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Circadian rhythms are endogenous biological cycles that regulate physiology and behavior for optimal adaptive function and survival; they are synchronized to precisely 24 hours by daily light exposure. Disruption of the daily light-dark (LD) cycle by exposure to artificial light at night (ALAN) dysregulates core clock genes and biological function. Exposure to ALAN has been associated with increased health risks in humans, and elderly individuals are at elevated risk for poor outcome from disease and often experience elevated exposure to ALAN due to increased care requirements. The role of disrupted circadian rhythms in healthy, aged animals remains unspecified; thus, we hypothesized that disrupted circadian rhythms via chronic exposure to dim ALAN (dLAN) impair immune response and survival in aged mice. Twenty-month-old C57BL/6 male and female mice were exposed to 24 weeks of LD conditions or dLAN (5 lux); then, cell-mediated immune response was assessed using a delayed-type hypersensitivity test. Aged female mice exposed to dLAN displayed dysregulated hypersensitivity and inflammation as a measure of cell-mediated immune response and decreased lifespan compared to females housed in dark nights. Nighttime lighting did not affect cell-mediated immune response or lifespan in males but dysregulated body mass and increased adrenal mass after immune challenge after chronic exposure to dLAN. Together, these data indicate that chronic exposure to dLAN affects lifespan in aged females and suggest that females are more susceptible to the detrimental consequences of disrupted circadian rhythms.

Disruption of circadian rhythms has detrimental host consequences. Indeed, both clinical and foundational science demonstrate a clear relationship between disruption of circadian rhythms and cancer initiation and progression. Because timing of food intake can act as a zeitgeber (i.e., entrainment signal) for the circadian clock, and most individuals in the developed world have access to food at all times of the day in a “24/7” society, we sought to determine the effects of timing of food intake on mammary tumor growth. We hypothesized that restricting access to food to during the inactive phase would accelerate tumor growth. Adult female Balb/C mice received a unilateral orthotopic injection of murine mammary carcinoma 4T1 cells into the ninth inguinal mammary gland. Beginning on the day of tumor injection and continuing until the end of the experiment, mice were food restricted to their active phase (ZT12 (lights off)- ZT0 (lights on), inactive phase (ZT0 - ZT12), or had ad libitum access to food. Mice that were food restricted to their inactive phase displayed a significant increase in body mass on days 7 and 14 of tumor growth relative to active phase or ad libitum fed mice. Additionally, mice fed during their inactive phase demonstrated a 20% reduction in food consumption relative to mice fed during their active phase and a 17% reduction in food consumption relative to ab libitum fed mice. Tumor volume was not significantly different between groups. However, food restricting mice to their inactive phase increased mammary tumor growth efficiency (i.e., mg of tumor mass per gram of food intake) relative to mice fed during the active phase and approached significance (p=0.06) relative to ad libitum fed mice. To determine a potential explanation for the increased tumor growth efficiency, we examined rhythms of activity and body temperature. Mice fed during the inactive phase displayed significantly disrupted daily activity and body temperature rhythms relative to both other feeding regimens. Together, these data demonstrate that improperly timed food intake can have detrimental consequences on mammary tumor growth likely via disrupted circadian rhythms.

The suprachiasmatic nucleus (SCN) contains a pacemaker that generates circadian rhythms and entrains them with the 24-h light-dark cycle (LD). The SCN is composed of 16,000 to 20,000 heterogeneous neurons in bilaterally paired nuclei. γ-amino butyric acid (GABA) is the primary neurochemical signal within the SCN and plays a key role in regulating circadian function. While GABA is the primary inhibitory neurotransmitter in the brain, there is now evidence that GABA can also exert excitatory effects in the adult brain. Cation chloride cotransporters determine the effects of GABA on chloride equilibrium, thereby determining whether GABA produces hyperpolarizing or depolarizing actions following activation of GABAA receptors. The activity of Na-K-2Cl cotransporter1 (NKCC1), the most prevalent chloride influx cotransporter isoform in the brain, plays a critical role in determining whether GABA has depolarizing effects. In the present study, we tested the hypothesis that NKCC1 protein expression in the SCN is regulated by environmental lighting and displays daily and circadian changes in the intact circadian system of the Syrian hamster. In hamsters housed in constant light (LL), the overall NKCC1 immunoreactivity (NKCC1-ir) in the SCN was significantly greater than in hamsters housed in LD or constant darkness (DD), although NKCC1 protein levels in the SCN were not different between hamsters housed in LD and DD. In hamsters housed in LD cycles, no differences in NKCC1-ir within the SCN were observed over the 24-h cycle. NKCC1 protein in the SCN was found to vary significantly over the circadian cycle in hamsters housed in free-running conditions. Overall, NKCC1 protein was greater in the ventral SCN than in the dorsal SCN, although no significant differences were observed across lighting conditions or time of day in either subregion. These data support the hypothesis that NKCC1 protein expression can be regulated by environmental lighting and circadian mechanisms within the SCN.

Circadian rhythms are internal manifestations of the solar day that permit adaptations to predictable environmental temporal changes. These ~24-h rhythms are controlled by molecular clockworks within the brain that are reset daily to precisely 24 h by exposure to the light–dark cycle. Information from the master clock in the mammalian hypothalamus conveys temporal information to the entire body via humoral and neural communication. A bidirectional relationship exists between mood disorders and circadian rhythms. Mood disorders are often associated with disrupted circadian clock-controlled responses, such as sleep and cortisol secretion, whereas disruption of circadian rhythms via jet lag, night-shift work, or exposure to artificial light at night, can precipitate or exacerbate affective symptoms in susceptible individuals. Evidence suggests strong associations between circadian rhythms and mental health, but only recently have studies begun to discover the direct interactions between the circadian system and mood regulation. This review provides an overview of disrupted circadian rhythms and the relationship to behavioral health and psychiatry. The focus of this review is delineating the role of disruption of circadian rhythms on mood disorders using human night shift studies, as well as jet lag studies to identify links. We also review animal models of disrupted circadian rhythms on affective responses. Lastly, we propose low-cost behavioral and lifestyle changes to improve circadian rhythms and presumably behavioral health.

