Author: Claudia Schettini
Date: 25/09/2012


HPA and CRH implication in stress-induced depressive disorders.

Everybody in everyday life is exposed to various kind of physical, psycological, social and organic stimuli or events that incite human body to react.
These stimuli are better known as “stressors” and they are responsible for stress reactions that mainly activate corticotrophin releasing hormone (CRH) and norepinephrine released by locus coeruleus.
The first one involves the Hypophisis-adrenal axis (HPA) and the second one the autonomous nervous system.
It's possible to draw a map of stress system: it includes also amygdala and hyppocampus that reciprocally interact with the other pathways.
The adaptability of the organism to enviromental changes is absolutely a necessary feature for survival on earth and this is the main purpose of stress system activation;
particularly human's ability to respond to stressors permits homeostasis, nevertheless conditions of stress chronicity, psychosocial and life events may disrupt the equilibrium of nervous, immune, cardiovascular as well as metabolic system, leading to disease susceptibility.

This study focus on the hypotalamic-pituitary-adrenal axis and CRH implication in stress-induced depressive disorders.

Regolazione neuroendocrina dello stress: recenti acquisizioni. Pozzi F, Frajese G. Rapporti tra life events e patologia psichiatrica; Noos. 2004; 143-154.

CRH. Corticotrophin-releasing hormone (CRH) is a 41-aa peptide derived from a 191-aa prprohormone, it is secreted by paraventricular nucleus (PVN) of the hypotalamus; in this region the cells responsible for its synthesis and secretion are parvocellular neuroendocrine cells that through their neurosecretory terminals put CRH into the primary capillary plexus of the hypothalamo-hypophyseal portal system.
Thanks to these vessels CRH reaches the anterior lobe of pituitary gland where it stimulates corticotropes to secret adrenocorticotropic hormone (ACTH) and other biologically-active substances like beta-endorphin.
CRH exerts its action by means of CRH receptors (CRHRs), to this family belong two different type, 1 and 2, each encoded by a separate gene (CRHR1 and CRHR2). They have different localization throughout the brain, infact CRHR1 is widely expressed in neocortical areas, the basolateral and medial nucleus of amygdala, anterior pituitary, hypotalamic nuclei and cerebellar Purkinje cells. CRHR2, instead is present in the lateral septum, ventromedial hypotalamus, and cortical nucleus of the amygdala. Both receptors have been identified in the hippocampus.
CRH shows a different affinity for its receptors, it prefers CRHR1, otherwise CRHR2
is activated by other CHR related-peptide such as stresscopin.
CRHRs are G protein-coupled seven-transmembrane receptors linked to a number of intracellular signaling pathways, particularly ligand-dependent increase of intracellular cAMP.
Increased cAMP concentration activates protein kinase A (PKA), which induces its associated transcription factor CREB.

Corticotropin-releasing hormone activates ERK1/2 MAPK in specific brain areas. Refojo D, Echenique C, Muller M, Reul J, Deussing J, Wurst W, Sillaber I, Paez-Pereda M, Holsboer F, Arzt E. Neuroscience, 2005.

ACTH.* Adrenocorticotropic hormone (ACTH)* is secreted by corticotropes in the anterior pituitary gland. It is a 39-aa peptide which originates from pre-pro-opiomelanocortin (pre-POMC).
ACTH induces glucocorticoid steroid hormones secretion from adrenal cortex cells, especially in the zona fasciculata, thanks to ACTH receptors.
ACTHRs are seven-transmembrane G protein-coupled receptors and are responsible of ligand-dependent increased cAMP levels that lead to the subsequent activation of protein kinase A; all these reactions stand for the first step of glucocorticoid's synthesis.

Glucocorticoids. Glucocorticoids are a class of steroid hormones that regulate and support a variety of important cardiovascular, immunologic and homeostatic function, but above all they are implicated in stress response.
The most rappresentative hormone of this family is cortisol.

HPA axis. The hypotalamic-pituitary-adrenal axis is a multi-step biochemical pathways which includes a series of chemical messengers: step by step information is trasmitted from one area of the body to another one.
HPA axis is regulated through a feedback mechanism, according with this system every step recives feedback from messangers produced later in the pathways to either enhance or suppress earlier steps.
Stress response cascade begins when the hypotalamus receives some kind of stressors, everything that deviate from an ideal homeostatic state such as alarming sensory stimulus, emotionally charged event, energy deficiency.
This kind of perturbation improves CRH's release and the subsequent ACTH's secretion, whose target is the adrenal gland which put into the bloodstream the final key messenger in the cascade: cortisol.
The several effects catalyzed by this hormone move towards the recovery of homeostasis; when the body regain it, cortisol reaches pituitary gland and hypotalamus where exercises its feedback inibition.
These pathways represent the normal and phisiological response to stressors, however
traumatic or chronic uncontrollable stress can induce the onset of depressive disorders.

Conti Fiorenzo (2005), Fisiologia medica, seconda edizione, Milano, edi-ermes.

Stress-induced depressive disorders. CRHRs are distributed widely throughout the brain. They are also in nucleus accumbens (NA), the main part of ventral striatum; here CRH facilitates cue-elicted motivation and social bonding behaviours that are thought to be mediated by dopamine transmission.
CRH facilitates dopamine's release, through the coactivation of both receptors (CRHR1 and CRHR2).
It's proved that CRH acts in the nucleus accumbens to produce a positive affective state; this effect could be completely abolished by cathecholaminergic-neuron-selective neurotoxin-6 hydroxydopamine (6-OHDA) who plays as inhibitor causing dopamine depletion.
To sum up, endogenous CRH in NA is used under physiological conditions to mediate appetitive responses to arousing enviromental stimuli.
However sever or chronic stress produces an alteration in normal stress signaling that can be detrimental to physical and mental health, predisposing individuals to depression. Infact in mices exposed to sever stress, CRH's ability to potentiate dopamine release is suppressed without recovery for 90 days; during this period is manteined a depression-like phenotype.
CRH is now aversive.
Loss affect, cognitive impairment, homeostatic imbalance are most important depression's symptoms; they arise from dysregulation of several brain regions, for example cognitive impairment is related to glucocorticoid-dependent hippocampal atrophy, instead disruption of NA function produces affective symptomps.
Also this dysregulation is mediated by glucocorticoid receptors: genomic repressive effects on CRH system downregulate CRHR1 setting up an anxiety-like behaviour.
In the end depressive disorders produce a profound change in perception of, and behavioural response to, acute stressors and other arousing enviromental stimuli that elict CRH signaling.
The review shows neurobiological mechanism at the base of relationship between stress and depression.

Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive, Lemos JC, Wanat MJ, Smith JS, Reyes BA, Hollon NG, Van Bockstaele EJ, Chavkin C, Phillips PE, Nature, 2012.

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