Sleep and Rest-Activity Rhythms in Recovering Patients with Severe Concurrent Mental and Substance Use Disorder: A Pilot Study.

Objective: Mental health and substance use disorders are commonly associated with disrupted sleep and circadian rest-activity rhythms. How these disorders in combination relate to sleep and circadian organization is not well studied. We provide here the first quantitative assessment of sleep and rest-activity rhythms in inpatients with complex concurrent disorders, taking into account categories of substance use (stimulant vs. stimulant and opioid use) and psychiatric diagnosis (psychotic disorder and mood disorder). We also explore how sleep and rest-activity rhythms relate to psychiatric functioning. Methods: A total of 44 participants (10 female) between the age of 20-60 years (median = 29 years) wore wrist accelerometers over 5-70 days and completed standardized questionnaires assessing chronotype and psychiatric functioning (fatigue, psychiatric symptom severity, and impulsiveness). To examine potential influences from treatment, we computed (1) length of stay; (2) days of abstinence from stimulants and opioids as a measure of withdrawal; and (3) a sedative load based on prescribed medications. Results: Participants exhibited a sustained excessive sleep duration, frequent nighttime awakenings, and advanced rest-activity phase related to sedative load. Sleep disruptions were elevated in participants with a history of opioid use. Patients with a psychotic disorder showed the longest sleep and most fragmented and irregular rest-activity patterns. Non-parametric circadian rhythm analysis revealed a high rhythm amplitude by comparison with population norms, and this was associated with greater psychiatric symptom severity. Psychiatric symptom severity was also associated with greater fatigue and later MCTQ chronotype. Conclusions: This pilot study provides initial information on the prevalence and severity of sleep and circadian rhythm disturbances in individuals with severe concurrent disorders. The results underline the need for further studies to start to understand the role of sleep in the disease and recovery process in this understudied population.

Multiple entrained oscillator model of food anticipatory circadian rhythms.

For many animal species, knowing when to look for food may be as important as knowing where to look. Rats and other species use a feeding-responsive circadian timing mechanism to anticipate, behaviorally and physiologically, a predictable daily feeding opportunity. How this mechanism for anticipating a daily meal accommodates more than one predictable mealtime is unclear. Rats were trained to press a lever for food, and then limited to one or more daily meals at fixed or systematically varying times of day. The rats were able to anticipate up to 4 of 4 daily meals at fixed times of day and two 'daily' meals recurring at 24 h and 26 h intervals. When deprived of food, in constant dark, lever pressing recurred for multiple cycles at expected mealtimes, consistent with the periodicity of the prior feeding schedule. Anticipation did not require the suprachiasmatic nucleus circadian pacemaker. The anticipation rhythms could be simulated using a Kuramoto model in which clusters of coupled oscillators entrain to specific mealtimes based on initial phase and intrinsic circadian periodicity. A flexibly coupled system of food-entrainable circadian oscillators endows rats with adaptive plasticity in daily programming of foraging activity.

Anticipation of Scheduled Feeding in BTBR Mice Reveals Independence and Interactions Between the Light- and Food-Entrainable Circadian Clocks.

Many animal species exhibit food-anticipatory activity (FAA) when fed at a fixed time of the day. FAA exhibits properties of a daily rhythm controlled by food-entrainable circadian oscillators (FEOs). Lesion studies indicate that FEOs are separate from the light-entrainable circadian pacemaker (LEP) located in the suprachiasmatic nucleus. While anatomically distinct, food- and light-entrainable clocks do appear to interact, and the output of these clocks may be modulated by their phase relation. We report here an analysis of FAA in the BTBR T+ Itpr3tf/J (BTBR) mouse strain that provides new insights into the nature of interactions between food- and light-entrained clocks and rhythms. BTBR mice fed ad libitum exhibit an unusually short active phase and free-running circadian periodicity (~22.5 h). In a light-dark cycle, BTBR mice limited to a 4 h daily meal in the light period show robust FAA compared to the C57BL/6J mice. In constant darkness, BTBR mice exhibit clear and distinct free-running and food-anticipatory rhythms that interact in a phase-dependent fashion. The free-running rhythm exhibits phase advances when FAA occurs in the mid-to-late rest phase of the free run, and phase delays when FAA occurs in the late active phase. A phase-response curve (PRC) inferred from these shifts is similar to the PRC for activity-induced phase shifts in nocturnal rodents, suggesting that the effects of feeding schedules on the LEP in constant darkness are mediated by FAA. A phase-dependent effect of the free-running rhythm on FAA was evident in both its magnitude and duration; FAA counts were greatest when FAA occurred during the active phase of the free-running rhythm. The LEP inhibited FAA when FAA occurred at the end of the subjective day. These findings provide evidence for interactions between food- and light-entrainable circadian clocks and rhythms and demonstrate the utility of the BTBR mouse model in probing these interactions.

