Neural Regulation of the Stress Response: The Many Faces of Feedback

Abstract

The mammalian stress response is an integrated physiological and psychological reaction to real or perceived adversity. Glucocorticoids (GCs) are an important component of this response, acting to redistribute energy resources to both optimize survival in the face of challenge and restore homeostasis after the immediate threat has subsided. Release of GCs is mediated by the hypothalamo-pituitary-adrenocortical (HPA) axis, driven by a neural signal originating in the paraventricular nucleus (PVN). Stress levels of GCs bind to glucocorticoid receptors (GRs) in multiple body compartments, including brain, and consequently have wide-reaching actions. For this reason, GCs serve a vital function in feedback inhibition of their own secretion. Fast, non-genomic feedback inhibition of the HPA axis is mediated at least in part by GC signaling in the PVN, acting by a cannabinoid-dependent mechanism to rapidly reduce both neural activity and GC release. Delayed feedback termination of the HPA axis response is mediated by forebrain GRs, presumably by genomic mechanisms. GCs also act in the brainstem to attenuate neuropeptidergic excitatory input to the PVN via acceleration of mRNA degradation, providing a mechanism to attenuate future responses to stressors. Thus, rather than having a single defined feedback switch, GCs work through multiple neurocircuits and signaling mechanisms to coordinate HPA axis activity to suit the overall needs of multiple body systems.

Fig. 1

The HPA axis regulates the endocrine stress response with activation mediated by CRH-containing neurons in the hypothalamic PVN. The release of CRH onto cells of the anterior pituitary induces the secretion of ACTH into systemic circulation. At the adrenal cortex, ACTH stimulates synthesis and release of GCs (cortisol in humans and corticosterone in rodents). GCs then activate MRs and GRs providing a feedback signal to regulate HPA axis activity

Fig. 2

GCs can rapidly inhibit CRH release from PVN neurons by acting on membrane-associated receptors. Receptor activation leads to retrograde eCB signaling at CB1 receptors which suppresses excitation of presynaptic glutamatergic neurons

Fig. 3

GC negative feedback can generally be divided into three interacting domains. First, GCs provide rapid, nongenomic inhibition of excitatory inputs to the PVN. In addition, GCs affect RNA stability in brain structures with direct, excitatory innervation of the PVN. Forebrain genomic GC signaling is also a key component of feedback regulation. Importantly, these structures have little or no direct interactions with the PVN and require intermediary synapses in PVN-projecting cell groups. Specifically, GCs act in the plPFC and the ventral subiculum to inhibit the PVN via GABAergic synaptic relays. BST: bed nucleus of stria terminalis, DMH dorsomedial hypothalamus, EC endocannabinoid, GLP-1 glucagon-like peptide-1, Glu glutamate, NTS nucleus of the solitary tract, PH posterior hypothalamus, plPFC prelimbic prefrontal cortex, VMH ventromedial hypothalamus, vSub ventral subiculum, + denotes excitation and − inhibition

Fig. 4

Depending on physiological demand and anticipatory signals from the forebrain, GCs may provide feedforward excitation of the HPA axis. GCs can upregulate CRH signaling in the amygdala and BST, potentially prolonging GC secretion. GCs may also act on glutamatergic neurons in the ilPFC and BLA to excite PVN CRH neurons via synaptic relays in the hypothalamus. BLA basolateral amygdala, CeA central amygdala, ilPFC infralimbic prefrontal cortex, MeA medial amygdala, NE norepinephrine, + denotes excitation and − inhibition