Stanton Laura M, Price Aidan J, Manning Elizabeth E
School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia.
Brain Neuromodulation Program, Hunter Medical Research Institute (HMRI), New Lambton Heights, Australia.
J Neuroendocrinol. 2023 Apr;35(4):e13268. doi: 10.1111/jne.13268. Epub 2023 Apr 20.
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 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 neural function, consider how this may influence synaptic targets of PVN neurons, and discuss the potential role of these PVN 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 neurons in chronic stress, their potential interactions, and therapeutic opportunities for the treatment of stress related disorders.
压力对全球心理健康有着强大的影响。数十年来的研究一直试图确定压力导致诸如抑郁症等精神疾病的机制，以潜在地指导针对压力系统的治疗方法的开发。下丘脑-垂体-肾上腺（HPA）轴是关键的内分泌系统，负责协调在压力下生存所必需的全身变化，并且许多旨在理解压力导致抑郁症机制的研究都集中在HPA轴功能障碍上。下丘脑室旁核（PVN）中的促肾上腺皮质激素释放激素（CRH）神经元位于HPA轴的顶端，整合与压力和外部威胁相关的信号，以确保HPA轴的活动适合给定的情境。除此之外，新出现的研究表明，PVN神经元的神经活动通过调节下游突触靶点来调节与压力相关的行为。本综述将总结来自慢性应激临床前研究和情绪障碍临床研究的趋同证据，这些证据表明PVN神经功能发生了变化，考虑这可能如何影响PVN神经元的突触靶点，并讨论这些PVN突触通路在慢性应激后与抑郁症相关的适应不良行为发展中的潜在作用。我们还将突出未来研究的重要问题，这些研究旨在精确剖析PVN神经元在慢性应激中的内分泌和突触作用、它们的潜在相互作用以及治疗与压力相关疾病的治疗机会。