Thermoregulatory significance of immobility in the forced swim test.

The forced swim test (FST) is a widely used animal model of depression and antidepressant drug screen. Rats are forced to swim on two test days in a restricted space from which there is no escape. On the first test day the rats attempt to escape and then become largely immobile; on the second test day the onset of immobility is more rapid. Immobility is said to reflect a state of lowered mood or "behavioral despair", but the validity of the FST as a model of depression has been questioned. We show here that whatever psychological states the FST may induce, immobility is water temperature dependent and thermoregulatory. In Experiment 1, separate groups of rats were first tested in water of 15, 20, 22, 25, 30, 35, 37, or 40 °C. When retested at the same temperature, reduced activity was evident only in those groups tested above 20 °C and below 37 °C. On a third test, rats previously tested in 35 °C water failed to show reduced activity in 15 °C water, whereas rats previously tested at 15 °C water did exhibit reduced activity when tested in 35 °C water. Thus, activity was dependent on current water temperature rather than prior experience. In Experiment 2, activity and body temperature were monitored during 30 min swim tests in 27 °C water. The more the animals moved, the greater the loss of body temperature. The results are consistent with a hypothesis that immobility in the FST is an adaptive thermoregulatory response that increases survival by minimizing convective heat loss. This interpretation is also aligned with best practices for survival of humans in water that is below thermoneutral.

Mice hypomorphic for Pitx3 show robust entrainment of circadian behavioral and metabolic rhythms to scheduled feeding.

Pitx3ak mice lack a functioning retina and develop fewer than 10% of dopamine neurons in the substantia nigra. Del Río-Martín et al. (2019) reported that entrainment of circadian rhythms to daily light-dark (LD) cycles is absent in these mice, and that rhythms of locomotor activity, energy expenditure, and other metabolic variables are disrupted with food available ad libitum and fail to entrain to a daily feeding. The authors propose that retinal innervation of the suprachiasmatic nucleus is required for development of cyclic metabolic homeostasis, but methodological issues limit interpretation of the results. Using standardized feeding schedules and procedures for distinguishing free-running from entrained circadian rhythms, we confirm that behavioral and metabolic rhythms in Pitx3ak mice do not entrain to LD cycles, but we find no impairment in circadian organization of metabolism with food available ad libitum and no impairment in entrainment of metabolic or behavioral rhythms by daily feeding schedules. This Matters Arising paper is in response to Del Río-Martín et al. (2019), published in Cell Reports. See also the response by Fernandez-Perez et al. (2022), published in this issue.

Impact of COVID-19 social-distancing on sleep timing and duration during a university semester.

