A Multidimensional Dissection of Antipsychotic Treatment Response in Early Schizophrenia

早期精神分裂症抗精神病药物治疗反应的多维剖析

• 批准号: 10181080
• 负责人: Rhiana Catherine Simon
• 金额: $ 4.13万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10181080
• 关键词: Affect; Anatomy; Anhedonia; Antipsychotic Agents; Anxiety; Architecture; Area; Behavior; Biological; Biological Process; Brain region; Candidate Disease Gene; Cells; Chronic; Chronic stress; Clinical Pathology; Cognitive deficits; Conflict (Psychology); Corticosterone; Data; Development; Disease; Dissection; Dopamine; Electrophysiology (science); Emotions; Female; Future; Gene Expression; Genes; Genetic Markers; Genetic Predisposition to Disease; Genetic Transcription; Glutamates; Goals; Health; Heterogeneity; Hormones; In Situ Hybridization; Individual; Knowledge; Label; Lead; Learning; Life; Light; Link; Longevity; Measures; Membrane; Mental Depression; Mental disorders; Methods; Midbrain structure; Molecular; Molecular Profiling; Mus; Neurons; Neurotransmitters; Nuclear Receptors; Pathology; Pattern; Pharmaceutical Preparations; Physiological; Physiology; Population; Property; Psyche structure; Public Health; RNA; Rewards; Schizophrenia; Signal Transduction; Stress; Surveys; Synapses; Techniques; Testing; Therapeutic; Tissues; Training; Ventral Tegmental Area; addiction; allostatic load; behavioral study; bioinformatics pipeline; biological adaptation to stress; cell type; coping; differential expression; dopaminergic neuron; drinking water; droplet sequencing; effective therapy; experience; experimental study; functional adaptation; insight; male; motivated behavior; neural circuit; neurophysiology; neuropsychiatric disorder; novel therapeutics; patch clamp; pleasure; programs; relating to nervous system; response; single-cell RNA sequencing; stressor; transcriptome; treatment response

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.

项目总结 应对压力是日常生活中普遍存在的问题，慢性压力会导致神经精神障碍-- 易感人群中的DES。应激性精神障碍包括大规模的公共健康问题，如焦虑、 抑郁和上瘾。尽管我们知道与压力相关的临床病理，但准确的 应激信号的神经基础仍不清楚，因此开发治疗非常困难。 针对某些神经精神障碍的策略。受慢性应激影响的大脑区域之一是腹侧 被盖区(VTA)，一个异质性的中脑区域。VTA是细胞多样性的，具有多巴胺能 (DA)、GABA(GABA)和Glu(Glu)神经元共同管理和协调兴奋的BE- 行为者。将慢性应激对VTA神经生理学的影响解释为VTA神经元是具有挑战性的。 根据应激源的环境、寿命和强度显示不同的激发模式。它也有可能是 VTA内存在依赖细胞类型的应激反应。因此，我假设慢性压力 引起特定细胞类型的转录变化，导致VTA神经元活动的功能适应。至 严格测试慢性应激对VTA神经生理学的影响，我建议直接和长期使用 皮质酮(CORT)对雄性和雌性小鼠。在CORT管理之后，我将首先雇用Drop-Seq，一个高级- 吞吐量单细胞RNA-seq(ScRNAseq)方法，以描述单细胞VTA基因表达的变化 慢性压力所产生的水平(目标1)。接下来，我将利用膜片钳电生理学和单细胞定量聚合酶链式反应 在特定细胞类型中测量应激调节的VTA神经元的膜特性和突触活性 举止。使用单细胞定量聚合酶链式反应，我将不仅测量压力信号-和神经递质-re-的变化。 但也将测量从Drop-Seq(目标2)中确定的遗传标记的变化。在这里，我会 将生理学和解剖学归因于基因表达，从而更全面地了解慢性 应激在分子水平和生理水平上调节VTA神经元。这些实验的结果将 还为高针对性的行为研究提供候选遗传标记，这些研究将阐明离散的细胞如何 VTA中的人群在压力下协调动机行为。这些目标加在一起，将促进我们的 对精神疾病中失调的精确神经回路的理解，有助于寻找 有效的治疗方法。