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

心理健康挑战是全球范围内导致残疾的主要原因之一，每年仅抑郁症和焦虑症就影响数百万人。虽然心理健康可以影响所有年龄组的个人，但儿童和青年在生命早期特别容易受到逆境的影响，这些逆境可能使他们终身承受一系列神经和代谢紊乱的负担。现有的疗法和治疗方法只对一小部分人有效，尽管几十年的努力，我们仍然缺乏有效的治疗各种情感障碍的方法。这是因为缺乏对使一个人容易患上疾病而另一些人却有能力患上疾病的机制的完全理解。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。有毒的压力，情感或身体虐待，或生命早期经历的极端忽视会对个人的成年生活产生累积的影响。童年经历的压力越大，成年后患病的风险就越高。此外，在现代社会，压力水平正在上升，与压力有关的疾病也在上升。因此，迫切需要确定应激源如何被调节的潜在机制以及慢性应激对人类发育的不利影响，以制定治疗干预措施。下丘脑-垂体-肾上腺轴（HPA轴）调节应激的生理反应。在这个轴上，下丘脑室旁核（PVN）中产生促肾上腺皮质激素释放激素神经元的神经元亚群诱导血液中应激激素的增加，以应对应激源。然而，持续升高的压力激素水平，因为它们发生在慢性压力下，会对大脑和身体产生有害影响。值得注意的是，在生命早期如此高的水平可以诱导特定电路的结构和分子改变，使年轻人易患多种疾病。在这个项目中，我们将使用成熟的慢性社会压力源实验模型，它可以有一个动态范围，从完全的社会隔离到严重的身体或精神虐待，已知会导致情感障碍。该项目的创新之处在于新神经技术的应用，这些新技术可以选择性地分离特定电路中的单个神经元，并分析它们的转录组，以确定它们的分子身份以及它们用来与下游神经元伙伴交流的信号分子。利用这些强大的新工具，再加上病毒追踪和绘制特定回路中单个神经元的神经元活动，我们将在单细胞水平上研究青春期不同的社会压力源如何影响CRH神经元功能，并绘制其上游突触前伙伴中发生的结构连接、功能和分子损伤。这些研究将为年轻人如何易受慢性社会压力影响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。这些方法将具有广泛的应用，并且可以很容易地适应于研究具有电路功能障碍的神经系统疾病，例如神经发育性自闭症谱系障碍，这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.