Gene Expression Profiling of Stress Resilient Mice within the Nucleus Accumbens

伏核内应激恢复小鼠的基因表达谱

• 批准号: 10676411
• 负责人: Trevonn Michael Gyles
• 金额: $ 4.77万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676411
• 关键词: Anhedonia; Animal Model; Animals; Antidepressive Agents; Autopsy; Behavior; Behavioral; Behavioral Paradigm; Bioinformatics; Biological; Brain region; Chronic; Chronic stress; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Development; Exhibits; Experimental Designs; Exposure to; Fellowship; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Goals; Human; Individual; Investigation; Major Depressive Disorder; Mediating; Mental Depression; Mental disorders; Molecular; Mus; Network-based; Neurobiology; Neurons; Nucleus Accumbens; Outcome; Patients; Persons; Phenotype; Physiological; Population; Predisposition; Process; Publishing; Reproducibility; Research; Research Personnel; Rest; Risk Factors; Rodent; Standardization; Stress; Study models; Syndrome; Testing; Time; Training; Validation; Viral; Work; behavioral phenotyping; brain tissue; cohort; combinatorial; depression prevention; depressive symptoms; design; differential expression; disability; drug discovery; experience; experimental study; gene network; genetic variant; genome wide association study; insight; mouse model; novel; overexpression; protective allele; resilience; risk variant; social; social defeat; stress related disorder; stress resilience; success; transcriptome sequencing

Project Summary Chronic stress exposure increases vulnerability to a variety of mental illnesses including depression. However, not all individuals that experience stress develop depression. Furthermore, the mechanisms that lead to stress -resilience, the ability to avoid the negative social, physiological, and biological consequences of stress have yet to be identified. Here, we focus on understanding the transcriptional mechanisms of resilience to identify genes that may be protective against stress-related disorders to guide drug discovery efforts. The chronic social defeat stress (CSDS) paradigm in mice has proven to be a highly useful animal model for studying depression- related behavioral abnormalities. Following CSDS, a subset of mice exhibit depressive-like behavior and changes in gene expression that recapitulate changes seen in depression patients examined postmortem. Importantly, this paradigm allows for the distinction of animals that succumb to the effects of the stress, termed susceptible, from those that do not, termed resilient. Previously published work has identified a gene network in the Nucleus Accumbens (NAc) that is specific to resilient mice. In this proposal, I will establish a reproducible pipeline to characterize the regulatory dynamics of resilient-specific gene networks in order to better understand the transcriptional circuitry that exist within these networks. I will then activate these transcriptional circuits in stress-naïve mice before subjecting them to CSDS to test their influence on resilience. The proposed research will provide a framework to study the transcriptional mechanism(s) of resilience by providing mechanistic insight into the transcriptional circuitry regulating stress resilience in mice. Together these aims will, for the first time, establish a novel experimental approach for studying the control over resilience by a complex network of genes as opposed to standard approaches which interrogate one gene at a time. This approach is designed to be applicable to any brain region, animal model, or network-based bioinformatics approach.

项目摘要 长期的压力暴露会增加对各种精神疾病的脆弱性，包括抑郁症。 然而，并不是所有经历压力的人都会患上抑郁症。此外，导致 压力-弹性，避免压力的负面社会，生理和生物后果的能力 还有待确认在这里，我们专注于了解弹性的转录机制，以确定 可能对压力相关疾病有保护作用的基因，以指导药物发现工作。慢性社会 小鼠中的失败压力（CSDS）范例已被证明是研究抑郁症的非常有用的动物模型， 相关的行为异常CSDS后，一部分小鼠表现出抑郁样行为， 基因表达的变化，概括了抑郁症患者死后检查的变化。 重要的是，这种范式允许区分屈服于压力影响的动物，称为 易受影响的，不受影响的，称为弹性。以前发表的工作已经确定了一个基因网络， 伏隔核（NAc），其特异于弹性小鼠。在本提案中，我将建立一个可复制的 管道，以表征特定基因网络的调控动态，以便更好地了解 存在于这些网络中的转录回路。然后我会激活这些转录回路 在对小鼠进行CSDS之前，对它们进行压力测试，以测试它们对恢复力的影响。拟议研究 将提供一个框架，研究转录机制（S）的弹性，提供机械的见解 进入调节小鼠应激恢复能力的转录回路。这些目标将首次， 建立了一种新的实验方法，用于研究复杂基因网络对恢复力的控制 与一次询问一个基因的标准方法相反。该方法旨在 适用于任何大脑区域、动物模型或基于网络的生物信息学方法。