"Circuit-omics": A Novel Approach to Investigate Neural Circuitry of Stress

精神健康挑战是全球残疾的主要原因之一，仅抑郁症和焦虑症每年就影响数百万人。虽然心理健康可以影响所有年龄段的人，但儿童和年轻人在早年特别容易受到逆境的影响，使他们容易受到一系列神经和新陈代谢疾病的终身负担。现有的治疗方法和治疗只对一小部分人有效，尽管经过几十年的努力，我们仍然缺乏对各种情感障碍的有效治疗。这是因为对使一个人容易患上障碍而其他人有弹性发展任何障碍的机制缺乏完整的了解。众所周知，童年时期的不良经历会对身心健康产生不良影响。在生命早期经历的有毒压力、情感或身体虐待或极端疏忽可能会对个人成年生活造成累积损失。童年经历的压力越大，成年后罹患疾病的风险就越高。此外，在现代社会，压力水平正在上升，与压力相关的疾病也在上升。因此，迫切需要确定应激源如何调节的潜在机制以及慢性应激对人类发育的不利影响，以开发治疗干预措施。下丘脑-垂体-肾上腺轴(HPA轴)调节对应激的生理反应。在这个轴上，位于下丘脑室旁核(PVN)中产生CRH(促肾上腺皮质激素释放激素产生神经元)的神经元亚群引起应激激素的血液增加，以响应应激源。然而，在慢性应激过程中，压力荷尔蒙水平持续升高，可能会对大脑和身体产生有害影响。值得注意的是，早期生命中如此高的水平可能会导致特定回路的结构和分子变化，使年轻人容易患上多种疾病。在这个项目中，我们将使用成熟的慢性社会压力源的实验模型，这些压力源可以具有从完全的社会孤立到严重的身体或情感虐待的动态范围，众所周知，这些虐待会导致情感障碍。该项目的创新方面是应用新的神经技术，能够选择性地分离特定电路中的单个神经元，并描绘它们的转录本，以确定它们的分子身份以及它们用来与下游神经元伙伴通信的信号分子。使用这些强大的新工具，结合病毒追踪和绘制特定回路中单个神经元的神经元活动图，我们将研究青春期不同的社会应激源如何影响CRH神经元的功能，并在单细胞水平上绘制其上游突触前伙伴发生的结构连接、功能和分子损伤的图谱。这些研究将对年轻人如何容易受到慢性社会压力的神经基础提供重要的新见解，这些发现将有助于发现新的治疗干预措施。这些方法将有广泛的应用，并可以很容易地适应于研究具有电路功能障碍的神经疾病，如神经发育性自闭症谱系障碍，这些障碍通常与严重的神经内分泌缺陷和社交能力受损有关。

Mental health challenges are one of the leading causes of disabilities across the globe, with depression and anxiety alone affecting millions every year. While mental health can affect individuals across all age groups, children and young adults are particularly vulnerable to adversities during early life that can render them susceptible to a lifelong burden to a range of neurological and metabolic disorders. Available therapies and treatments are effective only in a fraction of individuals, and despite decades of efforts, we still lack an effective therapy for various affective disorders. This is because of the lack of complete understanding of the mechanisms that make an individual susceptible to disorders while others are resilient to develop any. Adverse experiences during childhood are known to have ill effects on mental and physical health. Toxic stress, emotional or physical abuse, or extreme neglect experienced early in life can have a cumulative toll on individual adult life. The more stressful childhood experiences, the higher are the risks of developing diseases during adulthood. Moreover, in modern societies, stress levels are rising, and so are the diseases related to stress. Therefore, it is urgent to identify the underlying mechanisms of how stressors are regulated and the adverse effects of chronic stress on human development to develop therapeutic interventions. The hypothalamic-pituitary-adrenal axis (HPA axis) regulates the physiological responses to stress. In this axis, a subset of neurons that produce CRH (corticotropin-releasing hormone-producing neurons) located in the paraventricular nucleus of the hypothalamus (PVN) induce increases in blood of stress hormones in response to stressors. However, constantly elevated stress hormone levels, as they occur during chronic stress, can have deleterious effects on the brain and the body. Notably, such high levels during early life can induce structural and molecular alterations in specific circuits, predisposing young individuals to a multitude of disorders. In this project, we will use well-established experimental models of chronic social stressors, which can have a dynamic range from complete social isolation to severe physical or emotional abuse, known to cause affective disorders. The innovating aspect of this project is the application of new neurotechnologies that enable selective isolation of individual neurons in specific circuits and profile their transcriptomes to define their molecular identities and the signaling molecules they use to communicate with their downstream neuronal partners. Using these powerful new tools, together with viral tracing and mapping neuronal activity of individual neurons in specific circuits, we will investigate how different social stressors during adolescence impact CRH neuron function and map the structural connectivity, functional and molecular impairments occurring in its upstream presynaptic partners - at a single-cell level. These studies will provide important new insights on the neural basis of how young individuals are susceptible to chronic social stress, and these findings will help the discovery of new therapeutic interventions. These approaches will have broad applications and can be readily adapted to study neurological disorders with circuit dysfunction, such as neurodevelopmental autism spectrum disorders, which are often associated with severe neuroendocrine deficits and impaired sociability.