During the evolution of life, the temporal rhythm of our rotating planet was internalized in the form of circadian rhythms. Circadian rhythms are ~24h internal manifestations that drive daily patterns of physiology and behavior. These rhythms are entrained (synchronized) to the external environment, primarily by the light-dark cycle, and precisely controlled via molecular clocks located within the suprachiasmatic nucleus of the hypothalamus. Misalignment and/or disruption of circadian rhythms can have detrimental consequences for human health. Indeed, studies suggest strong associations between mental health and circadian rhythms. However, direct interactions between mood regulation and the circadian system are just beginning to be uncovered and appreciated. This chapter examines the relationship between disruption of circadian rhythms and mental health. The primary focus will be outlining the association between circadian disruption, in the form of night shift work, exposure to light at night, jet lag, and social jet lag, and psychiatric illness (i.e., anxiety, major depressive disorder, bipolar disorder, and schizophrenia). Additionally, we review animal models of disrupted circadian rhythms, which provide further evidence in support of a strong association between circadian disruption and affective responses. Finally, we discuss future directions for the field and suggest areas of study that require further investigation.

During the evolution of life, the temporal rhythm of our rotating planet was internalized in the form of circadian rhythms. Circadian rhythms are ~24h internal manifestations that drive daily patterns of physiology and behavior. These rhythms are entrained (synchronized) to the external environment, primarily by the light-dark cycle, and precisely controlled via molecular clocks located within the suprachiasmatic nucleus of the hypothalamus. Misalignment and/or disruption of circadian rhythms can have detrimental consequences for human health. Indeed, studies suggest strong associations between mental health and circadian rhythms. However, direct interactions between mood regulation and the circadian system are just beginning to be uncovered and appreciated. This chapter examines the relationship between disruption of circadian rhythms and mental health. The primary focus will be outlining the association between circadian disruption, in the form of night shift work, exposure to light at night, jet lag, and social jet lag, and psychiatric illness (i.e., anxiety, major depressive disorder, bipolar disorder, and schizophrenia). Additionally, we review animal models of disrupted circadian rhythms, which provide further evidence in support of a strong association between circadian disruption and affective responses. Finally, we discuss future directions for the field and suggest areas of study that require further investigation.

Although much has been learned about circadian clocks and rhythms over the past few decades, translation of this foundational science underlying the temporal regulation of physiology and behavior to clinical applications has been slow. Indeed, acceptance of the modern study of circadian rhythms has been blunted because the phenomenology of cyclic changes had to counteract the 20th century dogma of homeostasis in the biological sciences and medicine. We are providing this review of clinical data to highlight the emerging awareness of circadian variation in efficacy of medications for physicians, clinicians, and pharmacists. We are suggesting that gold-standard double-blind clinical studies should be conducted to determine the best time of day for optimal effectiveness of medications; also, we suggest that time of day should be tracked and reported as an important biological variable in ongoing clinical studies hereafter. Furthermore, we emphasize that time of day is, and should be considered, a key biological variable in research design similar to sex. In common with biomedical research data that have been historically strongly skewed toward the male sex, most pharmaceutical data have been skewed toward morning dosing without strong evidence that this is the optimal time of efficacy.

The growing presence of artificial lighting across the globe presents a number of challenges to human and ecological health despite its societal benefits. Exposure to artificial light at night, a seemingly innocuous aspect of modern life, disrupts behavior and physiological functions. Specifically, light at night induces neuroinflammation, which is implicated in neuropathic and nociceptive pain states, including hyperalgesia and allodynia. Because of its influence on neuroinflammation, we investigated the effects of dim light at night exposure on pain responsiveness in male mice. In this study, mice exposed to four days of dim (5 lux) light at night exhibited cold hyperalgesia. Further, after 28 days of exposure, mice exhibited both cold hyperalgesia and mechanical allodynia. No heat/hot hyperalgesia was observed in this experiment. Altered nociception in mice exposed to dim light at night was concurrent with upregulated interleukin-6 and nerve growth factor mRNA expression in the medulla and elevated μ-opioid receptor mRNA expression in the periaqueductal gray region of the brain. The current results support the relationship between disrupted circadian rhythms and altered pain sensitivity. In summary, we observed that dim light at night induces cold hyperalgesia and mechanical allodynia, potentially through elevated neuroinflammation and dysregulation of the endogenous opioid system.

Sex as a biological variable is the focus of much literature and has been emphasized by the National Institutes of Health, in part, to remedy a long history of male-dominated studies in preclinical and clinical research. We propose that time-of-day is also a crucial biological variable in biomedical research. In common with sex differences, time-of-day should be considered in analyses and reported to improve reproducibility of studies and to provide the appropriate context to the conclusions. Endogenous circadian rhythms are present in virtually all living organisms, including bacteria, plants, invertebrates, and vertebrates. Virtually all physiological and behavioral processes display daily fluctuations in optimal performance that are driven by these endogenous circadian clocks; importantly, many of those circadian rhythms also show sex differences. In this review, we describe some of the documented sex differences in circadian rhythms.

