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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要长期承受压力会增加患抑郁症等各种精神疾病的可能性。然而，并非所有经历压力的人都会患上抑郁症。此外，导致抑郁的机制也不同。压力恢复力，避免压力带来的负面社会、生理和生物后果的能力在这里，我们重点了解弹性的转录机制以识别。可能预防压力相关疾病的基因，以指导药物发现工作。小鼠的失败应激（CSDS）范式已被证明是研究抑郁症的非常有用的动物模型 CSDS 后，一部分小鼠表现出抑郁样行为，并且基因表达的变化概括了抑郁症患者尸检中观察到的变化。重要的是，这种范式允许区分屈服于压力影响的动物，称为先前发表的工作已经确定了基因网络易感性在这个提案中，我将建立一个可重复的伏核（NAc）。表征弹性特异性基因网络的调控动态的管道，以便更好地理解然后我将激活这些网络中存在的转录电路。研究中提出的研究先对未受过压力的小鼠进行 CSDS 测试，以测试其对复原力的影响。将提供一个框架，通过提供机制洞察来研究弹性的转录机制这些目标将首次进入调节小鼠应激能力的转录回路。建立一种新的实验方法来研究复杂的基因网络对弹性的控制与一次询问一个基因的标准方法相反，这种方法的设计目的是。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。