Stress-induced plasticity in serotonin neurons: vulnerability and resilience.

压力诱导的血清素神经元可塑性：脆弱性和恢复力。

• 批准号: 8853976
• 负责人: John F Neumaier
• 金额: $ 27.31万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8853976
• 关键词: Affect; Animals; Antibodies; Anxiety; Anxiety Disorders; Autoreceptors; Behavior; Behavioral; Behavioral Assay; Brain region; Cells; Chronic; Chronic stress; Clozapine; Complex; Corticosterone; Engineering; Epitopes; Exposure to; Fingerprint; Future; Gene Expression; Gene Expression Profile; Gene Proteins; Genes; Genetic Translation; Goals; Health Priorities; Histone Acetylation; Individual; Lead; Ligands; Measures; Mediating; Mental Depression; Messenger RNA; Methods; Midbrain structure; Molecular; Molecular Target; Mood Disorders; Motivation; Mus; Neurons; Oxides; Pathway Analysis; Pathway interactions; Pattern; Pharmacological Treatment; Phenotype; Physiological Adaptation; Play; Polyribosomes; Post-Traumatic Stress Disorders; Proteins; Psychological adjustment; RNA Sequence Analysis; Regulation; Ribosomal Proteins; Risk; Role; Saccharin; Sampling; Sensory Receptors; Series; Serotonergic System; Serotonin; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Social Interaction; Solutions; Specific qualifier value; Specificity; Stimulus; Stress; Swimming; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Translating; Translations; Viral Vector; anxiety-like behavior; biological adaptation to stress; cell type; cytokine; depressive behavior; dorsal raphe nucleus; emotional behavior; experience; hedonic; improved; novel; prevent; receptor; resilience; response; restraint; selective expression; social; stress disorder; stress reactivity; stressor; therapeutic development; transcriptome sequencing

Project Summary Repeated, uncontrollable stress is a key contributor to depression and anxiety disorders, including posttraumatic stress disorder. Stress causes a series of psychological and physiological adaptations that can be chronic and sustained, and likely contribute to the vulnerability to subsequent bouts of depression and anxiety. On the other hand, some individuals can be exposed to stress repeatedly and appear to be relatively resilient. Given that the serotonin system plays a key role in stress responses and the pharmacological treatment of stress disorders, we presume that the adaptations associated with vulnerability and resilience are represented in cellular and molecular plasticity in the raphe neurons of individuals following exposure to stress, especially in pathways that are involved in signal transduction. This project will use mouse behavioral and molecular strategies to investigate these adaptations and how resilience might be promoted while vulnerability might be prevented or reversed. Aim 1 will examine how modulating signal transduction pathways within serotonergic neurons might alter the behavioral phenotype of animals exposed to repeated social defeat stress. We proposed to express DREADDs that activate Gi or Gs signaling pathways selectively in serotonergic neurons (ePet1-Cre mice). The effects of DREADD activation prior to repeated social defeat on stress responsiveness in behavioral assays of depression-like and anxiety-like behaviors. This Aim will provide new mechanistic and therapeutic clues regarding how plasticity in the serotonin system confers vulnerability or resilience to stress. In Aim 2 we will evaluate whether DREADD-mediated inhibition of serotonergic neurons in the interval after repeated social defeat stress can reverse the enhanced vulnerability to subsequent stressors, using corticosterone responses to restraint and immobility in the forced swim test to assess different domains of stress reactivity. Aim 3 will selectively interrogate the translation of mRNA by selectively expressing “RiboTag” in the serotonergic neurons of ePET1-Cre mice. RiboTag is an epitope-tagged ribosomal protein that allows for antibody-mediated pull down only of polysomes from target cells derived from a complex cell homogenate (in this case a fresh midbrain tissue punch). Enrichment of mRNA from serotonergic neurons will allow us to perform RNA-seq to investigate the totality of actively translated mRNA at key points during and after stress exposure. We will focus on mRNAs associated with excitability, signal transduction pathways, and cytokine responses, and use pathway analysis to identify co-regulation of mRNA translation in response to stress; this is intended to provide new mechanistic information and new targets for therapeutic development.

项目摘要 反复，无法控制的压力是抑郁症和焦虑症的关键因素，包括 创伤后应激障碍。压力会导致一系列心理和身体适应 长期持久和持续，并可能导致对随后的抑郁症的脆弱性和 焦虑。另一方面，某些人可以反复承受压力，并且似乎是相对的 有弹性的。鉴于5-羟色胺系统在压力反应和药物中起关键作用 治疗压力障碍，我们认为与脆弱性和韧性相关的适应性是 在暴露于应力后，在个体的raphe神经元中以细胞和分子可塑性表示 特别是在涉及信号转导的途径中。该项目将使用鼠标行为和 研究这些适应以及如何促进弹性的分子策略，而脆弱性 AIM 1将检查如何调节信号转导途径 血清素能神经元可能会改变暴露于反复社会失败的动物的行为表型 压力。我们提议表达在选择性地激活GI或GS信号通路的可怕 血清素能神经元（EPET1-CRE小鼠）。在重复社会失败之前，Dreadd激活的影响 在类似抑郁症和动画行为的行为测定中的压力响应能力。这个目标将提供 关于5-羟色胺系统的可塑性如何赋予脆弱性或 压力的韧性。在AIM 2中，我们将评估Dreadd介导的抑制血清素能神经元中的抑制 反复的社交失败压力后的间隔可以扭转增强的脆弱性，以使随后的压力源， 使用皮质酮反应来克制和在强制游泳测试中的固定性来评估不同的领域 压力反应性。 AIM 3将通过选择性表达选择性地询问mRNA的翻译 EPET1-CRE小鼠的血清素能神经元中的“ Ribotag”。 Ribotag是表位标记的核糖体蛋白 这允许抗体介导的仅在衍生自复杂细胞的靶细胞的多聚体中拉下来 匀浆（在这种情况下是新鲜的中脑组织打孔）。血清素能神经元的mRNA富集将 允许我们执行RNA-seq，以调查在和 压力暴露后。我们将专注于与兴奋性，信号传输途径和 细胞因子反应，并使用途径分析来确定mRNA翻译的共同调节 压力;这旨在为治疗开发提供新的机械信息和新目标。