8/8: INIA Stress and Chronic Alcohol Interactions: Cross-species plasticity signatures of alcohol and stress

8/8：INIA 压力和慢性酒精相互作用：酒精和压力的跨物种可塑性特征

• 批准号: 10412379
• 负责人: Cody Siciliano
• 金额: $ 40.81万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-10 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412379
• 关键词: Alcohol abuse; Alcohol consumption; Alcohols; Automobile Driving; Behavior; Behavioral; Behavioral Assay; Brain; Brain region; Calcium; Cells; Cessation of life; Chronic; Cognition; Cognitive; Cognitive deficits; Collaborations; Complex; Data Set; Development; Dyes; Exposure to; Female; Goals; Grant; Head; Heavy Drinking; Human; Image; Immunohistochemistry; Impaired cognition; Individual Differences; Intoxication; Label; Macaca mulatta; Maps; Medial; Mediating; Mediator of activation protein; Methodology; Microscope; Modeling; Monkeys; Mus; Neurobiology; Neuronal Plasticity; Neurons; Pattern; Phase; Phenotype; Play; Population; Predisposition; Prefrontal Cortex; Prevention strategy; Probability; Procedures; Prognosis; Public Health; Punishment; Resistance; Resolution; Reversal Learning; Risk Factors; Rodent; Role; Sampling; Self Administration; Slice; Stress; Swimming; System; Technology; Testing; Tissues; Transgenes; Transgenic Organisms; United States; Ventral Tegmental Area; addiction; alcohol consequences; alcohol craving; alcohol exposure; alcohol seeking behavior; alcohol use disorder; alcohol use initiation; cell type; cognitive function; cognitive performance; combinatorial; comorbidity; disease prognosis; drinking; experimental study; flexibility; histological image; imaging approach; improved; in vivo; insight; longitudinal design; male; mind control; mouse model; neurobehavioral; neuroimaging; nonhuman primate; novel; optogenetics; photoactivation; recruit; relating to nervous system; resilience; response; stress reactivity; stressor; treatment strategy

Project Summary Preexisting cognitive deficits or exposure to stressors both increase the probability of alcohol use disorder (AUD). These relationships are bidirectional, and excessive alcohol consumption can also directly impact cognition and dysregulate stress systems. Individual differences in cognition and stress reactivity are thought to define phenotypes within the AUD spectrum which may differ in disease prognosis and responsivity across treatment strategies. As such, precisely defining the behavioral and neurobiological substrates mediating covariance across cognitive, stress, and drinking domains is critical for our understanding of AUD. However, until recently we have lacked technical approaches which would allow for determination of whether individual differences in these behaviors arise from the same neurons or from distinct populations within brain regions. To parse how these phenotypes manifest we must 1) quantify the complex individual differences that emerge at the intersection of stress, alcohol drinking, and cognitive function and 2) determine the precise neurons in the brain that control these interactions. To this end, we will first use deep phenotyping of both behavioral and neuronal features to computationally define individual differences across domains in mice. Previous studies have demonstrated that prefrontal cortex is a critical mediator of cognitive function, responses to stressors, and drinking, but the precise degree of shared circuitry between these behaviors is unclear. Thus, we will use a longitudinal design to define the neuronal plasticity signatures in prefrontal cortex that govern expression and interactions between these behaviors within the same subjects. Mouse models offer unique advantages for defining the precise cell-types within the prefrontal cortex that give rise to these behaviors, but it will also be essential to determine if these neurobehavioral relationships are conserved in higher-order species. Using a cross-species approach, conservation of relationships between plasticity in specific cortical cell-types and individual differences in cognitive, stress, and alcohol interactions observed in mice will then be directly tested in ex vivo brain slices from non-human primates. Successful completion of this proposal will provide novel insight into the circuit basis of alcohol and stress interactions and advance these hypotheses across species towards translational endpoints.

项目摘要 先前存在的认知缺陷或暴露于压力源都会增加酒精使用障碍（AUD）的可能性。 这些关系是双向的，过度饮酒也会直接影响认知， 压力系统失调认知和压力反应的个体差异被认为是定义 AUD谱内的表型，其在疾病预后和治疗反应方面可能不同 战略布局因此，精确定义行为和神经生物学基质介导的协方差 在认知、压力和饮酒领域的研究对于我们理解AUD至关重要。然而，直到最近， 我们缺乏技术方法来确定个体差异是否存在， 这些行为来自相同的神经元或来自脑区域内的不同群体。解析如何 这些表型表明，我们必须1）量化在交叉点出现的复杂个体差异， 压力，饮酒和认知功能的影响，2）确定大脑中控制的精确神经元 这些互动。为此，我们将首先使用行为和神经元特征的深度表型分析， 通过计算来定义小鼠中跨域的个体差异。先前的研究表明， 前额叶皮层是认知功能、对压力源的反应和饮酒的关键调节器，但精确的 这些行为之间共享电路的程度尚不清楚。因此，我们将使用纵向设计来定义 前额叶皮层中的神经元可塑性特征控制着这些神经元之间的表达和相互作用， 在相同的主题中。小鼠模型为确定精确的细胞类型提供了独特的优势 引起这些行为的前额叶皮层，但它也将是至关重要的，以确定这些 神经行为关系在高级物种中是保守的。使用跨物种方法， 特定皮质细胞类型的可塑性与个体差异之间的关系 在小鼠中观察到的认知、压力和酒精的相互作用将直接在离体脑切片中进行测试， 非人类灵长类动物该提案的成功完成将为以下电路基础提供新的见解： 酒精和压力的相互作用，并推动这些假设跨物种的翻译终点。