Optogenetic recruitment of hypothalamic corticotrophin-releasing-hormone (CRH) neurons reduces motivational drive.

Impaired motivational drive is a key feature of depression. Chronic stress is a known antecedent to the development of depression in humans and depressive-like states in animals. Whilst there is a clear relationship between stress and motivational drive, the mechanisms underpinning this association remain unclear. One hypothesis is that the endocrine system, via corticotropin-releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN; PVNCRH), initiates a hormonal cascade resulting in glucocorticoid release, and that excessive glucocorticoids change brain circuit function to produce depression-related symptoms. Another mostly unexplored hypothesis is that the direct activity of PVNCRH neurons and their input to other stress- and reward-related brain regions drives these behaviors. To further understand the direct involvement of PVNCRH neurons in motivation, we used optogenetic stimulation to activate these neurons 1 h/day for 5 consecutive days and showed increased acute stress-related behaviors and long-lasting deficits in the motivational drive for sucrose. This was associated with increased Fos-protein expression in the lateral hypothalamus (LH). Direct stimulation of the PVNCRH inputs in the LH produced a similar pattern of effects on sucrose motivation. Together, these data suggest that PVNCRH neuronal activity may be directly responsible for changes in motivational drive and that these behavioral changes may, in part, be driven by PVNCRH synaptic projections to the LH.

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

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 PVNCRH 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 PVNCRH neural function, consider how this may influence synaptic targets of PVNCRH neurons, and discuss the potential role of these PVNCRH 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 PVNCRH neurons in chronic stress, their potential interactions, and therapeutic opportunities for the treatment of stress related disorders.