Social-distancing directives to contain community transmission of the COVID-19 virus can be expected to affect sleep timing, duration or quality. Remote work or school may increase time available for sleep, with benefits for immune function and mental health, particularly in those individuals who obtain less sleep than age-adjusted recommendations. Young adults are thought to regularly carry significant sleep debt related in part to misalignment between endogenous circadian clock time and social time. We examined the impact of social-distancing measures on sleep in young adults by comparing sleep self-studies submitted by students enrolled in a university course during the 2020 summer session (entirely remote instruction, N = 80) with self-studies submitted by students enrolled in the same course during previous summer semesters (on-campus instruction, N = 452; cross-sectional study design). Self-studies included 2-8 week sleep diaries, two chronotype questionnaires, written reports, and sleep tracker (Fitbit) data from a subsample. Students in the 2020 remote instruction semester slept later, less efficiently, less at night and more in the day, but did not sleep more overall despite online, asynchronous classes and ~44% fewer work days compared to students in previous summers. Subjectively, the net impact on sleep was judged as positive or negative in equal numbers of students, with students identifying as evening types significantly more likely to report a positive impact, and morning types a negative impact. Several features of the data suggest that the average amount of sleep reported by students in this summer course, historically and during the 2020 remote school semester, represents a homeostatic balance, rather than a chronic deficit. Regardless of the interpretation, the results provide additional evidence that social-distancing measures affect sleep in heterogeneous ways.

Light in the Senior Home: Effects of Dynamic and Individual Light Exposure on Sleep, Cognition, and Well-Being.

Disrupted sleep is common among nursing home patients and is associated with cognitive decline and reduced well-being. Sleep disruptions may in part be a result of insufficient daytime light exposure. This pilot study examined the effects of dynamic "circadian" lighting and individual light exposure on sleep, cognitive performance, and well-being in a sample of 14 senior home residents. The study was conducted as a within-subject study design over five weeks of circadian lighting and five weeks of conventional lighting, in a counterbalanced order. Participants wore wrist accelerometers to track rest-activity and light profiles and completed cognitive batteries (National Institute of Health (NIH) toolbox) and questionnaires (depression, fatigue, sleep quality, lighting appraisal) in each condition. We found no significant differences in outcome variables between the two lighting conditions. Individual differences in overall (indoors and outdoors) light exposure levels varied greatly between participants but did not differ between lighting conditions, except at night (22:00-6:00), with maximum light exposure being greater in the conventional lighting condition. Pooled data from both conditions showed that participants with higher overall morning light exposure (6:00-12:00) had less fragmented and more stable rest-activity rhythms with higher relative amplitude. Rest-activity rhythm fragmentation and long sleep duration both uniquely predicted lower cognitive performance.

Food anticipatory circadian rhythms in mice entrained to long or short day photoperiods.

Food anticipatory activity (FAA) rhythms that emerge in nocturnal rodents fed once daily are mediated by food-entrainable circadian oscillators (FEOs) located outside of the suprachiasmatic nucleus (SCN), the site of a circadian pacemaker required for entrainment to daily light-dark (LD) cycles. Specification of the neural and molecular substrates of FEOs driving FAA is complicated by homeostatic, hedonic and environmental factors that can modulate expression of activity independent of circadian timing. Here, we examined the effect of photoperiod (duration of the daily light period) on FAA in mice fed during the last 4 h or middle 4 h of the light period for at least 5 weeks. Long photoperiods decrease SCN pacemaker amplitude, which may favor expression of FAA during the day, when the SCN normally opposes activity in nocturnal rodents. To test this prediction, in Experiment 1, mice housed with or without running discs were entrained to 24 h LD cycles with 8 h (L8) or 16 h (L16) photoperiods. When food was restricted to the last 4 h of the light period (late-day), mice housed with running discs showed more FAA in L16, whereas mice without running discs showed more FAA in L8. In Experiment 2, mice were entrained to L8 or L16 photoperiods, and the 4 h daily meal was centered in the light period (mid-day). FAA was decreased relative to late-day fed mice, but did not vary by photoperiod. In Experiment 3, mice with or without running discs were entrained to L12 or L18 photoperiods, with mealtime centered in the light period. FAA again did not differ between photoperiods. In constant dark (DD) prior to food restriction, the period (τ) of free-running rhythms was shorter in mice entrained to long days. This known after-effect of photoperiod on τ was absent in DD immediately following restricted feeding. The phase of LD entrainment, unmasked on the first day of DD with food ad-libitum, was significantly advanced in mice from the late-day feeding schedule, compared to mice from the mid-day schedules. These results indicate that FAA in mice does not vary systematically with photoperiod, possibly because daytime feeding schedules attenuate the effect of photoperiod on the mouse SCN pacemaker. FAA in the present study was more strongly influenced by running disc availability and by meal time within the light period, possibly due to effects on LD entrainment, which was phase advanced by late-day but not midday feeding.

