Principles of synaptic encoding of brainstem circadian rhythms.

Circadian regulation of autonomic tone and reflex pathways pairs physiological processes with the daily light cycle. However, the underlying mechanisms mediating these changes on autonomic neurocircuitry are only beginning to be understood. The brainstem nucleus of the solitary tract (NTS) and adjacent nuclei, including the area postrema and dorsal motor nucleus of the vagus, are key candidates for rhythmic control of some aspects of the autonomic nervous system. Recent findings have contributed to a working model of circadian regulation in the brainstem which manifests from the transcriptional, to synaptic, to circuit levels of organization. Vagal afferent neurons and the NTS possess rhythmic clock gene expression, rhythmic action potential firing, and our recent findings demonstrate rhythmic spontaneous glutamate release. In addition, postsynaptic conductances also vary across the day producing subtle changes in membrane depolarization which govern synaptic efficacy. Together these coordinated pre- and postsynaptic changes provide nuanced control of synaptic transmission across the day to tune the sensitivity of primary afferent input and likely govern reflex output. Further, given the important role for the brainstem in integrating cues such as feeding, cardiovascular function and temperature, it may also be an underappreciated locus in mediating the effects of such non-photic entraining cues. This short review focuses on the neurophysiological principles that govern NTS synaptic transmission and how circadian rhythms impacted them across the day.

Circadian regulation of glutamate release pathways shapes synaptic throughput in the brainstem nucleus of the solitary tract (NTS).

Circadian regulation of autonomic reflex pathways pairs physiological function with the daily light cycle. The brainstem nucleus of the solitary tract (NTS) is a key candidate for rhythmic control of the autonomic nervous system. Here we investigated circadian regulation of NTS neurotransmission and synaptic throughput using patch-clamp electrophysiology in brainstem slices from mice. We found that spontaneous quantal glutamate release onto NTS neurons showed strong circadian rhythmicity, with the highest rate of release during the light phase and the lowest in the dark, that were sufficient to drive day/night differences in constitutive postsynaptic action potential firing. In contrast, afferent evoked action potential throughput was enhanced during the dark and diminished in the light. Afferent-driven synchronous release pathways showed a similar decrease in release probability that did not explain the enhanced synaptic throughput during the night. However, analysis of postsynaptic membrane properties revealed diurnal changes in conductance, which, when coupled with the circadian changes in glutamate release pathways, tuned synaptic throughput between the light and dark phases. These coordinated pre-/postsynaptic changes encode nuanced control over synaptic performance and pair NTS action potential firing and vagal throughput with time of day. KEY POINTS: Vagal afferent neurons relay information from peripheral organs to the brainstem nucleus of the solitary tract (NTS) to initiate autonomic reflex pathways as well as providing important controls of food intake, digestive function and energy balance. Vagally mediated reflexes and behaviours are under strong circadian regulation. Diurnal fluctuations in presynaptic vesicle release pathways and postsynaptic membrane conductances provide nuanced control over NTS action potential firing and vagal synaptic throughput. Coordinated pre-/postsynaptic changes represent a fundamental mechanism mediating daily changes in vagal afferent signalling and autonomic function.

Profiling rhythmicity of bile salt hydrolase activity in the gut lumen with a rapid fluorescence assay.

Diurnal rhythmicity of cellular function is key to survival for most organisms on Earth. Many circadian functions are driven by the brain, but regulation of a separate set of peripheral rhythms remains poorly understood. The gut microbiome is a potential candidate for regulation of host peripheral rhythms, and this study sought to specifically examine the process of microbial bile salt biotransformation. To enable this work, an assay for bile salt hydrolase (BSH) that could work with small quantities of stool samples was necessary. Using a turn-on fluorescence probe, we developed a rapid and inexpensive assay to detect BSH enzyme activity with concentrations as low as 6-25 µM, which is considerably more robust than prior approaches. We successfully applied this rhodamine-based assay to detect BSH activity in a wide range of biological samples such as recombinant protein, whole cells, fecal samples, and gut lumen content from mice. We were able to detect significant BSH activity in small amounts of mouse fecal/gut content (20-50 mg) within 2 h, which illustrates its potential for use in various biological/clinical applications. Using this assay, we investigated the diurnal fluctuations of BSH activity in the large intestine of mice. By using time restricted feeding conditions, we provided direct evidence of 24 h rhythmicity in microbiome BSH activity levels and showed that this rhythmicity is influenced by feeding patterns. Our novel function-centric approach has potential to aid in the discovery of therapeutic, diet, or lifestyle interventions for correction of circadian perturbations linked to bile metabolism.

