Synaptic regulation of the hypothalamic-pituitary-adrenal axis and its modulation by glucocorticoids and stress

Abstract

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in a range of affective and stress-related disorders. The regulatory systems that control HPA activity are subject to modulation by environmental influences, and stressful life events or circumstances can promote subsequent HPA dysregulation. The brain is a major regulator of the HPA axis, and stress-induced plasticity of the neural circuitry involved in HPA regulation might constitute an etiological link between stress and the development of HPA dysregulation. This review focuses on the synaptic regulation of neuroendocrine corticotropin-releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus, which are the cells through which the brain predominantly exerts its influence on the HPA axis. CRH neuronal activity is largely orchestrated by three neurotransmitters: GABA, glutamate, and norepinephrine. We discuss our current understanding of the neural circuitry through which these neurotransmitters regulate CRH cell activity, as well as the plastic changes in this circuitry induced by acute and chronic stress and the resultant changes in HPA function.

Keywords: GABA; corticosteroid; depression; glutamate; neural circuits; norepinephrine; paraventricular nucleus; synaptic plasticity.

FIGURE 1

Distinct electrophysiological fingerprints of PVN magnocellular and parvocellular neurons. (A) Magnocellular neuroendocrine cells recorded in current-clamp mode generate an A-type K⁺ current-mediated transient outward rectification (arrow) that is generated by depolarization from a hyperpolarized holding membrane potential and delays the onset of spiking. Lower traces: current injection protocol. (B) Parvocellular neuroendocrine cells fail to generate a transient outward rectification and delay to spiking (arrow) in response to a similar current injection protocol. (C) Parvocellular preautonomic cells do not display a transient outward rectification, but generate a low-threshold spike (arrow), mediated by a T-type Ca²⁺ current, and clustered action potentials in response to a similar current injection protocol. Modified from Luther and Tasker (2000).

FIGURE 2

Model of noradrenergic regulation of PVN CRH neuron activity. Noradrenergic inputs (NE) originate in the brainstem and regulate CRH neuronal activity by modulating glutamate and GABA release. Norepinephrine both suppresses and enhances GABAergic inhibition of CRH neuron activity, suppressing GABA release via α₂-adrenoceptor activation at presynaptic terminals and promoting GABA release by activating α₁-adrenoceptors on upstream GABAergic somata/dendrites. Noradrenergic facilitation of glutamate release onto CRH neurons is spike-dependent and is mediated by α₁-adrenoceptor activation. Preliminary evidence suggests that the facilitatory effect on glutamate release may be mediated by the release of a retrograde messenger that stimulates upstream local glutamatergic circuits (dashed arrow). 3V, thrid ventricle; OT, optic tract.