Food as circadian time cue for appetitive behavior.

Feeding schedules entrain circadian clocks in multiple brain regions and most peripheral organs and tissues, thereby synchronizing daily rhythms of foraging behavior and physiology with times of day when food is most likely to be found. Entrainment of peripheral clocks to mealtime is accomplished by multiple feeding-related signals, including absorbed nutrients and metabolic hormones, acting in parallel or in series in a tissue-specific fashion. Less is known about the signals that synchronize circadian clocks in the brain with feeding time, some of which are presumed to generate the circadian rhythms of food-anticipatory activity that emerge when food is restricted to a fixed daily mealtime. In this commentary, I consider the possibility that food-anticipatory activity rhythms are driven or entrained by circulating ghrelin, ketone bodies or insulin. While evidence supports the potential of these signals to participate in the induction or amount of food-anticipatory behavior, it falls short of establishing either a necessary or sufficient role or accounting for circadian properties of anticipatory rhythms. The availability of multiple, circulating signals by which circadian oscillators in many brain regions might entrain to mealtime has supported a view that food-anticipatory rhythms of behavior are mediated by a broadly distributed system of clocks. The evidence, however, does not rule out the possibility that multiple peripheral and central food-entrained oscillators and feeding-related signals converge on circadian oscillators in a defined location which ultimately set the phase and gate the expression of anticipatory activity rhythms. A candidate location is the dorsal striatum, a core component of the neural system which mediates reward, motivation and action and which contains circadian oscillators entrainable by food and dopaminergic drugs. Systemic metabolic signals, such as ghrelin, ketones and insulin, may participate in circadian food anticipation to the extent that they modulate dopamine afferents to circadian clocks in this area.

Circadian misalignment impairs ability to suppress visual distractions.

Evening-type individuals often perform poorly in the morning because of a mismatch between internal circadian time and external social time, a condition recognized as social jet lag. Performance impairments near the morning circadian (~24 hr) trough have been attributed to deficits in attention, but the nature of the impairment is unknown. Using electrophysiological indices of attentional selection (N2pc) and suppression (PD ), we show that evening-type individuals have a specific disability in suppressing irrelevant visual distractions. More specifically, evening-type individuals managed to suppress a salient distractor in an afternoon testing session, as evidenced by a PD , but were less able to suppress the distractor in a morning testing session, as evidenced by an attenuated PD and a concomitant distractor-elicited N2pc. Morning chronotypes, who would be well past their circadian trough at the time of testing, did not show this deficit at either test time. These results indicate that failure to filter out irrelevant stimuli at an early stage of perceptual processing contributes to impaired cognitive functioning at nonoptimal times of day and may underlie real-world performance impairments, such as distracted driving, that have been associated with circadian mismatch.

Sleep timing and duration in indigenous villages with and without electric lighting on Tanna Island, Vanuatu.

It has been hypothesized that sleep in the industrialized world is in chronic deficit, due in part to evening light exposure, which delays sleep onset and truncates sleep depending on morning work or school schedules. If so, societies without electricity may sleep longer. However, recent studies of hunter-gatherers and pastoralists living traditional lifestyles without electricity report short sleep compared to industrialized population norms. To further explore the impact of lifestyles and electrification on sleep, we measured sleep by actigraphy in indigenous Melanesians on Tanna Island, Vanuatu, who live traditional subsistence horticultural lifestyles, in villages either with or without access to electricity. Sleep duration was long and efficiency low in both groups, compared to averages from actigraphy studies of industrialized populations. In villages with electricity, light exposure after sunset was increased, sleep onset was delayed, and nocturnal sleep duration was reduced. These effects were driven primarily by breastfeeding mothers living with electric lighting. Relatively long sleep on Tanna may reflect advantages of an environment in which food access is reliable, climate benign, and predators and significant social conflict absent. Despite exposure to outdoor light throughout the day, an effect of artificial evening light was nonetheless detectable on sleep timing and duration.