The hypothalamic-pituitary-adrenal axis as a substrate for stress resilience: Interactions with the circadian clock.

Stress, primarily processed via the hypothalamic-pituitary-adrenal (HPA) axis, engages biological pathways throughout the brain and body which promote adaptation and survival to changing environmental demands. Adaptation to environmental challenges is compromised when these pathways are no longer functioning optimally. The physiological and behavioral mechanisms through which HPA axis function influences stress adaptation and resilience are not fully elucidated. Our understanding of stress biology and disease must take into account the complex interactions between the endocrine system, neural circuits, and behavioral coping strategies. In addition, further consideration must be taken concerning influences of other aspects of physiology, including the circadian clock which is critical for regulation of daily changes in HPA activity. While adding a layer of complexity, it also offers targets for intervention. Understanding the role of HPA function in mediating these diverse biological responses will lead to important insights about how to bolster successful stress adaptation and promote stress resilience.

Corticosterone inhibits vagal afferent glutamate release in the nucleus of the solitary tract via retrograde endocannabinoid signaling.

Circulating blood glucocorticoid levels are dynamic and responsive to stimuli that impact autonomic function. In the brain stem, vagal afferent terminals release the excitatory neurotransmitter glutamate to neurons in the nucleus of the solitary tract (NTS). Vagal afferents integrate direct visceral signals and circulating hormones with ongoing NTS activity to control autonomic function and behavior. Here, we investigated the effects of corticosterone (CORT) on glutamate signaling in the NTS using patch-clamp electrophysiology on brain stem slices containing the NTS and central afferent terminals from male C57BL/6 mice. We found that CORT rapidly decreased both action potential-evoked and spontaneous glutamate signaling. The effects of CORT were phenocopied by dexamethasone and blocked by mifepristone, consistent with glucocorticoid receptor (GR)-mediated signaling. While mRNA for GR was present in both the NTS and vagal afferent neurons, selective intracellular quenching of G protein signaling in postsynaptic NTS neurons eliminated the effects of CORT. We then investigated the contribution of retrograde endocannabinoid signaling, which has been reported to transduce nongenomic GR effects. Pharmacological or genetic elimination of the cannabinoid type 1 receptor signaling blocked CORT suppression of glutamate release. Together, our results detail a mechanism, whereby the NTS integrates endocrine CORT signals with fast neurotransmission to control autonomic reflex pathways.

Circadian desynchronization alters metabolic and immune responses following lipopolysaccharide inoculation in male mice.

Metabolism and inflammation are linked at many levels. Sickness behaviors are elicited by the immune system's response to antigenic stimuli, and include changes in feeding and metabolism. The immune system is also regulated by the circadian (daily) clock, which generates endogenous rhythms, and synchronizes these rhythms to the light-dark cycle. Modern society has resulted in chronic misalignment or desynchronization of the circadian clock and the external environment. We have demonstrated that circadian desynchronization (CD) in mice alters metabolic function, and also affects both peripheral and central immune responses following a low-dose lipopolysaccharide (LPS) challenge. However, it is unclear how this altered immune response impacts sickness behaviors and metabolism following challenge. To test this, we housed male mice in circadian desynchronized (10-hours light:10-hours dark) or control (12-hours light:12-hours dark) conditions for 5-6 weeks. We then challenged mice with LPS (i.p., 0.4 mg/kg) or PBS and measured changes in body mass, feeding, drinking and locomotion using a comprehensive phenotyping system. Plasma, liver, and brain were collected 36 h post-inoculation (hpi) and inflammatory messengers were measured via multiplex cytokine/chemokine array and qPCR. We find that recovery of locomotion and body mass is prolonged in CD mice following LPS challenge. Additionally, at 36 hpi the expression of several proinflammatory cytokines differ depending on pre-inoculation lighting conditions. Our findings add to the growing literature which documents how desynchronization of circadian rhythms can lead to disrupted immune responses and changes in metabolic function.

Stress: Common themes toward the next frontier.

"Stress is complicated". A phrase uttered by many a stress researcher. This is true, from the vast array of stimuli considered "stressors" to the interactive and hormetic nature of the molecular, cellular, endocrine, and behavioral responses generated by such stressors. This commentary takes the position that stress researchers are poised to make even bigger contributions if they begin to shift from investigating the myriad effects of stress on brain and body, and to refocus a larger part of our efforts on more in-depth investigations of common themes in stress biology, with the goal of uncovering potential "universal principles" of stress that may help us better interpret the findings at higher levels of analysis, and provide a structured approach to help breach the next frontiers of stress research.

