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

点击翻译按钮获取中文摘要

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.