Genetic Approaches to Hypothalamic-Pituitary-Adrenal Axis Regulation

Abstract

The normal function of the hypothalamic-pituitary-adrenal (HPA) axis, and resultant glucocorticoid (GC) secretion, is essential for human health. Disruption of GC regulation is associated with pathologic, psychological, and physiological disease states such as depression, post-traumatic stress disorder, hypertension, diabetes, and osteopenia, among others. As such, understanding the mechanisms by which HPA output is tightly regulated in its responses to environmental stressors and circadian cues has been an active area of investigation for decades. Over the last 20 years, however, advances in gene targeting and genome modification in rodent models have allowed the detailed dissection of roles for key molecular mediators and brain regions responsible for this control in vivo to emerge. Here, we summarize work done to elucidate the function of critical neuropeptide systems, GC-signaling targets, and inflammation-associated pathways in HPA axis regulation and behavior, and highlight areas for future investigation.

Figure 1

HPA axis regulation by the endocrine and central nervous systems neurons in the central nervous system (CNS) can affect HPA axis activity by regulating CRH secretion in the PVN. Extrahypothalamic regions that influence the HPA axis through neuropeptide secretion include the bed nucleus of the stria terminalis (BnST), dorsal raphe nucleus (raphe), nucleus of the solitary tract (NTS), and the ventral subiculum (Vsub). The neurotransmitters from these regions can have an inhibitory (γ-aminobutyric acid [GABA]) or excitatory (norepinephrine [NE], and serotonin [5-HT]) effect on the PVN. +=excites, −=inhibits.

Figure 2

HPA axis regulation in PVN GR exon 3-deleted mice (Sim1Cre-GRe3Δ). Left side: Control—Under normal circumstances, cort acts on glucocorticoid receptors (red dots) at negative feedback sites in the pituitary and PVN to inhibit further HPA axis activation. Right side: PVN GR deletion—Loss of PVN GR (shaded yellow region) prevents cort-feedback inhibition of the HPA axis and leads to increased PVN CRH and increased plasma ACTH that further elevate cort levels. The chronic glucocorticoid excess leads to impaired negative feedback, exaggerated stress-induced HPA axis activation, locomotor deficits, and a Cushingoid phenotype.