Thalamostriatal circuit contributions to behavioral inflexibility following adolescent ethanol exposure

项目摘要 酒精使用障碍（AUD）是一种慢性疾病，具有重大的健康和社会经济后果。 青少年时期饮酒会增加青少年时期出现AUD相关症状的风险。 成年期，包括酗酒。该项目的总体目标是确定功能适应， 青少年酒精暴露引起的大脑回路，并确定这些适应的作用 适应不良的行为。行为灵活性的缺陷（即，改变行为的能力受损， 这种行为的结果的变化）与药物和酒精滥用有关。以前的研究表明 青春期的酒精暴露会降低成年啮齿动物的行为灵活性。这项建议会 探索青少年酒精暴露对涉及行为灵活性的大脑回路的影响。 具体来说，拟议的研究将确定青少年酒精暴露对大脑中神经元的影响。 丘脑中央外侧核（CL）投射到背内侧纹状体（DMS）。病变或抑制 这些神经元的缺陷导致在常用任务中的行为灵活性，包括逆转学习， 注意力定势转移这些缺陷与青少年饮酒后观察到的缺陷相似; 然而，酒精对这些神经元的影响，以及CL神经元参与酒精诱导的 行为灵活性的缺陷，还没有被探索。核心假设是青少年酗酒 暴露降低了DMS投射CL神经元的活性，并且降低的CL神经元活性有助于 雄性和雌性小鼠的行为灵活性受损。目标1中的实验将比较 成年酒精未处理小鼠和暴露于汽化酒精的小鼠的CL神经元的变化。 青春期脑切片电生理实验将测量DMS投射的内在兴奋性 CL神经元以及它们的兴奋性和抑制性突触输入。将这些发现扩展到完整的大脑 来自酒精未处理小鼠和有青春期病史的小鼠的DMS投射CL神经元的回路、活动 酒精暴露将在反向学习期间测量。这些神经元中的钙动力学 使用遗传编码的钙指示剂jGCaMP 7s通过纤维光度法监测。实验目的 2将检验使用光遗传学刺激增加DMS投射CL神经元的活性的假设， 将改善青春期接触酒精的小鼠的行为灵活性。这些实验结果 将提供关于青少年酒精暴露如何影响丘脑纹状体回路的重要信息， 发育中的大脑以及酒精诱导的丘脑纹状体生理学变化与适应不良的关系 导致成年期酒精滥用的行为。发现新的电路， 青少年酒精暴露将为操纵回路活动以减少酒精滥用的策略提供信息。

Project Summary Alcohol use disorder (AUD) is a chronic disease with substantial health and socioeconomic consequences. Drinking alcohol during adolescence increases the risk of developing symptoms associated with AUD during adulthood, including heavy drinking. The overarching goal of this project is to identify functional adaptations in brain circuitry that are caused by adolescent alcohol exposure, and to determine the role of those adaptations in maladaptive behaviors. Deficits in behavioral flexibility (i.e., impaired ability to alter behavior in response to changes in the outcome of that behavior) are associated with drug and alcohol misuse. Previous studies show that alcohol exposure during adolescence decreases behavioral flexibility in adult rodents. This proposal will explore the impact of adolescent alcohol exposure on brain circuitry involved in behavioral flexibility. Specifically, the proposed studies will determine the effects of adolescent alcohol exposure on neurons in the centrolateral nucleus of the thalamus (CL) that project to the dorsomedial striatum (DMS). Lesion or inhibition of these neurons causes deficits in behavioral flexibility in commonly used tasks including reversal learning and attentional set-shifting. These deficits are similar to those observed after adolescent alcohol exposure; however, the impact of alcohol on these neurons, and the involvement of CL neurons in alcohol-induced deficits in behavioral flexibility, have not been explored. The central hypothesis is that adolescent alcohol exposure reduces activity in DMS-projecting CL neurons, and that reduced CL neuron activity contributes to impaired behavioral flexibility in male and female mice. The experiments in Aim 1 will compare the physiology of CL neurons from adult alcohol-naïve mice and mice that were exposed to vaporized alcohol during adolescence. Brain slice electrophysiology experiments will measure the intrinsic excitability of DMS-projecting CL neurons as well as their excitatory and inhibitory synaptic inputs. To extend these findings to intact brain circuits, activity of DMS-projecting CL neurons from alcohol-naïve mice and mice with a history of adolescent alcohol exposure will be measured during reversal learning. Calcium dynamics in these neurons will be monitored via fiber photometry using the genetically-encoded calcium indicator jGCaMP7s. Experiments in Aim 2 will test the hypothesis that increasing activity of DMS-projecting CL neurons using optogenetic stimulation will improve behavioral flexibility in mice exposed to alcohol during adolescence. Results of these experiments will provide important information about how adolescent alcohol exposure affects thalamostriatal circuitry in the developing brain and how alcohol-induced changes in thalamostriatal physiology relate to maladaptive behaviors that contribute to alcohol misuse in adulthood. Discovery of novel circuitry that is impacted by adolescent alcohol exposure will inform strategies for manipulating circuit activity to reduce alcohol misuse.