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.

Associations between CSF cortisol and CSF norepinephrine in cognitively normal controls and patients with amnestic MCI and AD dementia

“… How these changes in AD may influence HPA axis activation is less clear. In animal studies, LC projections to the PVN are present, although the substantial proportion noradrenergic input comes from the nucleus of the solitary tract . There also may not be detectable differences in NE measured in the hypothalami of AD subjects compared with controls .…”

“…These range from direct projections and indirect paths between brain structures, signaling through peripheral sympathetic input, and glucocorticoid negative feedback. 2,22 Given the complexity of the relationships between these 2 stress systems, it is not surprising that we did not find the association between CSF cortisol and CSF NE in controls we had anticipated. These multiple regulatory mechanisms likely obscure finding a significant relationship between CSF NE and CSF cortisol, particularly as the latter hormone is derived from the periphery and must cross the blood brain barrier.…”

“…Although stimulatory regulation of the HPA access by central noradrenergic system input is well established, this mechanism is one among multiple neural and endocrine regulators of the HPA axis. These range from direct projections and indirect paths between brain structures, signaling through peripheral sympathetic input, and glucocorticoid negative feedback . Given the complexity of the relationships between these 2 stress systems, it is not surprising that we did not find the association between CSF cortisol and CSF NE in controls we had anticipated.…”

Corticotropin‐releasing factor receptor 2‐deficiency eliminates social behaviour deficits and vulnerability induced by cocaine

“…Studies also suggest a complex role for the CRF system in social behaviour. Indeed, AVP is co-released with CRF from the paraventricular nucleus of the hypothalamus (PVN) to potentiate stress responses, whereas OT reduces the stress-induced PVN-CRF transcription (Bulbul et al, 2011;Jurek et al, 2015;Herman and Tasker, 2016). administration of CRF facilitates partner preference in male prairie voles (DeVries et al, 2002).…”

The relationship between GABA and stress: ‘it's complicated’

“…Previous studies have demonstrated stress‐induced changes in the GABAergic regulation of CRH neurons, including altered GABA A R subunit expression, a reduction in presynaptic GABA release, and overall impairments in GABAergic signalling onto CRH neurons (Herman & Tasker, ). The CORT‐mediated effects on the GABAergic regulation of CRH neurons demonstrated in Colmers & Bains () may contribute to these stress‐induced changes in GABAergic regulation of CRH neurons.…”