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

项目摘要 先前存在的认知缺陷或暴露在应激源下都会增加酒精使用障碍(AUD)的可能性。 这些关系是双向的，过量饮酒也会直接影响认知和 失调的压力系统。认知和应激反应的个体差异被认为定义了 AUD谱系中的表型在疾病预后和不同治疗反应方面可能不同 战略。因此，精确定义调节协方差的行为和神经生物学底物 跨越认知、压力和饮酒领域对我们理解AUD至关重要。然而，直到最近， 我们一直缺乏技术方法来确定个体差异是否 这些行为来自相同的神经元，或来自大脑区域内不同的群体。要分析如何 这些表型表明，我们必须1)量化在交叉路口出现的复杂的个体差异 压力、饮酒和认知功能的关系，以及2)决定大脑中控制 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来 通过计算确定小鼠不同领域的个体差异。之前的研究已经证明 前额叶皮质是认知功能、对应激源的反应和饮酒的关键中介，但准确的 这些行为之间的共同回路程度尚不清楚。因此，我们将使用纵向设计来定义 前额叶皮质神经元可塑性信号支配这些基因的表达和相互作用 相同受试者的行为。鼠标模型为定义精确的细胞类型提供了独特的优势 在前额叶皮质内产生这些行为，但也有必要确定这些 在高级物种中，神经行为关系是保守的。使用跨物种的方法， 特定皮质细胞类型的可塑性与个体差异之间关系的保守性 然后，在小鼠中观察到的认知、压力和酒精相互作用将直接在体外脑片中进行测试 非人灵长类动物。本提案的成功完成将提供对以下电路基础的新见解 酒精和压力的相互作用，并将这些假设跨物种推向翻译终点。

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.