Artificial light at night (ALAN) is a pervasive phenomenon. Although initially assumed to be innocuous, recent research has demonstrated its deleterious effects on physiology and behavior. Exposure to ALAN is associated with disruptions to sleep/wake cycles, development of mood disorders, metabolic disorders, and cancer. However, the influence of ALAN on affective behavior in tumor-bearing mice has not been investigated. We hypothesize that exposure to ALAN accelerates mammary tumor growth and predict that ALAN exacerbates negative affective behaviors in tumor-bearing mice. Adult (&gt, 8 weeks) female C3H mice received a unilateral orthotropic injection of FM3A mouse mammary carcinoma cells (1.0 × 105 in 100 μL) into the fourth inguinal mammary gland. Nineteen days after tumor inoculation, mice were tested for sucrose preference (anhedonia-like behavior). The following day, mice were subjected to an open field test (anxiety-like behavior), followed by forced swim testing (depressive-like behavior). Regardless of tumor status, mice housed in ALAN increased body mass through the first ten days. Tumor-bearing ALAN-housed mice demonstrated reduced latency to tumor onset (day 5) and increased terminal tumor volume (day 21). Exposure to ALAN reduced sucrose preference independent of tumor status. Additionally, tumor-bearing mice housed in dark nights demonstrated significantly increased anxiety-like behavior that was normalized via housing in ALAN. Together, these data reaffirm the negative effects of ALAN on tumorigenesis and demonstrate the potential anxiolytic effect of ALAN in the presence of mammary tumors.

Although Syrian hamsters are thought to be naturally solitary, recent evidence from our laboratory demonstrates that hamsters may actually prefer social contact. Hamsters increase their preference for a location associated with an agonistic encounter regardless of whether they have "won" or "lost". It has also been reported that social housing as well as exposure to intermittent social defeat or to a brief footshock stressor increase food intake and body mass in hamsters. By contrast, it has also been suggested that housing hamsters in social isolation causes anxiety-induced anorexia and reductions in body mass selectively in females. The purpose of this study was to determine the physiological consequences of housing hamsters in social isolation versus in social groups. Male and female hamsters were housed singly or in stable groups of 5 for 4weeks after which they were weighed and trunk blood was collected. In addition, fat pads and thymus and adrenal glands were extracted and weighed. Serum and fecal cortisol were measured using an enzyme-linked immunoassay. Housing condition had no effect on serum or fecal cortisol, but socially housed hamsters displayed modest thymus gland involution. Socially housed females weighed more than did any other group, and socially housed females and males had more fat than did socially isolated hamsters. No wounding or tissue damage occurred in grouped hamsters. Overall, these data suggest that Syrian hamsters tolerate both stable social housing and social isolation in the laboratory although social housing is associated with some alteration in stress-related and bioenergetic measures.

Understanding the neurobiological mechanisms mediating dominance and competitive aggression is essential to understanding the development and treatment of various psychiatric disorders. Previous research suggests that these mechanisms are both sexually differentiated and influenced substantially by social experience. In numerous species, GABA(A) receptors in the lateral septum have been shown to play a significant role in aggression in males. However, very little is known about the role of these GABA(A) receptors in female aggression, the role of social experience on GABA(A) receptor mediated aggression, or the roles of different GABA(A) subtypes in regulating aggression. Thus, in the following set of experiments we determined the role of social experience in modulating GABA(A) receptor induced aggression in both male and female Syrian hamsters, with a particular focus on the GABA(A) receptor subtype mediating these effects. Activation of GABA(A) receptors in the dorsal lateral septum increased aggression in both males and females. Social housing, however, significantly decreased the ability of GABA(A) receptor activation to induce aggression in males but not females. No significant differences were observed in the effects of GABA(A) receptor activation in dominant and subordinate group housed hamsters. Finally, examination of potential GABA(A) receptor subtype specificity revealed that social housing decreased the ratio of extrasynaptic to synaptic subunit GABA(A) receptor mRNA expression in the anterior dorsal lateral septum. While activation of extrasynaptic, but not synaptic GABA(A) receptors in the dorsal lateral septum increased aggression. These data suggest that social experience can have profound effects on the neuronal mechanisms mediating aggression, especially in males, and that δ extrasynaptic GABA(A) receptors may be an important therapeutic target in disorders characterized by high levels of aggression.

For many individuals in industrialized nations, the widespread adoption of electric lighting has dramatically affected the circadian organization of physiology and behavior. Although initially assumed to be innocuous, exposure to artificial light at night (ALAN) is associated with several disorders, including increased incidence of cancer, metabolic disorders, and mood disorders. Within this review, we present a brief overview of the molecular circadian clock system and the importance of maintaining fidelity to bright days and dark nights. We describe the interrelation between core clock genes and the cell cycle, as well as the contribution of clock genes to oncogenesis. Next, we review the clinical implications of disrupted circadian rhythms on cancer, followed by a section on the foundational science literature on the effects of light at night and cancer. Finally, we provide some strategies for mitigation of disrupted circadian rhythms to improve health.

Over 90% of neurons within the suprachiasmatic nucleus (SCN) express γ-aminobutyric acid (GABA). Although GABA is primarily an inhibitory neurotransmitter, in vitro studies suggest that the activation of GABAA receptors (GABAAR) elicits excitation in the adult SCN. The ratio of excitatory to inhibitory responses to GABA depends on the balance of chloride influx by Na+-K+-Cl– cotransporter 1 (NKCC1) and chloride efflux by K+-Cl– cotransporters (KCCs). Excitatory responses to GABA can be blocked by inhibition of the inward chloride cotransporter, NKCC1, with the loop diuretic bumetanide. Here we investigated the role of NKCC1 activity in phase shifting the circadian pacemaker in response to photic and nonphotic signals in male Syrian hamsters housed in constant darkness. In the early subjective night (CT 13.5), injection of bumetanide into the SCN reduced light-induced phase delays. However, during the late subjective night (CT 19), bumetanide administration did not alter light-induced phase advances. Injection of bumetanide during the subjective day (CT 6) did not alter the phase of free-running circadian rhythms but attenuated phase advances induced by injection of the GABAAR agonist muscimol into the SCN. These data support the hypothesis that the excitatory effects of endogenously released GABA contribute to the ability of light to induce phase delays, thereby contributing to the most important function of the circadian system, its entrainment with the day-night cycle. Further, the finding that bumetanide inhibits the phase-advancing effects of muscimol during the subjective day supports the hypothesis that the excitatory responses to GABA also contribute to the ability of nonphotic stimuli to phase shift the circadian pacemaker.

