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，并且已得到充分记录 导致多种神经精神疾病。暴露于反复的社交失败压力（SDS） 在啮齿动物中，增强了包括酒精在内的几种滥用药物的奖赏和强化作用，并且是一种 未来药物使用的可靠预测器。 SDS 通过社会失败范式在动物中有效建模， 同一物种的两只动物之间开始对抗。有大量的 介导对压力源的行为反应的大脑区域与介导药物的大脑区域之间存在重叠 成瘾，意味着共享的神经回路。然而，社会压力源的精确神经机制 增加饮酒量尚不清楚。该应用程序将通过以下方式解决这一知识差距： 使用与细胞类型无关的方法来识别和分析被两者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（Targeted 激活群体中的重组）系统和 SDS 诱导酒精浓度升高的小鼠模型 饮酒时，我们检查了由社会压力和酒精激活的神经群之间的重叠 同一动物的消费。我们的初步结果表明 SDS 增加了酒精消耗量 室旁丘脑 (PVT) 和下丘脑室旁核的神经元激活 （PVN），已知调节压力动机影响的大脑区域。我们发现压力和酒精 它们本身会激活 PVT 和 PVN 中的大量细胞。有趣的是，我们的结果还表明 这些大脑区域中超过 80% 的应激激活细胞也会被酒精激活。根据这些结果，我们 假设细胞中的转录程序在 PVT 中被压力和酒精激活，并且 与那些仅由压力或仅由酒精激活并构成压力的PVN相比，PVN是独特的- 导致饮酒量增加。我们建议使用单核测序来转录 分析 PVT 和 PVN 中被压力和酒精激活的细胞。然后我们将识别基因， 这些细胞中失调的途径和过程。我们还向我们建议建立综合图书馆 细胞特征 (LINC) 用于识别可逆转这些转录特征的化合物，从而 预计可以防止压力引起的饮酒量增加。