Nuclear receptor REV-ERBα mediates circadian sensitivity to mortality in murine vesicular stomatitis virus-induced encephalitis.

Certain components and functions of the immune system, most notably cytokine production and immune cell migration, are under circadian regulation. Such regulation suggests that circadian rhythms may have an effect on disease onset, progression, and resolution. In the vesicular stomatitis virus (VSV)-induced encephalitis model, the replication, caudal penetration, and survivability of intranasally applied VSV depends on both innate and adaptive immune mechanisms. In the current study, we investigated the effect of circadian time of infection on the progression and outcome of VSV-induced encephalitis and demonstrated a significant decrease in the survival rate in mice infected at the start of the rest cycle, zeitgeber time 0 (ZT0). The lower survival rate in these mice was associated with higher levels of circulating chemokine (C-C motif) ligand 2 (CCL2), a greater number of peripherally derived immune cells accumulating in the olfactory bulb (OB), and increased production of proinflammatory cytokines, indicating an immune-mediated pathology. We also found that the acrophase of molecular circadian clock component REV-ERBα mRNA expression in the OB coincides with the start of the active cycle, ZT12, when VSV infection results in a more favorable outcome. This result led us to hypothesize that REV-ERBα may mediate the circadian effect on survival following VSV infection. Blocking REV-ERBα activity before VSV administration resulted in a significant increase in the expression of CCL2 and decreased survival in mice infected at the start of the active cycle. These data demonstrate that REV-ERBα-mediated inhibition of CCL2 expression during viral-induced encephalitis may have a protective effect.

Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function.

Obesity is a major public health problem affecting overall physical and emotional well-being. Despite compelling data suggesting an association between obesity and cognitive dysfunction, this phenomenon has received relatively little attention. Neuroimaging studies in obese humans report reduced size of brain regions involved in cognition, but few studies have investigated the cellular processes underlying cognitive decline in obesity or the influence of obesity on cognition in the absence of obesity-related illnesses. Here, a rat model of diet-induced obesity was used to explore changes in brain regions important for cognition. Obese rats showed deficits on cognitive tasks requiring the prefrontal and perirhinal cortex. Cognitive deficits were accompanied by decreased dendritic spine density and synaptic marker expression in both brain regions. Microglial morphology was also changed in the prefrontal cortex. Detrimental changes in the prefrontal cortex and perirhinal cortex occurred before metabolic syndrome or diabetes, suggesting that these brain regions may be particularly vulnerable to early stage obesity.

A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome.

Glucocorticoids are known to promote the development of metabolic syndrome through the modulation of both feeding pathways and metabolic processes; however, the precise mechanisms of these effects are not well-understood. Recent evidence shows that glucocorticoids possess the ability to increase endocannabinoid signaling, which is known to regulate appetite, energy balance, and metabolic processes through both central and peripheral pathways. The aim of this study was to determine the role of endocannabinoid signaling in glucocorticoid-mediated obesity and metabolic syndrome. Using a mouse model of excess corticosterone exposure, we found that the ability of glucocorticoids to increase adiposity, weight gain, hormonal dysregulation, hepatic steatosis, and dyslipidemia was reduced or reversed in mice lacking the cannabinoid CB1 receptor as well as mice treated with the global CB1 receptor antagonist AM251. Similarly, a neutral, peripherally restricted CB1 receptor antagonist (AM6545) was able to attenuate the metabolic phenotype caused by chronic corticosterone, suggesting a peripheral mechanism for these effects. Biochemical analyses showed that chronic excess glucocorticoid exposure produced a significant increase in hepatic and circulating levels of the endocannabinoid anandamide, whereas no effect was observed in the hypothalamus. To test the role of the liver, specific and exclusive deletion of hepatic CB1 receptor resulted in a rescue of the dyslipidemic effects of glucocorticoid exposure, while not affecting the obesity phenotype or the elevations in insulin and leptin. Together, these data indicate that glucocorticoids recruit peripheral endocannabinoid signaling to promote metabolic dysregulation, with hepatic endocannabinoid signaling being especially important for changes in lipid metabolism.

Suprachiasmatic vasopressin and the circadian regulation of voluntary locomotor behavior.

