Hypothalamic corticotrophin releasing hormone neurons in stress‐induced psychopathology: Revaluation of synaptic contributions

Abstract

Stress has a strong influence on mental health around the world. Decades of research has sought to identify mechanisms through which stress contributes to psychiatric disorders such as depression, to potentially guide the development of therapeutics targeting stress systems. The hypothalamic pituitary adrenal (HPA) axis is the key endocrine system that is responsible for coordinating body-wide changes that are necessary for survival under stress, and much of the research aimed at understanding the mechanisms by which stress contributes to depression has focussed on HPA axis dysfunction. Corticotrophin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) sit at the apex of the HPA axis, integrating signals relevant to stress and external threats, to ensure HPA axis activity is appropriate for the given context. In addition to this, emerging research has demonstrated that neural activity in PVN CRH neurons regulates stress related behaviours via modulation of downstream synaptic targets. This review will summarize convergent evidence from preclinical studies on chronic stress and clinical research in mood disorders demonstrating changes in PVN CRH neural function, consider how this may influence synaptic targets of PVN CRH neurons, and discuss the potential role of these PVN CRH synaptic pathways in the development of maladaptive behaviours following chronic stress that are relevant to depression. We will also highlight important questions for future research aimed at precisely dissecting endocrine and synaptic roles of PVN CRH neurons in chronic stress, their potential interactions, and therapeutic opportunities for the treatment of stress related disorders.

Chemogenetic activation of PVN CRH neurons disrupts the estrous cycle and LH dynamics in female mice

“…Repeated daily cat exposure ( 41 ), CVS ( 47 – 49 ) and repeated immobilization ( 50 ) up-regulated PVN mRNA CRH expression in the rat. It has also been demonstrated that PVN neurons remain active after long-term glucocorticoid negative feedback ( 51 ), and chronic stress may even increase the excitability of PVN CRH neurons via multiple mechanisms ( 52 ). Our mathematical modeling could also be extended to interrogate other physiological phenomena such as the mechanisms by which the PVN CRH neural system underlies the adverse outcomes of nutritional programming on cardiovascular disease ( 53 ).…”

An Interaction between Brain-Derived Neurotrophic Factor and Stress-Related Glucocorticoids in the Pathophysiology of Alzheimer’s Disease

“…Importantly, secreted GCs from the adrenal glands, located on top of the kidneys, contribute to regulated blood levels of GCs via the negative feedback mechanism of the HPA axis. Since the HPA axis is considered a key endocrine system that has a critical role in the coordination of body-wide changes to survive stress, a lot of studies are focusing on the relationship between depression and the dysfunction of the HPA axis [22]. Recent evidence also shows changed neuronal function of corticotrophin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) is involved in stress-related behaviors [22].…”

“…Since the HPA axis is considered a key endocrine system that has a critical role in the coordination of body-wide changes to survive stress, a lot of studies are focusing on the relationship between depression and the dysfunction of the HPA axis [22]. Recent evidence also shows changed neuronal function of corticotrophin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) is involved in stress-related behaviors [22]. Generally, an activation of the HPA axis, which is required for the secretion of GCs acting on a variety of organs to cope with stress during the process of adaptation, invokes CRH release from PVN neurons.…”