Neural regulation of the stress response: glucocorticoid feedback mechanisms

Abstract

The mammalian stress response is an integrated physiological and psychological reaction to real or perceived adversity. Glucocorticoids are an important component of this response, acting to redistribute energy resources to both optimize survival in the face of challenge and to restore homeostasis after the immediate challenge has subsided. Release of glucocorticoids is mediated by the hypothalamo-pituitary-adrenal (HPA) axis, driven by a neural signal originating in the paraventricular nucleus (PVN). Stress levels of glucocorticoids bind to glucocorticoid receptors in multiple body compartments, including the brain, and consequently have wide-reaching actions. For this reason, glucocorticoids serve a vital function in negative feedback inhibition of their own secretion. Negative feedback inhibition is mediated by a diverse collection of mechanisms, including fast, non-genomic feedback at the level of the PVN, stress-shut-off at the level of the limbic system, and attenuation of ascending excitatory input through destabilization of mRNAs encoding neuropeptide drivers of the HPA axis. In addition, there is evidence that glucocorticoids participate in stress activation via feed-forward mechanisms at the level of the amygdala. Feedback deficits are associated with numerous disease states, underscoring the necessity for adequate control of glucocorticoid homeostasis. Thus, rather than having a single, defined feedback ‘switch’, control of the stress response requires a wide-reaching feedback ‘network’ that coordinates HPA activity to suit the overall needs of multiple body systems.

Blocking the Mineralocorticoid Receptor in Humans Prevents the Stress-Induced Enhancement of Centromedial Amygdala Connectivity with the Dorsal Striatum

“…Both receptors have two modes of action, a rapid non-genomic mode and a slow genomic mode, mediated by receptors residing at the membrane or in the cytoplasm, respectively, as demonstrated mostly in rodents or in vitro (Joëls et al, 2012). Whereas the slow genomic effects promote reinstalling homeostasis in humans and rodents (presumably GR-mediated, Henckens et al, 2011;Herman et al, 2012), rapid non-genomic (MR-mediated) effects seem to enhance catecholaminergic effects within minutes, for example, by enhancing excitability of the amygdala in vitro (Karst et al, 2010). Studies investigating emotional memories in rodents have already demonstrated that both stress-systems have synergistic effects in the amygdala (eg, Roozendaal et al, 2006).…”

Peripheral and central CB1 cannabinoid receptors control stress-induced impairment of memory consolidation

“…Increased activity in the sympathetic-adrenal system involves a rapid release of adrenaline and noradrenaline from adrenal chromaffin cells and sympathetic nerve terminals, respectively (7). Moreover, stress-induced activation of the HPA axis involves the synthesis and secretion of glucocorticoids (cortisol in humans and corticosterone in most rodents) from the adrenal cortex (8). Both animal and human studies have shown that these stress hormones have profound effects on cognition by acting on specific brain regions involved in the processing of emotional stimuli (1,(9)(10)(11)(12).…”

Prenatal Stress and its effects of human cognition, behavior and psychopathology: A review of the literature

“…An excessive concentration of glucocorticoids can have deleterious effects on the developing organism [41,42] and it could permanently affect the expression of Glucocorticoid receptors [43] which are vital for the negative feedback circuit that inhibits Glucocorticoid secretion [44].…”