A role for arginine vasopressin in the circadian regulation of voluntary locomotor behavior (wheel running activity) was investigated in the golden hamster, Mesocricetus auratus. Spontaneous nocturnal running was suppressed in a dose-dependent manner by systemic injections of vasopressin, and also in a concentration-dependent manner by microinjections directly into the hypothalamic suprachiasmatic nucleus. Pre-injections of a vasopressin V1 receptor antagonist into the nucleus reduced the suppression of behavior by vasopressin. Ethogram analyses revealed that peripheral drug injections predominantly increased grooming, flank marking, and sleep-related behaviors. Central injections did not induce sleep, but increased grooming and periods of 'quiet vigilance' (awake but not moving). Nocturnal behavioral profiles following either peripheral or central injections were similar to those shown by untreated animals in the hour prior to the onset of nocturnal wheel running. Site control vasopressin injections into the medial preoptic area or periaqueductal gray increased flank marking and grooming, but had no significant effect on locomotion, suggesting behavioral specificity of a vasopressin target near the suprachiasmatic nucleus. Both peripheral and central administration increased FOS-like immunoreactivity in the retinorecipient core of the suprachiasmatic nucleus. The distribution of FOS-positive cells overlapped the calbindin subregion, but was more extensive, and most calbindin-positive cells did not co-express FOS. We propose a model of temporal behavioral regulation wherein voluntary behavior, such as nocturnal locomotor activity, is inhibited by the activity of neurons in the suprachiasmatic ventrolateral core that project to the posterior hypothalamus and are driven by rhythmic vasopressin input from the dorsomedial shell.

Environmental disruption of the circadian clock leads to altered sleep and immune responses in mouse.

In mammals, one of the most salient outputs of the circadian (daily) clock is the timing of the sleep-wake cycle. Modern industrialized society has led to a fundamental breakdown in the relationship between our endogenous timekeeping systems and the solar day, disrupting normal circadian rhythms. We have argued that disrupted circadian rhythms could lead to changes in allostatic load, and the capacity of organisms to respond to other environmental challenges. In this set of studies, we apply a model of circadian disruption characterized in our lab in which mice are housed in a 20h long day, with 10h of light and 10h of darkness. We explored the effects of this environmental disruption on sleep patterns, to establish if this model results in marked sleep deprivation. Given the interaction between circadian, sleep, and immune systems, we further probed if our model of circadian disruption also alters the innate immune response to peripheral bacterial endotoxin challenge. Our results demonstrate that this model of circadian disruption does not lead to marked sleep deprivation, but instead affects the timing and quality of sleep. We also show that while circadian disruption does not lead to basal changes in the immune markers we explored, the immune response is affected, both in the brain and the periphery. Together, our findings further strengthen the important role of the circadian timing system in sleep regulation and immune responses, and provide evidence that disrupting the circadian clock increases vulnerability to further environmental stressors, including immunological challenges.

Food for thought: hormonal, experiential, and neural influences on feeding and obesity.

Obesity is a growing public health problem. Although convenient, the notion that obesity is simply a problem of will power is increasingly antiquated. It is becoming clear that complex interactions of environment, neurohormonal systems, and transgenerational effects directly contribute to obesity. This review highlights data presented at the Society for Neuroscience Annual Meeting in San Diego, California in 2013; and although not meant as an exhaustive review of the area, this reivew will explore seemingly disparate areas of research that, when taken as a whole, illuminate the complex topography of the causes and consequences of obesity. We discuss how disruption of the biological clock, a consequence of modern society, can lead to changes in the brain and periphery that lead to obesity. We explore how obesity can actually cause pathological changes within the hypothalamus of the brain (a key regulator of food intake and metabolic homeostasis). How reward circuitry, particularly the ventral tegmental area, responds to insulin and how these effects modulate feeding and the salience of feeding cues are mechanistically described. We also investigate how nutrition may cross generational boundaries to affect the development and function of offspring, underscoring the long reach of metabolic effects. Finally, the role of the endocannabinoid system is emphasized as a critical node in the transduction of many of these effects. Together, this review should provide perspective into the neural causes and consequences of obesity, and hopefully lead to new areas of interdisciplinary research to tackle this important public health epidemic.

Disruption of circadian clocks has ramifications for metabolism, brain, and behavior.