Delayed daily activity and reduced NREM slow-wave power in the APPswe/PS1dE9 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is associated with disrupted circadian rhythms and sleep, which are thought to reflect an impairment of internal circadian timekeeping that contribute to clinical symptoms and disease progression. To evaluate these hypotheses, a suitable preclinical model of AD is needed. We performed a comprehensive assessment of circadian rhythms and sleep in the APPswe/PS1dE9 (APP/PS1) mouse model using long-term in vivo electroencephalogram (EEG) monitoring and behavioral assays from 5 to 22 months of age. APP/PS1 mice were crossed with a PERIOD2::LUCIFERASE (PER2::LUC) mouse model to evaluate synchrony among peripheral circadian oscillators. The APP/PS1 mice exhibited a mild but persistent phase delay of nocturnal activity onset in 12:12h light:dark conditions, as well as a shift toward higher frequencies in the EEG power spectra compared to littermate controls. Our results suggest that APP/PS1 mice may not be the optimal preclinical model for studying the specific circadian changes associated with AD but that quantitative EEG may offer a sensitive measure of AD-associated changes in sleep quality that can be modeled in APP/PS1 mice.

Midday meals do not impair mouse memory.

Nocturnal mice fed in the middle of the light period exhibit food anticipatory rhythms of behavior and physiology under control of food-entrainable circadian clocks in the brain and body. This is presumed to be adaptive by aligning behavior and physiology with predictable mealtimes. This assumption is challenged by a report that daytime feeding schedules impair cognitive processes important for survival, including object memory and contextual fear conditioning assessed at two times of day. To further evaluate these effects, mice were restricted to a 6 h daily meal in the middle of the light or dark period and object memory was tested at four times of day. Object memory was not impaired by daytime feeding, and did not exhibit circadian variation in either group. To determine whether impairment might depend on methodology, experimental procedures used previously to detect impairment were followed. Daytime feeding induced food anticipatory rhythms and shifted hippocampal clock genes, but again did not impair object memory. Spontaneous alternation and contextual fear conditioning were also not impaired. Hippocampal memory function appears more robust to time of day and daytime feeding schedules than previously reported; day-fed mice can remember what they have seen, where they have been, and where it is dangerous.

Feeding Time Entrains the Olfactory Bulb Circadian Clock in Anosmic PER2::LUC Mice.

Circadian rhythms in many brain regions and peripheral organs can be entrained by daily feeding schedules. The set of feeding-related signals that entrain peripheral clocks are tissue specific and include nutrients, metabolic hormones and temperature. Signals that entrain neural circadian clocks to mealtime have yet to be established for any brain region. The olfactory bulb (OB) contains a robust circadian clock that can cycle independently of the suprachiasmatic nucleus (SCN) master pacemaker. We used PER2::LUC mice to evaluate the suitability of the OB for analysis of inputs that mediate entrainment of neural clocks by feeding schedules. Explants of SCN and OB from mice fed ad-libitum exhibited robust circadian rhythms of bioluminescence for three or more days in vitro, with rhythm peaks occurring late in the day and night, respectively. Mice restricted to a 4 h meal/day in the light period exhibited food anticipatory activity and a 6.3 h advance of the OB PER2::LUC rhythm. The cumulative phase shift of the OB rhythm increased gradually in OB explants harvested after 2-7 days of restricted feeding. In mice anosmic after nasal irrigation with zinc sulfate and fed ad-libitum for one week, OB phases were desynchronized. Group synchrony in anosmic mice was restored by restricted feeding. The OB circadian clock is food-entrainable, entrains gradually to a mid-day meal, and requires neither olfaction nor circadian signaling from olfactory sensory neurons. The OB can be used as a model system for analysis of input pathways by which circadian clocks in the brain entrain to daily mealtimes.

Interval Timing Is Preserved Despite Circadian Desynchrony in Rats: Constant Light and Heavy Water Studies.

