Paraventricular Hypothalamic Mechanisms of Chronic Stress Adaptation

Abstract

The hypothalamic paraventricular nucleus (PVN) is the primary driver of hypothalamo-pituitary-adrenocortical (HPA) responses. At least part of the role of the PVN is managing the demands of chronic stress exposure. With repeated exposure to stress, hypophysiotrophic corticotropin-releasing hormone (CRH) neurons of the PVN display a remarkable cellular, synaptic, and connectional plasticity that serves to maximize the ability of the HPA axis to maintain response vigor and flexibility. At the cellular level, chronic stress enhances the production of CRH and its co-secretagogue arginine vasopressin and rearranges neurotransmitter receptor expression so as to maximize cellular excitability. There is also evidence to suggest that efficacy of local glucocorticoid feedback is reduced following chronic stress. At the level of the synapse, chronic stress enhances cellular excitability and reduces inhibitory tone. Finally, chronic stress causes a structural enhancement of excitatory innervation, increasing the density of glutamate and noradrenergic/adrenergic terminals on CRH neuronal cell somata and dendrites. Together, these neuroplastic changes favor the ability of the HPA axis to retain responsiveness even under conditions of considerable adversity. Thus, chronic stress appears able to drive PVN neurons via a number of convergent mechanisms, processes that may play a major role in HPA axis dysfunction seen in variety of stress-linked disease states.

Keywords: corticotropin-releasing hormone; glucocorticoids; hypothalamo–pituitary–adrenal axis; neuroendocrine system; vasopressin.

Figure 1

Plasticity across the hypothalamo–pituitary–adrenocortical (HPA) axis following chronic stress. HPA axis activation is initiated by CRH (and AVP)-containing neurons in the medial parvocellular paraventricular nucleus (PVN), which releases ACTH secretagogues into hypophysial portal vessels in the median eminence. ACTH is released from the pituitary and travels via the systemic circulation to the adrenal cortex, where it causes the synthesis and secretion of glucocorticoids [e.g., cortisol or corticosterone (CORT)]. Under conditions of chronic stress, there are marked changes in cellular reactivity across the HPA axis, including (1) increased CRH and AVP expression in, and enhanced excitability of CRH neurons in the PVN, (2) increased CRH/AVP colocalization and CRH release in the median eminence, (3) increased CRHR1 and V1b gene expression in and sensitivity to CRH and AVP of pituitary corticotropes, and (4) adrenal hypertrophy and enhanced adrenal sensitivity to ACTH. All changes are consistent with increased potential for HPA axis activation. Modified from Myers et al. (4), with permission.

Figure 2

Cellular plasticity in parvocellular paraventricular nucleus neurons following chronic stress. Chronic stress causes a number of neuroplastic changes in parvocellular neurons consistent with increased excitability, including (1) increased number of (excitatory) glutamergic (VGluT2) terminal appositions, (2) enhanced excitatory synaptic inputs (increase in mEPSC frequency), (3) enhanced NR2A/NR2B ratio, predictive of increased NMDA receptor calcium permeability, and (4) increased number of (putative excitatory) norepinephrine/epinephrine terminal appositions. In addition, there is evidence for reduced inhibition of the PVN neurons, in terms of (1) reduced GABAergic synaptic inputs (decrease in mIPSC frequency), (2) decreased expression of synaptic and extrasynaptic GABA_A receptor subunits, (3) decreased cannabinoid type 1 receptor signaling, and (4) reduced GR expression/signaling, in some, but not all, studies.