Molecular Signatures of Social Stress-Induced Escalation of Drinking

社会压力引起饮酒增加的分子特征

基本信息

批准号：
10667840
负责人：
Rajani Maiya
金额：
$ 23.81万
依托单位：
LSU HEALTH SCIENCES CENTER
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：
2023-05-20 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667840
关键词：
Addictive Behavior Alcohol consumption Alcohols Animals Anxiety Arousal Behavioral Brain region Candidate Disease Gene Cell Nucleus Cells Code Databases Dimensions Disease Drug Addiction Drug usage Enterobacteria phage P1 Cre recombinase Estrogen Receptors Exposure to FOS gene Female Future Gene Expression Profile Genes Genetic Genetic Recombination Genetic Transcription Grant Human Human Development Hypothalamic structure In Situ Hybridization Individual Knowledge Label Lead Libraries Maps Mediating Mental Depression Mental disorders Messenger RNA Modeling Molecular Molecular Profiling Motivation Mus Neurons Neurosecretory Systems Pathway Analysis Pathway interactions Population Process RNA Reporter Resolution Reverse Transcription Rewards Risk Factors Rodent Role Signal Transduction Social Environment Social Interaction Source Stress Stressful Event Structure of paraventricular nucleus of thalamus System Testing Thalamic structure Tissue-Specific Gene Expression addiction alcohol exposure alcohol use disorder behavioral response candidate identification cell type differential expression drinking drug candidate drug of abuse druggable target experience experimental study gene network high reward high risk inducible Cre male motivated behavior mouse model neural neural circuit neuroadaptation neuromechanism neuropsychiatry paraventricular nucleus preference prevent programs promoter response social social defeat social stress social stressor stressor transcriptome transcriptomic profiling

项目摘要

Social stress is one of the most common forms of stress experienced by humans and has been well documented to contribute to a wide variety of neuropsychiatric conditions. Exposure to repeated social defeat stress (SDS) in rodents enhances the rewarding and reinforcing effects of several drugs of abuse, including alcohol, and is a reliable predictor of future drug use. SDS is effectively modeled in animals through social defeat paradigms, where an antagonistic encounter is initiated between two animals of the same species. There is substantial overlap between brain regions that mediate the behavioral response to stressors and those that mediate drug addiction, implying shared neural circuitry. However, the precise neural mechanisms by which social stressors increase alcohol consumption are not well understood. This application will address this gap in knowledge by using a cell type agnostic approach to identify and profile the transcriptomes of cells that are activated by both SDS and alcohol exposure at single cell resolution. Using the recently developed TRAP2 (Targeted Recombination in Activated Populations) system and a mouse model for SDS-induced escalation of alcohol drinking, we examined the overlap between neural ensembles that are activated by social stress and alcohol consumption in the same animal. Our preliminary results indicate that SDS increased alcohol consumption and neuronal activation in the paraventricular thalamus (PVT) and the paraventricular nucleus of the hypothalamus (PVN), brain regions known to mediate the motivational effects of stress. We found that both stress and alcohol by themselves activate a large number of cells in the PVT and PVN. Interestingly, our results also indicate that >80% of stress-activated cells are also activated by alcohol in these brain regions. Based on these results, we hypothesize that transcriptional programs in cells that are activated by both stress and alcohol in the PVT and PVN are unique compared to those that are activated by stress alone or alcohol alone and underlie stress- induced escalation of alcohol consumption. We propose to use single nuclei sequencing to transcriptionally profile cells in the PVT and PVN that are activated by both stress and alcohol. We will then identify genes, pathways and processes that are dysregulated in these cells. We also propose to us the Library of Integrated Cellular Signatures (LINCs) to identify compounds that will reverse these transcriptional signatures and are thus predicted to prevent stress-induced escalation of alcohol consumption.

社会压力是人类所经历的最常见的压力形式之一，并已得到充分记录为各种神经精神疾病做出贡献。暴露于反复的社交失败压力（SD）在啮齿动物中，增强了包括酒精在内的几种滥用药物的奖励和增强作用，是一种可靠的未来吸毒的预测指标。通过社交失败范式在动物中有效地建模SD，在同一物种的两种动物之间开始拮抗遇到的地方。有实质性介导对压力源的行为反应和介导药物的大脑区域之间的重叠成瘾，意味着共有的神经回路。但是，社会压力源的确切神经机制增加饮酒量尚不清楚。此应用程序将通过使用细胞类型的不可知道方法来识别和介绍两者都激活的细胞的转录组单细胞分辨率下的SDS和酒精暴露。使用最近开发的TRAP2（针对性激活人群中的重组）系统和用于SDS诱导的酒精升级的小鼠模型喝酒，我们检查了由社会压力和酒精激活的神经合奏之间的重叠同一动物的消费。我们的初步结果表明，SDS增加了酒精消耗和旁丘脑丘脑（PVT）和下丘脑的室核核中的神经元激活（PVN），已知介导压力动机作用的大脑区域。我们发现压力和酒精都本身会激活PVT和PVN中的大量细胞。有趣的是，我们的结果也表明在这些大脑区域，> 80％的应激激活细胞也被酒精激活。基于这些结果，我们假设在PVT中被压力和酒精激活的细胞中的转录程序与单独的压力或仅饮酒激活的PVN相比，PVN是独一无二的，而应力是诱导饮酒升级。我们建议使用单核测序进行转录由应力和酒精激活的PVT和PVN中的轮廓细胞。然后，我们将识别基因，这些细胞中失调的途径和过程。我们还向我们提出了综合的库细胞特征（lincs）以识别可以逆转这些转录特征的化合物，因此预计可以防止压力引起的饮酒升级。