The mechanisms that enable mammals to time events that recur at 24-h intervals (circadian timing) and at arbitrary intervals in the seconds-to-minutes range (interval timing) are thought to be distinct at the computational and neurobiological levels. Recent evidence that disruption of circadian rhythmicity by constant light (LL) abolishes interval timing in mice challenges this assumption and suggests a critical role for circadian clocks in short interval timing. We sought to confirm and extend this finding by examining interval timing in rats in which circadian rhythmicity was disrupted by long-term exposure to LL or by chronic intake of 25% D2O. Adult, male Sprague-Dawley rats were housed in a light-dark (LD) cycle or in LL until free-running circadian rhythmicity was markedly disrupted or abolished. The rats were then trained and tested on 15- and 30-sec peak-interval procedures, with water restriction used to motivate task performance. Interval timing was found to be unimpaired in LL rats, but a weak circadian activity rhythm was apparently rescued by the training procedure, possibly due to binge feeding that occurred during the 15-min water access period that followed training each day. A second group of rats in LL were therefore restricted to 6 daily meals scheduled at 4-h intervals. Despite a complete absence of circadian rhythmicity in this group, interval timing was again unaffected. To eliminate all possible temporal cues, we tested a third group of rats in LL by using a pseudo-randomized schedule. Again, interval timing remained accurate. Finally, rats tested in LD received 25% D2O in place of drinking water. This markedly lengthened the circadian period and caused a failure of LD entrainment but did not disrupt interval timing. These results indicate that interval timing in rats is resistant to disruption by manipulations of circadian timekeeping previously shown to impair interval timing in mice.

Sleep and hippocampal neurogenesis: Implications for Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia and currently there are no effective disease-modifying treatments available. Hallmark symptoms of AD include impaired hippocampus-dependent episodic memory and disrupted sleep and circadian rhythms. The pathways connecting these symptoms are of particular interest because it is well established that sleep and circadian disruption can impair hippocampus-dependent learning and memory. In rodents, these procedures also markedly suppress adult hippocampal neurogenesis, a form of brain plasticity that is believed to play an important role in pattern separation, and thus episodic memory. A causal role for sleep disruptions in AD pathophysiology is suggested by evidence for sleep-dependent glymphatic clearance of metabolic waste products from the brain. This review explores a complementary hypothesis that sleep and circadian disruptions in AD contribute to cognitive decline by activating neuroendocrine and neuroinflammatory signaling pathways that suppress hippocampal neurogenesis. Evidence for this hypothesis underscores the promise of sleep, circadian rhythms, and neurogenesis as therapeutic targets for remediation of memory impairment in AD.

Driving home from the night shift: a bright light intervention study.

Sleep deprivation (SD) impairs vigilance and increases the risk of driving accidents during the commute home after night work. Bright light (BL) can enhance alertness and cognitive performance. We examined the effects of BL (5600 lux) versus dim light (DL, 35 lux) at the end of a night awake on driving performance. METHODS: Subjects (N = 19, 22.8 ± 4 ya) completed three conditions, counterbalanced for order at >1 week intervals. The two overnight SD conditions began in the lab at usual bedtime. After six hours in DL, subjects were exposed to 45 min BL or continued DL, and then completed a 44 min driving test (two lap circuit) in a high fidelity simulator. In the rested condition, subjects slept at home until habitual wakeup time, were transported to the lab and ∼45 min after wakeup, received BL and then the driving test. RESULTS: Oral temperature decreased while reaction time and sleepiness increased across both SD nights. BL suppressed salivary melatonin but had little or no effect on sleepiness or reaction time. SD markedly increased incidents and accidents. Five subjects (26%) sustained a terminal accident (eg, car flip) in the SD-DL condition, but none did so in the SD-BL or rested-BL conditions. Compared to SD-DL, SD-BL was associated with fewer incidents and accidents overall, and with better performance on the second lap of the circuit on several performance measures. CONCLUSION: BL at the end of a night shift may have potential as a countermeasure to improve driving following night work.

Organisational characteristics associated with shift work practices and potential opportunities for intervention: findings from a Canadian study.

