Organisms have developed concurrent behavioral and physiological adaptations to the strong influence of day/night cycles, as well as to unforeseen, random stress stimuli. These circadian and stress-related responses are achieved by two highly conserved and interrelated regulatory networks, the circadian CLOCK and stress systems, which respectively consist of oscillating molecular pacemakers, the Clock/Bmal1 transcription factors, and the hypothalamic–pituitary–adrenal (HPA) axis and its end-effector, the glucocorticoid receptor. These systems communicate with one another at different signaling levels and dysregulation of either system can lead to development of pathologic conditions. In this review, we summarize the mutual physiologic interactions between the circadian CLOCK system and the HPA axis, and discuss their clinical implications.

/pdf/interactions-of-the-circadian-clock-system-and-the-hpa-axis-4ltt8a6h1k.pdf

Interactions of the circadian CLOCK system and the HPA axis.

Stress constitutes a state of threatened homeostasis triggered by intrinsic or extrinsic adverse forces (stressors) and is counteracted by an intricate repertoire of physiologic and behavioral responses aiming to maintain/reestablish the optimal body equilibrium (eustasis). The adaptive stress response depends upon a highly interconnected neuroendocrine, cellular, and molecular infrastructure, i.e. the stress system. Key components of the stress system are the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS), which interact with other vital centers in the central nervous system (CNS) and tissues/organs in the periphery to mobilize a successful adaptive response against the imposed stressor(s). Dysregulation of the stress system (hyper- or hypo-activation) in association with potent and/or chronic stress can markedly disrupt the body homeostasis leading to a state of cacostasis or allostasis, with a spectrum of clinical manifestations. This chapter describes the organization and physiology of the stress system, focusing on its interactions with other CNS centers and endocrine axes, and reviews the existing evidence linking stress to pathophysiologic mechanisms implicated in the development of stress-related diseases affecting the endocrine, metabolic, gastrointestinal, and immune systems. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG .

Stress: Endocrine Physiology and Pathophysiology

The circadian system has pronounced influence on learning and memory, manifesting as marked changes in memory acquisition and recall across the day. From a mechanistic perspective, the majority of studies have investigated mammalian hippocampal-dependent learning and memory, as this system is highly tractable. The hippocampus plays a major role in learning and memory, and has the potential to integrate circadian information in many ways, including information from local, independent oscillators, and through circadian modulation of neurogenesis, synaptic remodeling, intracellular cascades, and epigenetic regulation of gene expression. These local processes are combined with input from other oscillatory systems to synergistically augment hippocampal rhythmic function. This overview presents an account of the current state of knowledge on circadian interactions with learning and memory circuitry and provides a framework for those interested in further exploring these interactions.

/pdf/a-time-to-remember-the-role-of-circadian-clocks-in-learning-4rpyqf6a9h.pdf

A time to remember: the role of circadian clocks in learning and memory.

Glucocorticoids (GCs) are used to treat pregnant women at risk for preterm delivery; however, prenatal exposure to GCs may trigger adverse neurological side effects due to reduced neural progenitor cell (NPC) proliferation. Whereas many established cell-cycle regulators impact NPC proliferation, other signaling molecules, such as the gap junction protein connexin-43 (Cx43), also influence proliferation. Gap junction intercellular communication (GJIC) is influenced by GCs in some cells, but such hormone effects have not been examined in coupled stem cells. We found that both continuous and transient exposure of embryonic day 14.5 mouse neurosphere cultures to dexamethasone (DEX) limits proliferation of coupled NPCs, which is manifested by both a reduction in S-phase progression and enhanced cell-cycle exit. A short (i.e., 1-h) DEX treatment also reduced GJIC as measured by live-cell fluorescence recovery after photobleaching, and altered the synchrony of spontaneous calcium transients in coupled NPCs. GC effects on GJIC in NPCs are transcription-independent and mediated through plasma membrane glucocorticoid receptors (GRs). This nongenomic pathway operates through lipid raft-associated GRs via a site-specific, MAPK-dependent phosphorylation of Cx43, which is linked to GR via caveolin-1 (Cav-1) and c-src. Cav-1 is essential for this nongenomic action of GR, as DEX effects on GJIC, Cx43 phosphorylation, and MAPK activation are not observed in Cav-1 knockout NPCs. As transient pharmacologic inhibition of GJIC triggers reduced S-phase progression but not enhanced cell-cycle exit, the nongenomic GR signaling pathway may operate via distinct downstream effectors to alter the proliferative capacity of NPCs.

https://www.pnas.org/content/pnas/108/40/16657.full.pdf

Nongenomic glucocorticoid receptor action regulates gap junction intercellular communication and neural progenitor cell proliferation

Circadian rhythms in mammalian behaviour and physiology rely on daily oscillations in the expression of canonical clock genes. Circadian rhythms in clock gene expression are observed in the master circadian clock, the suprachiasmatic nucleus but are also observed in many other brain regions that have diverse roles, including influences on motivational and emotional state, learning, hormone release and feeding. Increasingly, important links between circadian rhythms and metabolism are being uncovered. In particular, restricted feeding (RF) schedules which limit food availability to a single meal each day lead to the induction and entrainment of circadian rhythms in food-anticipatory activities in rodents. Food-anticipatory activities include increases in core body temperature, activity and hormone release in the hours leading up to the predictable mealtime. Crucially, RF schedules and the accompanying food-anticipatory activities are also associated with shifts in the daily oscillation of clock gene expression in diverse brain areas involved in feeding, energy balance, learning and memory, and motivation. Moreover, lesions of specific brain nuclei can affect the way rats will respond to RF, but have generally failed to eliminate all food-anticipatory activities. As a consequence, it is likely that a distributed neural system underlies the generation and regulation of food-anticipatory activities under RF. Thus, in the future, we would suggest that a more comprehensive approach should be taken, one that investigates the interactions between multiple circadian oscillators in the brain and body, and starts to report on potential neural systems rather than individual and discrete brain areas.

Food-entrainable circadian oscillators in the brain.

Brain glucocorticoid receptors are necessary for the rhythmic expression of the clock protein, PERIOD2, in the central extended amygdala in mice

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Brain glucocorticoid receptors are necessary for the rhythmic expression of the clock protein, PERIOD2, in the central extended amygdala in mice