Visual Abstract, Recent molecular studies suggest that the expression levels of δ and γ2 GABAA receptor (GABAAR) subunits regulate the balance between synaptic and extrasynaptic GABA neurotransmission in multiple brain regions. We investigated the expression of GABAAδ and GABAAγ2 and the functional significance of a change in balance between these subunits in a robust local GABA network contained within the suprachiasmatic nucleus of the hypothalamus (SCN). Muscimol, which can activate both synaptic and extrasynaptic GABAARs, injected into the SCN during the day phase advanced the circadian pacemaker, whereas injection of the extrasynaptic GABAA superagonist 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) had no effect on circadian phase. In contrast, injection of either THIP or muscimol during the night was sufficient to block the phase shifting effects of light. Gene expression analysis of the whole SCN revealed different temporal patterns in GABAAδ and GABAAγ2 mRNA expression. When examined across all subregions of the SCN, quantitative immunohistochemical analysis found no significant variations in GABAAδ protein immunoreactivity (IR) but did find significant variations in GABAAγ2 protein-IR in hamsters housed in either LD cycles or in constant darkness. Remarkably, significant interactions in the ratio of GABAAδ:GABAAγ2 subunits between lighting condition and circadian phase occurred only within one highly discrete anatomical area of the SCN; a region that functions as the input for lighting information from the retina. Taken together, these data support the hypothesis that the balance between synaptic and extrasynaptic GABAARs determines the functional response to GABA, and that this balance is differentially regulated in a region-specific manner.

Photoperiodism is a biological phenomenon, common among organisms living outside of the tropics, by which environmental day length is used to ascertain the time of year to engage in seasonally-appropriate adaptations. White-footed mice (Peromyscus leucopus) are small photoperiodic rodents which display a suite of adaptive winter responses to short day lengths mediated by the extended duration of nightly melatonin secretion. Exposure to short days alters hippocampal dendritic morphology, impairs spatial learning and memory, and impairs hippocampal long-term potentiation (LTP). To determine the role of melatonin in these photoperiod-induced alterations of behavioral, neuroanatomical, and neurophysiological processes in this species, we implanted male mice subcutaneously with melatonin or empty Silastic capsules and exposed them to long or short day lengths. After 10 weeks, mice were assessed for hippocampal LTP, tested for spatial learning and memory in the Barnes maze, and morphometric analysis of neurons in the hippocampus using Golgi staining. Extending the duration of melatonin exposure, by short-day exposure or via melatonin implants, impaired both Schaffer collateral LTP in the CA1 region of the hippocampus and spatial learning and memory, and altered neuronal morphology in all hippocampal regions. The current results demonstrate that chronic melatonin implants reproduce the effects of short days on the hippocampus and implicate melatonin signaling as a critical factor in day-length-induced changes in the structure and function of the hippocampus in a photoperiodic rodent.

Virtually every neuron within the suprachiasmatic nucleus (SCN) communicates via GABAergic signaling. The extracellular levels of GABA within the SCN are determined by a complex interaction of synthesis and transport, as well as synaptic and non-synaptic release. The response to GABA is mediated by GABAA receptors that respond to both phasic and tonic GABA release and that can produce excitatory as well as inhibitory cellular responses. GABA also influences circadian control through the exclusively inhibitory effects of GABAB receptors. Both GABA and neuropeptide signaling occur within the SCN, although the functional consequences of the interactions of these signals are not well understood. This review considers the role of GABA in the circadian pacemaker, in the mechanisms responsible for the generation of circadian rhythms, in the ability of non-photic stimuli to reset the phase of the pacemaker, and in the ability of the day-night cycle to entrain the pacemaker.

Many psychological disorders comprise a seasonal component. For instance, seasonal affective disorder (SAD) is characterized by depression during autumn and winter. Because hippocampal atrophy may underlie the symptoms of depression and depressive-like behaviors, one goal of this study was to determine whether short days also induce structural changes in the hippocampus using photoperiod responsive rodents--Siberian hamsters. Exposure to short days increases depressive-like responses (increased immobility in the forced swim test) in hamsters. Male hamsters were housed in either short (LD 8:16) or long days (LD 16:8) for 10 weeks and tested in the forced swim test. Brains were removed and processed for Golgi impregnation. HPA axis function may account for photoperiod-related changes in depressive-like responses. Thus, stress reactivity was assessed in another cohort of photoperiod-manipulated animals. Short days reduced soma size and dendritic complexity in the CA1 region. Photoperiod did not induce gross changes in stress reactivity, but an acute stressor disrupted the typical nocturnal peak in cortisol concentrations. These data reveal that immobility induced by exposure to short days is correlated with reduced CA1 cell complexity (and perhaps connectivity). This study is the first to investigate hippocampal changes in the context of short-day induced immobility and may be relevant for understanding psychological disorders with a seasonal component.