Circadian (daily) rhythms are present in almost all plants and animals. In mammals, a brain clock located in the hypothalamic suprachiasmatic nucleus maintains synchrony between environmental light/dark cycles and physiology and behavior. Over the past 100 y, especially with the advent of electric lighting, modern society has resulted in a round-the-clock lifestyle, in which natural connections between rest/activity cycles and environmental light/dark cycles have been degraded or even broken. Instances in which rapid changes to sleep patterns are necessary, such as transmeridian air travel, demonstrate negative effects of acute circadian disruption on physiology and behavior. However, the ramifications of chronic disruption of the circadian clock for mental and physical health are not yet fully understood. By housing mice in 20-h light/dark cycles, incongruous with their endogenous ∼24-h circadian period, we were able to model the effects of chronic circadian disruption noninvasively. Housing in these conditions results in accelerated weight gain and obesity, as well as changes in metabolic hormones. In the brain, circadian-disrupted mice exhibit a loss of dendritic length and decreased complexity of neurons in the prelimbic prefrontal cortex, a brain region important in executive function and emotional control. Disrupted animals show decreases in cognitive flexibility and changes in emotionality consistent with the changes seen in neural architecture. How our findings translate to humans living and working in chronic circadian disruption is unknown, but we believe that this model can provide a foundation to understand how environmental disruption of circadian rhythms impacts the brain, behavior, and physiology.

Annual Research Review: The neurobiology and physiology of resilience and adaptation across the life course.

BACKGROUND: Adaptation is key to survival. An organism must adapt to environmental challenges in order to be able to thrive in the environment in which they find themselves. Resilience can be thought of as a measure of the ability of an organism to adapt, and to withstand challenges to its stability. In higher animals, the brain is a key player in this process of adaptation and resilience, and through a process known as "allostasis" can obtain "stability through change"; protecting homeostasis in the face of stressors in the environment. Mediators of allostasis, such as glucocorticoids, can cause changes in the structure and function of neural circuits, clearly impacting behavior. How developmental stage interacts with stress and leads to long-lasting changes is a key question addressed in this review. SCOPE AND METHODS: We discuss the concept of allostasis, its role in resilience, the neural and physiological systems mediating these responses, the modulatory role of development, and the consequences for adult functioning. We present this in the context of mediators the brain and body engage to protect against threats to homeostasis. The review has been informed by comprehensive searches on PubMed and Scopus through November 2012. FINDINGS: Stressors in the environment can have long lasting effects on development, depending upon the stage of life at which they are experienced. As such, adverse childhood experiences can alter resilience of individuals, making it more difficult for them to respond normally to adverse situations in adulthood, but the brain maintains the capacity to re-enter a more plastic state where such effects can be mitigated. CONCLUSIONS: The brain regulates responses that allow for adaptation to challenges in the environment. The capacity of the brain and body to withstand challenges to stability can be considered as "resilience". While adverse childhood experiences can have long-term negative consequences, under the right circumstances, the brain can re-enter plastic states, and negative outcomes may be mitigated, even later in life.

Circadian desynchronization disrupts physiological rhythms of prefrontal cortex pyramidal neurons in mice.

Disruption of circadian rhythms, such as shift work and jet lag, are associated with negative physiological and behavioral outcomes, including changes in affective state, learning and memory, and cognitive function. The prefrontal cortex (PFC) is heavily involved in all of these processes. Many PFC-associated behaviors are time-of-day dependent, and disruption of daily rhythms negatively impacts these behavioral outputs. Yet how disruption of daily rhythms impacts the fundamental function of PFC neurons, and the mechanism(s) by which this occurs, remains unknown. Using a mouse model, we demonstrate that the activity and action potential dynamics of prelimbic PFC neurons are regulated by time-of-day in a sex specific manner. Further, we show that postsynaptic K+ channels play a central role in physiological rhythms, suggesting an intrinsic gating mechanism mediating physiological activity. Finally, we demonstrate that environmental circadian desynchronization alters the intrinsic functioning of these neurons independent of time-of-day. These key discoveries demonstrate that daily rhythms contribute to the mechanisms underlying the essential physiology of PFC circuits and provide potential mechanisms by which circadian disruption may impact the fundamental properties of neurons.

Metabolic dysfunctions following chronic oral corticosterone are modified by adolescence and sex in mice.

