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

Benjamin H Levy,Jeffrey G Tasker

doi:10.3389/fncel.2012.00024

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.

Highlights

Glucocorticoids are released in response to physical, emotional, and/or metabolic stress, and many of the effects of glucocorticoids are thought to serve as adaptive responses to stressful events or circumstances
Stressful life events have been implicated in the onset of each of these disorders (Kendler et al, 1995; Hatcher and House, 2003; Gupta and Silman, 2004; BrawmanMintzer et al, 2005; Garno et al, 2005; Goodwin et al, 2005; Sarkhel et al, 2011), and dysregulation of the HPA axis may be an etiological link between stress and the subsequent development of pathology
corticotropin-releasing hormone (CRH) and VP in the portal circulation bind to CRH and VP receptors on a subset of cells, the corticotropes, of the anterior pituitary to stimulate the secretion of adrenocorticotropic hormone (ACTH) into the systemic circulation

Summary

CELLULAR NEUROSCIENCE

Reviewed by: Yang Dan, University of California Berkeley, USA Corette Wierenga, Utrecht University, Netherlands. Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis has been implicated in a range of affective and stress-related disorders. 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

INTRODUCTION

Synaptic regulation of the HPA axis

Findings

METHODS