Molecular Signatures of Social Stress-Induced Escalation of Drinking

社会压力引起饮酒增加的分子特征

• 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
• 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

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.

社会压力是人类经历的最常见的压力形式之一，并且已经有很好的记录 导致了各种各样的神经精神疾病重复社交失败压力（SDS） 在啮齿类动物中，增强了包括酒精在内的几种滥用药物的奖励和强化作用， 未来药物使用的可靠预测。SDS在动物中通过社会失败范式有效地建模， 在同一物种的两只动物之间开始对抗性的遭遇。有大量 在调节对压力的行为反应的大脑区域和调节药物的大脑区域之间的重叠 成瘾，这意味着共享神经回路。然而，社会压力源的精确神经机制 人们对酒精消费量增加并不十分了解。此应用程序将通过以下方式解决这一知识差距 使用细胞类型不可知的方法来鉴定和分析被两种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TRAP 2（目标 活化群体中的酒精代谢）系统和SDS诱导的酒精递增的小鼠模型 饮酒，我们检查了由社会压力和酒精激活的神经系统之间的重叠 在同一个动物身上消费。我们的初步结果表明，SDS增加了酒精消费， 室旁丘脑（PVT）和室旁核的神经元激活 (PVN)这是已知的调节压力激励效应的大脑区域。我们发现压力和酒精 它们本身激活了PVT和PVN中的大量细胞。有趣的是，我们的研究结果还表明， 在这些大脑区域中，超过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中被应激和酒精激活的细胞中的转录程序， PVN是独特的相比，那些被激活的压力单独或酒精单独和压力的基础- 导致酒精消费量增加。我们建议使用单核测序来转录 在PVT和PVN中的细胞被压力和酒精激活。然后我们将识别基因， 这些细胞中失调的途径和过程。我们还建议我们的综合图书馆 细胞签名（LINCs）来鉴定将逆转这些转录签名的化合物， 预计可以防止压力引起的酒精消费升级。