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.

项目总结