Multilevel Interactions of Stress and Circadian System: Implications for Traumatic Stress

Abstract

The dramatic fluctuations in energy demands by the rhythmic succession of night and day on our planet has prompted a geophysical evolutionary need for biological temporal organization across phylogeny. The intrinsic circadian timing system (CS) represents a highly conserved and sophisticated internal "clock," adjusted to the 24-h rotation period of the earth, enabling a nyctohemeral coordination of numerous physiologic processes, from gene expression to behavior. The human CS is tightly and bidirectionally interconnected to the stress system (SS). Both systems are fundamental for survival and regulate each other's activity in order to prepare the organism for the anticipated cyclic challenges. Thereby, the understanding of the temporal relationship between stressors and stress responses is critical for the comprehension of the molecular basis of physiology and pathogenesis of disease. A critical loss of the harmonious timed order at different organizational levels may affect the fundamental properties of neuroendocrine, immune, and autonomic systems, leading to a breakdown of biobehavioral adaptative mechanisms with increased stress sensitivity and vulnerability. In this review, following an overview of the functional components of the SS and CS, we present their multilevel interactions and discuss how traumatic stress can alter the interplay between the two systems. Circadian dysregulation after traumatic stress exposure may represent a core feature of trauma-related disorders mediating enduring neurobiological correlates of trauma through maladaptive stress regulation. Understanding the mechanisms susceptible to circadian dysregulation and their role in stress-related disorders could provide new insights into disease mechanisms, advancing psychochronobiological treatment possibilities and preventive strategies in stress-exposed populations.

Keywords: HPA axis; autonomic nervous system; circadian clocks; circadian system; glucocorticoids; sleep; stress; trauma.

Figure 1

Basic anatomy of stress and circadian system related brain structures. AVP, arginine vasopressin; GABA, γ-aminobutyric acid; DM SCN, dorsomedial suprachiasmatic nucleus; IGL, thalamic intergeniculate leaflet; LC, locus caeruleus; RHT, retinohypothalamic tract; VIP, vasoactive intestinal peptide; VL SCN, ventrolateral SCN.

Figure 2

Central and peripheral circadian system and their interconnections. AC, adrenal cortex; ACh, acetylcholine; ACTH, adrenocorticotropic hormone; AD, adrenalin; AM, adrenal medulla; ANS, autonomic nervous system; AP, anterior pituitary; CAN, central autonomic network; CRH, corticotropin releasing hormone; DM SCN, dorsomedial SCN; DMH, dorsomedial hypothalamus; GCs, glucocorticoids; HPA axis, hypothalamic-pituitary-adrenal axis; InC, insular cortex; IGL, thalamic intergeniculate leaflet; ipRGC, intrinsically photosensitive retinal ganglion cells; LC, locus caeruleus; MLT, melatonin; MPA, medial preoptic area; NE, norepinephrine; NTS, nucleus of the solitary tract; OT, optic tract; PNS, parasympathetic nervous system; PGAN, preganglionic autonomic neurons; PGL, pineal gland; PVN, paraventricular nucleus; R&C, rodes and cones; RHT, retinohypothalamic tract; SCN, suprachiasmatic nucleus; SCG, superior cervical ganlia; SNS, sympathetic nervous system; subPVN, subparaventricular area; VL SCN, ventrolateral SCN; VLM, ventrolateral medulla.

Figure 3

Principal and auxiliary transcriptional/translational feedback loops of the circadian system. AMPK, adenosine monophosphate (AMP)-activated protein kinase; BMAL1, brain-muscle-arnt-like protein 1; CHRONO, ChIP-derived repressor of network oscillator; CLOCK, circadian locomotor output cycle kaput; CRYs: cryptochromes; Csnk1ϵ/δ, casein kinase 1ϵ/δ; P, phosphate residue on the phosphorylated molecules; PERs, periods; RORα, retinoic acid receptor-related orphan nuclear receptor α. REV-ERBα, reverse viral erythroblastosis oncogene product alpha.

Figure 4

Multilevel interactions between the circadian system and the hypothalamic-pituitary-adrenal (HPA) axis. AC, adrenal cortex; CRH, corticotropin releasing hormone; GCs, glucocorticoids; ipRGC, intrinsically photosensitive retinal ganglion cells; MT, melatonin receptor; PVN, paraventricular nucleus; RHT, retinohypothalamic tract; RNS, reactive nitrogen species; RORα, retinoic acid receptor-related orphan receptor α; ROS, radical oxygen species; RZRβ, retinoid acid receptor related Z receptor β; SCN, suprachiasmatic nucleus; SCG, superior cervical ganlia.

Figure 5

Multilevel interactions between the circadian system and the hypothalamic-pituitary-adrenal (HPA) axis. ACTH, adrenocorticotropic hormone; APG, anterior pituitary gland; AVP, arginine vasopressin; BMAL1, brain-muscle-arnt-like protein 1; CA, catecholamines; CLOCK, circadian locomotor output cycle kaput; CRH, corticotropin releasing hormone; CRYs, cryptochromes; HSD, hydroxysteroid dehydrogenase; ipRGC, intrinsically photosensitive retinal ganglion cells; GCs, glucocorticoids; GR, glucocorticoid receptor; PERs, periods; PVN, paraventricular nucleus; REV-ERBα, reverse viral erythroblastosis oncogene product alpha; RHT, retinohypothalamic tract; RORα, retinoic acid receptor-related orphan nuclear receptor alpha SCN, suprachiasmatic nucleus.

Figure 6

Schematic model of trauma-related chronodisruption as underlying biological pathway leading to posttraumatic stress disorder (PTSD) and PTSD-related comorbidities.