Neural control of chronic stress adaptation.

Inverted U-shaped relationship between physiologic or behavioral “performance' and HPA axis output (corticosterone secretion). Secretion of glucocorticoids following stress is likely an adaptive function, supplying needed energy to meet real or potential threats. Underactive stress axis activation does not mobilize the resources needed to meet a challenge, resulting in suboptimal performance (left arm of the U-shaped curve). Excessive glucocorticoid secretion (right arm of the U-shaped curve) can cause excessive or prolonged catabolic responses, which can result in turn-off of vital stress counter-regulatory systems or energetic challenge in the CNS (see text).

Time domains of glucocorticoid feedback. Fast glucocorticoid feedback occurs in the realm of minutes to seconds, and likely involves membrane effects of glucocorticoids on endocannabinoid synthesis at the PVN. Delayed feedback controls return of glucocorticoid levels to baseline, and likely involves glucocorticoid feedback signals at multiple brain regions, including the prefrontal cortex, ventral subiculum (hippocampus) and possibly the nucleus of the solitary tract. It is not clear whether delayed feedback is genomic, non-genomic or a combination of both.

Stress habituation and facilitation. Repeated exposure to the same stressor results in progressive diminution of response magnitude, thought to be mediated by structures such as the prefrontal cortex (PFC) and paraventricular thalamus (PVT). Exposure to a new stressor after either homotypic or hetertypic stressors causes a larger than normal (“sensitized' or “facilitated' response), which may be mediated by enhanced drive from the basolateral amygdala (BLA), PVT or locus coeruleus (LC).

Chronic unpredictable stress-recruited circuitry. Exposure to chronic variable stress (CVS) selectively recruits chronic cellular activation (in terms of FosB expression) in a discrete set of interconnected brain regions, including the prefrontal cortex (PFC), nucleus of the solitary tract (NTS), and the posterior hypothalamic nucleus (PH). The PH projects to both the PH and NTS, and both PH and NTS project to the PVN, creating the opportunity for PFC-PVN regulation in parallel, in series, or both. Via this pathway, chronic stress can increase drive to the PFC and subsequently cause glucocorticoid-mediated endocrine, behavioral, and metabolic dysfunction. This figure is reprinted from Flak et al. (2012), with permission.