
- Gorman MR. Male homosexual desire: neurological investigations and scientific bias. Perspect Biol Med 1994 Autumn;38(1):61-81.