A Multidimensional Dissection of Antipsychotic Treatment Response in Early Schizophrenia

项目摘要 应对压力是日常生活中普遍存在的问题，慢性压力会暴露出神经精神疾病， 易受影响的个体。压力引起的疾病包括大规模的公共卫生问题，如焦虑， 抑郁和成瘾尽管我们知道与压力相关的临床病理学，但精确的 应激信号传导的神经底物尚不清楚，因此开发治疗性药物非常困难。 某些神经精神疾病的治疗策略受慢性压力影响的一个大脑区域是腹侧 被盖区（VTA），一个异质性的中脑区域。腹侧被盖区细胞多样，具有多巴胺能 (DA)GABA能（GABA）和谷氨酸能（Glu）神经元共同控制和协调被激发的脑- 两个人解释慢性应激对腹侧被盖区神经生理学的影响具有挑战性，因为腹侧被盖区神经元 显示不同的放电模式取决于环境，寿命和强度的压力。也很可能 腹侧被盖区有细胞类型依赖的应激反应因此，我假设慢性压力 elevant细胞类型特异性转录变化，导致VTA神经元活动的功能适应。到 严格测试慢性压力如何影响腹侧被盖区神经生理学，我建议直接和长期管理 皮质酮（CORT）的雄性和雌性小鼠。在cort管理之后，我将首先雇用Drop-seq，一个高... 通量单细胞RNA-seq（scRNAseq）方法，以分析单细胞中VTA基因表达的变化。 长期压力导致的水平（目标1）。接下来，我将利用膜片钳电生理学和单细胞qPCR 在一个细胞类型特异性的细胞模型中测量应激调制的VTA神经元的膜特性和突触活性。 方式使用单细胞qPCR，我将不仅测量压力信号和神经递质的变化， 这将测量从Drop-seq（Aim 2）鉴定的遗传标记的改变。来，我来 将生理学和解剖学归因于基因表达，提供了一个更完整的理解， 应激在分子和生理水平上调节腹侧被盖区神经元。这些实验的结果将 还为高度针对性的行为研究提供了候选遗传标记， VTA中的人群在压力下协调有动机的行为。这些目标将共同促进我们的 了解精神疾病中失调的精确神经回路，有助于寻找 有效的治疗。

PROJECT SUMMARY Coping with stress is a pervasive issue in day-to-day life, with chronic stress unearthing neuropsychiatric disor- ders in susceptible individuals. Stress-induced disorders include massive public health issues such as anxiety, depression and addiction. Despite our knowledge of the clinical pathologies associated with stress, the precise neural substrates of stress signaling remain unclear, and it is thus exceedingly difficult to develop therapeutic strategies for certain neuropsychiatric disorders. One brain region influenced by chronic stress is the ventral tegmental area (VTA), a heterogeneous midbrain area. The VTA is cellularly diverse, possessing dopaminergic (DA), GABAergic (GABA) and glutamatergic (Glu) neurons that together govern and coordinate motivated be- haviors. It is challenging to interpret the impact of chronic stress on VTA neurophysiology, as VTA neurons display differing firing patterns depending on the context, longevity and intensity of the stressor. It is also likely that there are cell-type-dependent responses to stress in the VTA. Therefore, I hypothesize that chronic stress elicits cell-type-specific transcriptional changes, leading to functional adaptations in VTA neuronal activity. To critically test how chronic stress impacts VTA neurophysiology, I propose to directly and chronically administer corticosterone (cort) to male and female mice. Following cort administration, I will first employ Drop-seq, a high- throughput single cell RNA-seq (scRNAseq) method, to profile VTA gene expression changes at a single-cell level resultant from chronic stress (Aim 1). Next, I will utilize patch-clamp electrophysiology and single-cell qPCR to measure membrane properties and synaptic activity of stress-modulated VTA neurons in a cell-type-specific manner. Using single-cell qPCR, I will measure changes in not only stress signaling- and neurotransmitter-re- lated genes, but will also measure alterations in genetic markers identified from Drop-seq (Aim 2). Here, I will attribute physiology and anatomy to gene expression, providing a more complete understanding of how chronic stress modulates VTA neurons at both a molecular and physiological level. Results from these experiments will also provide candidate genetic markers for highly-targeted behavioral studies that will elucidate how discrete cell populations in the VTA orchestrate motivated behaviors under stress. Together, these aims will promote our understanding of the precise neural circuits that are dysregulated in mental illness, contributing to the search for effective treatments.