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。 青春期饮酒会增加在青春期出现AUD相关症状的风险 成年，包括酗酒。该项目的总体目标是确定 青少年酒精暴露引起的大脑回路，并确定这些适应的作用 在不适应行为上。行为灵活性缺陷(即改变行为以应对 这种行为结果的改变)与滥用药物和酒精有关。先前的研究表明 青春期的酒精暴露会降低成年啮齿动物的行为灵活性。这项提议将 探索青少年酒精暴露对参与行为灵活性的大脑回路的影响。 具体地说，拟议的研究将确定青少年酒精暴露对大脑皮质神经元的影响。 丘脑中央外侧核(CL)投射到背内侧纹状体(DMS)。损害或抑制 这些神经元导致在常用任务中行为灵活性的缺陷，包括反转学习和 注意力定势转移。这些缺陷与青少年酒精暴露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神经元在酒精诱导中的参与 行为灵活性方面的缺陷，还没有被研究过。中心假设是青少年饮酒 暴露降低了DMS投射的CL神经元的活性，而CL神经元活性的降低有助于 雄性和雌性小鼠的行为灵活性受损。目标1中的实验将比较生理学 成年酒精幼稚小鼠和暴露于汽化酒精的小鼠的CL神经元的变化 青春期。脑片电生理实验将测量DMS投射的内在兴奋性 CL神经元及其兴奋性和抑制性突触输入。将这些发现扩展到完整的大脑 酒精幼稚小鼠和有青春期病史的小鼠DMS投射CL神经元的环路和活动 酒精暴露将在反转学习期间进行测量。这些神经元中的钙动力学将是 通过使用遗传编码的钙指示剂jGCaMP7的纤维光度法进行监测。AIM中的实验 2将检验这样一种假设，即通过光发生刺激增加投射DMS的CL神经元的活动 将改善青春期酒精暴露小鼠的行为灵活性。这些实验的结果 将提供有关青少年酒精暴露如何影响脑内丘脑纹状体回路的重要信息 大脑发育及酒精引起的丘脑-纹状体生理改变与适应不良的关系 导致成年后酗酒的行为。发现受影响的新电路 青少年酒精暴露将为操纵电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.