Species have been adapted to specific niches optimizing survival and reproduction; however, urbanization by humans has dramatically altered natural habitats. Artificial light at night (LAN), termed ‘light pollution’, is an often overlooked, yet increasing disruptor of habitats, which perturbs physiological processes that rely on precise light information. For example, LAN alters the timing of reproduction and activity in some species, which decreases the odds of successful breeding and increases the threat of predation for these individuals, leading to reduced fitness. LAN also suppresses immune function, an important proxy for survival. To investigate the impact of LAN in a species naive to light pollution in its native habitat, immune function was examined in Siberian hamsters derived from wild-caught stock. After four weeks exposure to dim LAN, immune responses to three different challenges were assessed: (i) delayed-type hypersensitivity (DTH), (ii) lipopolysaccharide-induced fever, and (iii) bactericide activity of blood. LAN suppressed DTH response and reduced bactericide activity of blood after lipopolysaccharide treatment, in addition to altering daily patterns of locomotor activity, suggesting that human encroachment on habitats via night-time lighting may inadvertently compromise immune function and ultimately fitness.

The global increase in the prevalence of obesity and metabolic disorders coincides with the increase of exposure to light at night (LAN) and shift work. Circadian regulation of energy homeostasis is controlled by an endogenous biological clock that is synchronized by light information. To promote optimal adaptive functioning, the circadian clock prepares individuals for predictable events such as food availability and sleep, and disruption of clock function causes circadian and metabolic disturbances. To determine whether a causal relationship exists between nighttime light exposure and obesity, we examined the effects of LAN on body mass in male mice. Mice housed in either bright (LL) or dim (DM) LAN have significantly increased body mass and reduced glucose tolerance compared with mice in a standard (LD) light/dark cycle, despite equivalent levels of caloric intake and total daily activity output. Furthermore, the timing of food consumption by DM and LL mice differs from that in LD mice. Nocturnal rodents typically eat substantially more food at night; however, DM mice consume 55.5% of their food during the light phase, as compared with 36.5% in LD mice. Restricting food consumption to the active phase in DM mice prevents body mass gain. These results suggest that low levels of light at night disrupt the timing of food intake and other metabolic signals, leading to excess weight gain. These data are relevant to the coincidence between increasing use of light at night and obesity in humans.

Seasonal changes in day length (i.e., photoperiod) provide animals with a reliable environmental cue to determine time of year, and many physiological changes occur in laboratory animals simply by extending or shortening day length. Male Siberian hamsters (Phodopus sungorus) housed in long summer-like day lengths have significantly elevated body and fat masses compared to short-day hamsters. Because others have demonstrated that the intestinal microbiota of humans and rodents promotes host adiposity, we hypothesized that photoperiod-induced changes in body and fat masses could be associated with changes in the microbial composition in the intestines. We used bacterial tag-encoded FLX amplicon pyrosequencing (bTEFAP) to assess microbial diversity in the cecal contents of hamsters; long days significantly increased the relative abundance of bacteria in the phylum Proteobacteria. This effect was primarily due to a significant increase in the abundance of the genus Citrobacter, with both the abundance of Proteobacteria and Citrobacter spp. significantly correlated with body mass and with inguinal fat mass. In general, the abundance of the Firmicutes phylum was inversely associated with body mass. These data indicate that the intestinal microbiota are responsive to changes in photoperiod and suggest that these changes may in part influence photoperiodic changes in body and fat masses.

Individuals are increasingly exposed to light at night. Exposure to constant light (LL) disrupts circadian rhythms of locomotor activity, body temperature, hormones, and the sleep-wake cycle in animals. Other behavioural responses to LL have been reported, but are inconsistent. The present experiment sought to determine whether LL produces changes in affective responses and whether behavioural changes are mediated by alterations in glucocorticoid concentrations. Relative to conspecifics maintained in a light/dark cycle (LD, 16:8 light/dark), male Swiss-Webster mice exposed to LL for three weeks increased depressive-like behavioural responses as evaluated by the forced swim test and sucrose anhedonia. Furthermore, providing a light escape tube reversed the effects of LL in the forced swim test. LL mice displayed reduced anxiety as evaluated by the open field and elevated-plus maze. Glucocorticoid concentrations were reduced in the LL group suggesting that the affective behavioural responses to LL are not the result of elevated corticosterone. Additionally, mice housed in LD with a clear tube displayed increased paired testes mass as compared to LL mice. Taken together, these data provide evidence that exposure to unnatural lighting can induce significant changes in affect, increasing depressive-like and decreasing anxiety-like responses.

The physiological link between neuropathic pain and depression remains unknown despite a high comorbidity between these two disorders. A mouse model of spared nerve injury (SNI) was used to test the hypothesis that nerve injury precipitates depression through the induction of inflammation in the brain, and that prior exposure to stress exacerbates the behavioral and neuroinflammatory consequences of nerve injury. As compared with sham surgery, SNI induced mechanical allodynia, and significantly increased depressive-like behavior. Moreover, SNI animals displayed increased interleukin-1beta (IL-1beta) gene expression within the frontal cortex and concurrent increases in the expression of glial fibrillary acidic protein (GFAP) within the periaqueductal grey (PAG). Additionally, exposure to chronic restraint stress for 2 weeks before SNI exacerbated mechanical allodynia and depressive-like behavior, and resulted in an increase in IL-1beta gene expression in the frontal cortex and brain-derived neurotrophic factor (BDNF) gene expression in PAG. Treatment with metyrapone (MET), a corticosteroid synthesis inhibitor, before stress eliminated deleterious effects of chronic stress on SNI. Finally, this study showed that interference with IL-1beta signaling, through administration of IL-1 receptor antagonist (IL-1ra), ameliorated the effects of neuropathic pain on depressive-like behavior. Taken together, these data suggest that peripheral nerve injury leads to increased cytokine expression in the brain, which in turn, contributes to the development of depressive-like behavior. Furthermore, stress can facilitate the development of depressive-like behavior after nerve injury by promoting IL-1beta expression.