INTRODUCTION: Shift work is a common working arrangement with wide-ranging implications for worker health. Organisational determinants of shift work practices are not well characterised; such information could be used to guide evidence-based research and best practices to mitigate shift work's negative effects. This exploratory study aimed to describe and assess organisational-level determinants of shift work practices thought to affect health, across a range of industry sectors. METHODS: Data on organisational characteristics, shift work scheduling, provision of shift work education materials/training to employees and night-time lighting policies in the workplace were collected during phone interviews with organisations across the Canadian province of British Columbia. Relationships between organisational characteristics and shift work practices were assessed using multivariable logistic regression models. RESULTS: The study sample included 88 participating organisations, representing 30 700 shift workers. Long-duration shifts, provision of shift work education materials/training to employees and night-time lighting policies were reported by approximately one-third of participating organisations. Odds of long-duration shifts increased in larger workplaces and by industry. Odds of providing shift work education materials/training increased in larger workplaces, in organisations reporting concern for shift worker health and in organisations without seasonal changes in shift work. Odds of night-time lighting policies in the workplace increased in organisations reporting previous workplace accidents or incidents that occurred during non-daytime hours, site maintenance needs and client service or care needs. CONCLUSIONS: This study points to organisational determinants of shift work practices that could be useful for targeting research and workplace interventions. Results should be interpreted as preliminary in an emerging body of literature on shift work and health.

Circadian time-place (or time-route) learning in rats with hippocampal lesions.

Circadian time-place learning (TPL) is the ability to remember both the place and biological time of day that a significant event occurred (e.g., food availability). This ability requires that a circadian clock provide phase information (a time tag) to cognitive systems involved in linking representations of an event with spatial reference memory. To date, it is unclear which neuronal substrates are critical in this process, but one candidate structure is the hippocampus (HPC). The HPC is essential for normal performance on tasks that require allocentric spatial memory and exhibits circadian rhythms of gene expression that are sensitive to meal timing. Using a novel TPL training procedure and enriched, multidimensional environment, we trained rats to locate a food reward that varied between two locations relative to time of day. After rats acquired the task, they received either HPC or SHAM lesions and were re-tested. Rats with HPC lesions were initially impaired on the task relative to SHAM rats, but re-attained high scores with continued testing. Probe tests revealed that the rats were not using an alternation strategy or relying on light-dark transitions to locate the food reward. We hypothesize that transient disruption and recovery reflect a switch from HPC-dependent allocentric navigation (learning places) to dorsal striatum-dependent egocentric spatial navigation (learning routes to a location). Whatever the navigation strategy, these results demonstrate that the HPC is not required for rats to find food in different locations using circadian phase as a discriminative cue.

A sex difference in circadian food-anticipatory rhythms in mice: Interaction with dopamine D1 receptor knockout.

Restricted daily feeding schedules induce circadian rhythms of food-anticipatory activity (FAA) in mice and other species. The entrainment pathway(s) and location(s) of circadian oscillators driving these rhythms have not been definitively established. An important role for dopamine signaling and the dorsal striatum is suggested by a confluence of observations, including shifting of FAA rhythms by dopamine receptor agonists and attenuation by antagonists and D1 receptor knockout (D1R KO). The dopamine reward system exhibits sexual dimorphisms in structure and function; if FAA rhythms are regulated by this system, then FAA may also be sexually dimorphic. To assess this prediction, disk running and general activity were recorded continuously in male and female C57BL/6J mice with food available ad libitum and then restricted to a 4-hr daily meal in the middle of the light period. Compared with male mice, FAA in female mice was significantly reduced in duration, total count, peak level, and ratio relative to nocturnal activity. To determine whether these differences were mediated by D1 receptors, male and female homozygous D1R KO mice were examined. Compared with wild type and heterozygous mice, female and male D1R KO mice exhibited a marked attenuation of FAA parameters. The magnitude of the attenuation was greater in female mice. These results confirm an important role for dopamine D1 receptors in the circadian mechanism by which mice anticipate a daily meal, and they reveal a previously unreported sexual dimorphism in the expression of food-anticipatory rhythms that is amplified by D1R KO.