Adolescence is a period of development in which shifts in responses to glucocorticoids is well-documented. Obesity and metabolic syndrome are substantial health issues whose rates continue to rise in both adult and adolescent populations. Though many interacting factors contribute to these dysfunctions, how these shifts in glucocorticoid responses may be related remain unknown. Using a model of oral corticosterone (CORT) exposure in male and female mice, we demonstrate differential responses during adolescence (30-58 days of age) or adulthood (70-98 day of age) in endpoints relevant to metabolic function. Our data indicate that CORT resulted in significant weight gain in adult- and adolescent-exposed females and adult-exposed males, but not adolescent-exposed males. Despite this difference, all animals treated with high levels of CORT showed significant increases in white adipose tissue, indicating a dissociation between weight gain and adiposity in adolescent-treated males. Similarly, all experimental groups showed significant increases in plasma insulin, leptin, and triglyceride levels, further suggesting potential disconnects between overt weight gain, and underlying metabolic dysregulation. Finally, we found age- and dose-dependent changes in the expression of hepatic genes important in glucocorticoid receptor and lipid regulation, which showed different patterns in males and females. Thus, altered transcriptional pathways in the liver might be contributing differentially to the similar metabolic phenotype observed among these experimental groups. We also show that despite little CORT-induced changes in the hypothalamic levels of orexin-A and NPY, we found that food and fluid intake were elevated in adolescent-treated males and females. These data indicate chronic exposure to elevated glucocorticoid levels results in metabolic dysfunction in both males and females, which can be further modulated by developmental stage.

Recruitment of prefrontal cortical endocannabinoid signaling by glucocorticoids contributes to termination of the stress response.

The mechanisms subserving the ability of glucocorticoid signaling within the medial prefrontal cortex (mPFC) to terminate stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis are not well understood. We report that antagonism of the cannabinoid CB(1) receptor locally within the mPFC prolonged corticosterone secretion following cessation of stress in rats. Mice lacking the CB(1) receptor exhibited a similar prolonged response to stress. Exposure of rats to stress produced an elevation in the endocannabinoid 2-arachidonoylglycerol within the mPFC that was reversed by pretreatment with the glucocorticoid receptor antagonist RU-486 (20 mg/kg). Electron microscopic and electrophysiological data demonstrated the presence of CB(1) receptors in inhibitory-type terminals impinging upon principal neurons within layer V of the prelimbic region of the mPFC. Bath application of corticosterone (100 nm) to prefrontal cortical slices suppressed GABA release onto principal neurons in layer V of the prelimbic region, when examined 1 h later, which was prevented by application of a CB(1) receptor antagonist. Collectively, these data demonstrate that the ability of stress-induced glucocorticoid signaling within mPFC to terminate HPA axis activity is mediated by a local recruitment of endocannabinoid signaling. Endocannabinoid activation of CB(1) receptors decreases GABA release within the mPFC, likely increasing the outflow of the principal neurons of the prelimbic region to contribute to termination of the stress response. These data support a model in which endocannabinoid signaling links glucocorticoid receptor engagement to activation of corticolimbic relays that inhibit corticosterone secretion.

Effects of circadian disruption on mental and physical health.

Circadian (daily) rhythms in physiology and behavior are phylogenetically ancient and are present in almost all plants and animals. In mammals, these rhythms are generated by a master circadian clock in the suprachiasmatic nucleus of the hypothalamus, which in turn synchronizes "peripheral oscillators" throughout the brain and body in almost all cell types and organ systems. Although circadian rhythms are phylogenetically ancient, modern industrialized society and the ubiquity of electric lighting has resulted in a fundamental alteration in the relationship between an individual's endogenous circadian rhythmicity and the external environment. The ramifications of this desynchronization for mental and physical health are not fully understood, although numerous lines of evidence are emerging that link defects in circadian timing with negative health outcomes. This article explores the function of the circadian system, the effects of disrupted clocks on the brain and body, and how these effects impact mental and physical health.

Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory.

The prefrontal cortex (PFC), a key brain region controlling cognition and emotion, is strongly influenced by stress. While chronic stress often produces detrimental effects on these measures, acute stress has been shown to enhance learning and memory, predominantly through the action of corticosteroid stress hormones. We used a combination of electrophysiological, biochemical, and behavioral approaches in an effort to identify the cellular targets of acute stress. We found that behavioral stressors in vivo cause a long-lasting potentiation of NMDAR- and AMPAR-mediated synaptic currents via glucocorticoid receptors (GRs) selectively in PFC pyramidal neurons. This effect is accompanied by increased surface expression of NMDAR and AMPAR subunits in acutely stressed animals. Furthermore, behavioral tests indicate that working memory, a key function relying on recurrent excitation within networks of PFC neurons, is enhanced by acute stress via a GR-dependent mechanism. These results have identified a form of long-term potentiation of synaptic transmission induced by natural stimuli in vivo, providing a potential molecular and cellular mechanism for the beneficial effects of acute stress on cognitive processes subserved by PFC.