The neuroanatomical characteristics of vasotocin (VT) and vasopressin (VP) systems have been described in numerous species from diverse vertebrate groups, including teleost fish. However, there are very few teleost species in which VT’s effects on social behavior have been established and the neural circuits associated with that regulation fully described. We have previously shown that VT inhibits social approach behaviors in goldfish via actions in the hindbrain. Here we further describe that primitive VT circuit, as well as others throughout the goldfish brain that might contribute to social regulation in this species. In particular, we highlight forebrain projections to the dorsal telencephalon that have not been described previously in any teleost, projections to limbic forebrain areas, most notably the medial division of the dorsal telencephalon and the ventral telencephalon, and midbrain projections to the optic tectum and torus semicircularis that have rarely been described. However, the most dense VT projection in goldfish is to the hindbrain, particularly to motor divisions of the vagal complex and to area postrema, which we argue might influence social approach behaviors through autonomic regulatory mechanisms. Because hindbrain VT projections are some of the most primitive in vertebrates, we suggest they might represent an ancestral mechanism through which VT influenced social behavior.

At its core, the polyvagal theory proposes that peptides affect simple social behaviors through influences on hindbrain autonomic processes. To test this mechanism, we compared the effects of fore- and hindbrain infusions of vasotocin (VT) on social approach behavior in goldfish. VT infusions into the 4th ventricle, which ink infusions verified did not move rostrally to the forebrain, inhibited social approach at a lower dose than did infusions into the 3rd ventricle, which did diffuse to the hindbrain. Thus, VT actions in the hindbrain appear to modulate this simple social behavior. We then identified a population of substance P (SP)-immunoreactive cells in the hindbrain that are encapsulated by putative VT terminals, and determined that those cells project to the periphery. Injecting SP peripherally, as with infusing VT centrally, inhibited social approach, and peripheral injections of an SP antagonist, but not central infusions, abolished the behavioral effects of central VT infusions. We therefore propose that VT inhibits social approach by activating SP cells in the hindbrain, which then induce changes in body state that feed back to the brain. Central VT infusions did not inhibit feeding, suggesting that this VT mechanism selectively affects appetitive social responses. Because VT projections to the hindbrain are highly conserved in vertebrates, influences on peripheral feedback processes like the one we have described in goldfish may reflect how VT affected simple social behaviors in ancestral vertebrates and thus preadapted members of this peptide family to play increasingly complex roles in social and emotional regulation in modern animals.

Arginine vasopressin (AVP) and related peptides affect social behaviors in numerous species, but AVP influences on human social functions have not yet been established. Here, we describe how intranasal AVP administration differentially affects social communication in men and women, and we propose a mechanism through which it may exert those influences. In men, AVP stimulates agonistic facial motor patterns in response to the faces of unfamiliar men and decreases perceptions of the friendliness of those faces. In contrast, in women, AVP stimulates affiliative facial motor patterns in response to the faces of unfamiliar women and increases perceptions of the friendliness of those faces. AVP also affected autonomic responsiveness to threatening faces and increased anxiety, which may underlie both communication patterns by promoting different social strategies in stressful contexts in men and women.

Melatonin is the principle hormonal product of the pineal gland. It is secreted with a robust daily rhythm, peaking near the middle of the night. During the daytime, concentrations remain very low, as exposure to light robustly suppresses its secretion. The regulation of melatonin by light is well-characterized, but an interesting feature of the daily melatonin rhythm is that its peak occurs near the middle of the night and then levels begin to drop hours before morning light exposure. The mechanism underlying the light-independent drop in melatonin during late night remains unspecified. Feedback control is one mechanism of hormone regulation, but no studies thus far have explored the possibility of such regulation in the pineal of white-footed mice (Peromyscus leucopus). The pineal gland and SCN express melatonin receptors, and melatonin regulates its own receptor density in the brain. We investigated the possibility of feedback control of melatonin by administering melatonin receptor antagonists to female white-footed mice and then measuring plasma melatonin concentrations. In the first experiment, we observed that luzindole, a dual MT1/MT2 receptor antagonist administered 1h after lights off, caused an increase in plasma melatonin both 1 and 2h later. In a second experiment, we did not observe a change in melatonin concentrations following injection of an antagonist specific for the MT2 subtype. These results suggest the possibility of feedback control of melatonin release, occurring preferentially through the MT1 receptor subtype.

The authors measured the effects of centrally infused peptides on social approach behaviors in goldfish (Carassius auratus), a social teleost. Vasotocin (VT) inhibited approach responses toward the visual stimuli of conspecifics in the absence of aggressive or sexual olfactory contextual cues in males, and a V1 receptor antagonist stimulated such responses, at least in males that were not highly social in baseline conditions, as did isotocin (IT). In the absence of social stimuli, VT did not affect activity, therefore indicating that the inhibition was not the result of nonspecific effects on arousal or motor functioning. These experiments indicate that VT and IT induce opposite effects on social approach responses in male goldfish and that endogenous VT, at least, is associated with levels of sociality.

This study was meant to analyze the neural control of the branchial muscles of the clam Mercenaria mercenaria. Gills isolated from the animal contract in re- sponse to 5-hydroxytryptamine (5HT), dopamine (DA), and acetylcholine (ACh); but the ACh contraction occurred only if the gills had been pretreated with the cholinesterase inhibitor eserine. The 5HT antagonists cyproheptadine and mianserin blocked the contractile effects of all of the ago- nists. However, gills exposed to the 5HT antagonists and eserine relaxed in response to ACh. The DA antagonist SCH-83566 inhibited the effects of DA, but had no effect on contractions induced by 5HT and ACh. The ACh antagonist hexamethonium inhibited both the excitatory and inhibitory effects of ACh, but had no effect on contractions induced by 5HT and DA. 5HT and DA in gill tissue were visualized by using immunohistochemistry. Within each gill filament are dorsoventral neurons running adjacent to the epithelium and containing immunoreactive 5HT and DA. A complex net- work of 5HT-positive fibers is associated with the septa, blood vessels, and muscles, whereas DA-positive fibers are restricted to the septa. We propose that 5HT is the excitatory transmitter to the gill muscles, and that DA and ACh exert their excitatory effects by stimulating 5HT motor nerves. ACh may also be an inhibitory transmitter of the muscles.

Photoperiodic organisms monitor environmental day length to engage in seasonally appropriate adaptions in physiology and behavior. Among these adaptations are changes in brain volume and neurogenesis, which have been well-described in multiple species of birds, yet few studies have described such changes in the brains of adult mammals. White-footed mice (Peromyscus leucopus) are an excellent species in which to investigate the effects of day length on adult hippocampal neurogenesis as males, in addition to having reduced hippocampal volume in short days with concomitant impairments in hippocampus-mediated behaviors, have photoperiod-dependent changes in olfactory bulb neurogenesis. We performed the current experiment to assess the effects of photoperiod on hippocampal neurogenesis longitudinally, using the thymidine analog BrdU at multiple time points across ten weeks of short day exposure. Compared to counterparts held in long day lengths, across the first eight weeks of short day exposure hippocampal neurogenesis was reduced. However, at ten weeks in short day lengths neurogenic levels in the hippocampus were elevated above those levels in mice held in long day lengths. The current findings are consistent with the natural photoperiodic cycle of hippocampal function in male white-footed mice, and may help to inform research on photoperiodic plasticity in neurogenesis and provide insight into how the complex interplay among the environment, genes, and adaptive responses to changing day lengths affects brain structure, function, and behavior at multiple levels.

Both nitric oxide (NO) and reactive oxygen species (ROS) generated by nNOS and NADPH oxidase (NOX), respectively, in the brain have been implicated in an array of behaviors ranging from learning and memory to social interactions. Although recent work has elucidated how these separate redox pathways regulate neural function and behavior, the interaction of these two pathways in the regulation of neural function and behavior remains unspecified. Toward this end, the p47phox subunit of NOX, and nNOS were deleted to generate double knockout mice that were used to characterize the behavioral outcomes of concurrent impairment of the NO and ROS pathways in the brain. Mice were tested in a battery of behavioral tasks to evaluate learning and memory, as well as social, affective, and cognitive behaviors. p47phox deletion did not affect depressive-like behavior, whereas nNOS deletion abolished it. Both p47phox and nNOS deletion singly reduced anxiety-like behavior, increased general locomotor activity, impaired spatial learning and memory, and impaired preference for social novelty. Deletion of both genes concurrently had synergistic effects to elevate locomotor activity, impair spatial learning and memory, and disrupt prepulse inhibition of acoustic startle. Although preference for social novelty was impaired in single knockouts, double knockout mice displayed elevated levels of preference for social novelty above that of wild type littermates. These data demonstrate that, depending upon modality, deletion of p47phox and nNOS genes have dissimilar, similar, or additive effects. The current findings provide evidence that the NOX and nNOS redox signaling cascades interact in the brain to affect both cognitive function and social behavior.

Summary Sleep is restorative, whereas reduced sleep leads to negative health outcomes, such as increased susceptibility to disease. Sleep deprivation tends to attenuate inflammatory responses triggered by infection or exposure to endotoxin, such as bacterial lipopolysaccharide (LPS). Previous studies have demonstrated that Siberian hamsters (Phodopus sungorus), photoperiodic rodents, attenuate LPS-induced fever, sickness behavior, and upstream pro-inflammatory gene expression when adapted to short day lengths. Here, we tested whether manipulation of photoperiod alters the suppressive effects of sleep deprivation upon cytokine gene expression after LPS challenge. Male Siberian hamsters were adapted to long (16 h light (L):8 h dark(D)) or short (8L:16D) photoperiods for >10 weeks, and deprived of sleep for 24 h using the multiple platform method or remained in their home cage. Hamsters received an i.p. injection of LPS or saline (control) 18 h after starting the protocol, and were killed 6 h later. LPS increased liver and hypothalamic interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF) gene expression compared to vehicle. Among LPS-challenged hamsters, sleep deprivation reduced IL-1 mRNA levels in liver and hypothalamus, but not TNF. IL-1 attenuation was independent of circulating baseline cortisol, which did not increase after sleep deprivation. Conversely, photoperiod altered baseline cortisol, but not pro-inflammatory gene expression in sleep-deprived hamsters. These results suggest that neither photoperiod nor glucocorticoids influence the suppressive effect of sleep deprivation upon LPS-induced inflammation.

We previously reported motor and non-motor enhancements in a mouse mutant with an inactivated Purkinje cell-specific gene, Pcp2(L7), that encodes a GoLoco domain-containing modulator of Gi/o protein-coupled receptors. Effects included elevated learning asymptote with repeated rotarod training, increased acquisition rate in tone-conditioned fear (TCF), and subtle male-specific changes in both acoustic startle habituation and pre-pulse inhibition. We have further analyzed this mutant strain for higher-order behavioral alterations this time with a focus on male-female differences, and here we report a sex-dependent anxiety-like phenotype: male mutants are less anxious, and female mutants more anxious, than same-sex wild-types. Similarly, the fear responses measured during the tone in TCF acquisition are decreased in male mutants and increased in female mutants relative to same-sex wild-types. Overall the dynamics of both acquisition and extinction of TCF is affected in mutants but memory was not affected. Mutants display normal sociability and do not differ from wild-types in the social novelty test; however, compositional analysis supports that both L7 genotype and sex contribute to these behaviors. These results provide direct evidence of higher-order behavioral functions of the cerebellum due to the unambiguous cerebellar specificity of Pcp2(L7) expression, and the lack of any confounding motor defects in the mutant. We attempt to synthesize these new data with what is previously known both about Pcp2(L7) and about the effects of sex and sex hormones on anxiety and fear behaviors: specifically, L7 is a bidirectional and sex-dependent damper that regulates the amplitude and/or rate of sensorimotor responses, potentially acting as a mood stabilizer.

In response to changing day lengths, small photoperiodic rodents have evolved a suite of adaptations to survive the energetic bottlenecks of winter. Among these adaptations are changes in metabolism, adiposity, and energy balance. Whereas hypothalamic and neuroendocrine regulation of these adaptations has been extensively studied, the impact of day length, and interaction of day length and stress, on the energy balance of neurons within the central nervous system remains unspecified. Thus, we exposed male Siberian hamsters (Phodopus sungorus) to either short or long day lengths for 14 weeks to induce the full suite of adaptive responses, exposed them to 4 h of restraint, and then measured relative mRNA expression in the hippocampus for low- and high-affinity glucocorticoid receptors (glucocorticoid receptor (GR), mineralocorticoid receptor (MR)), brain-derived neurotrophic factor (BDNF), and the neuron-specific glucose transporter GLUT3. Independent of photoperiod, restraint elevated plasma cortisol (CORT) concentrations and reduced expression of GR, MR, and BDNF. Neither restraint nor photoperiod significantly altered GLUT3 expression. Among all groups, plasma cortisol concentrations were negatively correlated with GR and MR expression. MR, BDNF, and GLUT3 levels were positively correlated with one another, even when controlling for photoperiod and CORT. Taken together, these results suggest that, as peripheral energy balance changes across day length in this photoperiodic species, the neurons of the hippocampus do not alter relative gene expression levels of three proteins involved in monitoring neuronal glucose regulation and morphology.

a b s t r a c t Photoperiodism is a biological phenomenon in which environmental day length is monitored to ascertain time of year to engage in seasonally appropriate adaptations. This trait is common among organisms living outside of the tropics. White-footed mice (Peromyscus leucopus) are small photoperiodic rodents which display a suite of adaptive responses to short day lengths, including reduced hippocampal volume, impairments in hippocampal-mediated memory, and enhanced hypothalamic-pituitary-adrenal axis reactivity. Because these photoperiodic changes in brain and behavior mirror some of the etiology of post-traumatic stress disorder (PTSD), we hypothesized that photoperiod may also alter fear memory and neuronal morphology within the hippocampus–basolateral amygdala–prefrontal cortex fear circuit. Ten weeks of exposure to short days increased fear memory in an auditory-cued fear conditioning test. Short days also increased dendritic spine density of the neurons of the basolateral amygdala, without affecting morphology of pyramidal neurons within the infralimbic region of the medial prefrontal cortex. Taken together, photoperiodic phenotypic changes in brain morphology and physiology induced by a single environmental factor, exposure to short day lengths, affect responses to fearful stimuli in white-footed mice. These results have potential implications for understanding seasonal changes in fear responsiveness, as well as for expanding translational animal models for studying gene–environment interactions underlying psychiatric diseases, such as PTSD.

Brain plasticity, in relation to new adult mammalian neurons generated in the subgranular zone of the hippocampus, has been well described. However, the functional outcome of new adult olfactory neurons born in the subventricular zone of the lateral ventricles is not clearly defined, as manipulating neurogenesis through various methods has given inconsistent and conflicting results in lab mice. Several small rodent species, including Peromyscus leucopus, display seasonal (photoperiodic) brain plasticity in brain volume, hippocampal function, and hippocampus-dependent behaviors; plasticity in the olfactory system of photoperiodic rodents remains largely uninvestigated. We exposed adult male P. leucopus to long day lengths (LD) and short day lengths (SD) for 10 to 15 weeks and then examined olfactory bulb cell proliferation and survival using the thymidine analog BrdU, olfactory bulb granule cell morphology using Golgi-Cox staining, and behavioral investigation of same-sex conspecific urine. SD mice did not differ from LD counterparts in granular cell morphology of the dendrites or in dendritic spine density. Although there were no differences due to photoperiod in habituation to water odor, SD mice rapidly habituated to male urine, whereas LD mice did not. In addition, short day induced changes in olfactory behavior were associated with increased neurogenesis in the caudal plexiform and granule cell layers of the olfactory bulb, an area known to preferentially respond to water-soluble odorants. Taken together, these data demonstrate that photoperiod, without altering olfactory bulb neuronal morphology, alters olfactory bulb neurogenesis and olfactory behavior in Peromyscus leucopus.

Adult mammalian brains are capable of some structural plasticity. Although the basic cellular mechanisms underlying learning and memory are being revealed, extrinsic factors contributing to this plasticity remain unspecified. White-footed mice ( Peromyscus leucopus ) are particularly well suited to investigate brain plasticity because they show marked seasonal changes in structure and function of the hippocampus induced by a distinct environmental signal, viz., photoperiod (i.e. the number of hours of light/day). Compared to animals maintained in 16 h of light/day, exposure to 8 h of light/day for 10 weeks induces several phenotypic changes in P. leucopus , including reduction in brain mass and hippocampal volume. To investigate the functional consequences of reduced hippocampal size, we examined the effects of photoperiod on spatial learning and memory in the Barnes maze, and on long-term potentiation (LTP) in the hippocampus, a leading candidate for a synaptic mechanism underlying spatial learning and memory in rodents. Exposure to short days for 10 weeks decreased LTP in the Schaffer collateral–CA1 pathway of the hippocampus and impaired spatial learning and memory ability in the Barnes maze. Taken together, these results demonstrate a functional change in the hippocampus in male white-footed mice induced by day length.