Thalamostriatal circuit contributions to behavioral inflexibility following adolescent ethanol exposure

青少年乙醇暴露后丘脑纹状体回路对行为僵化的影响

• 批准号: 10579844
• 负责人: Kari Johnson
• 金额: $ 21.92万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10579844
• 关键词: Adolescent; Adult; Affect; Alcohol consumption; Alcohols; Anatomy; Animals; Attention; Behavior; Behavioral; Brain; Brain region; Calcium; Cell Nucleus; Cells; Chronic Disease; Cognitive; Corpus striatum structure; Dorsal; Economic Burden; Electrophysiology (science); Exposure to; Female; Fiber; Genetic; Glutamates; Goals; Heavy Drinking; Impairment; Intervention; Knowledge; Learning; Lesion; Life; Macaca mulatta; Male Adolescents; Measurement; Measures; Monitor; Mus; Neurobiology; Neurons; Opsin; Outcome; Persons; Pharmaceutical Preparations; Photometry; Physiology; Psychological reinforcement; Public Health; Rattus; Recording of previous events; Reversal Learning; Risk; Rodent; Role; Slice; Substance Use Disorder; Synapses; Synaptic Transmission; Testing; Thalamic Nuclei; Thalamic structure; Work; adolescent alcohol effect; adolescent alcohol exposure; alcohol and other drug; alcohol behavior; alcohol effect; alcohol exposure; alcohol misuse; alcohol use disorder; associated symptom; behavior measurement; behavior test; behavioral impairment; behavioral outcome; brain circuitry; calcium indicator; cognitive testing; drug misuse; early onset; emerging adult; experimental study; flexibility; functional adaptation; health economics; high risk; human imaging; imaging study; improved; in vivo; insight; maladaptive behavior; male; neuroadaptation; nonhuman primate; novel; optogenetics; patch clamp; response; socioeconomics; underage drinking

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.

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。 青春期饮酒会增加与AUD相关的症状的风险 成年，包括大量饮酒。该项目的总体目标是确定功能适应 由青春期酒精暴露引起的脑电路，并确定这些适应的作用 在适应不良的行为中。行为灵活性的缺陷（即，改变行为的能力受损 这种行为结果的变化）与滥用毒品和酒精有关。先前的研究表明 青少年期间的酒精暴露会下降成年啮齿动物的行为灵活性。该提议将 探索青少年酒精暴露对行为灵活性涉及的脑电路的影响。 具体而言，拟议的研究将确定青春期酒精暴露对神经元中神经元的影响 丘脑（Cl）的中心外侧核核，该核纹状体（DMS）投射到背侧纹状体（DMS）。病变或抑制 这些神经元在行为灵活性中引起了常用任务的定义，包括逆转学习和 注意设置转换。这些定义与青少年酒精暴露后观察到的定义相似。 但是，酒精对这些神经元的影响以及CL神经元参与酒精引起的 行为灵活性的缺陷尚未探索。中心假设是青春期酒精 暴露会降低DMS射击CL神经元的活性，而降低的CL神经元活性有助于 男性和雌性小鼠行为灵活性受损。 AIM 1中的实验将比较生理 来自成年酒精的小鼠和小鼠的CL神经元在暴露于蒸发酒精期间的CL神经元 青少年。脑切片电生理实验将测量DMS-Projection的内在兴奋 CL神经元及其兴奋和抑制性突触输入。将这些发现扩展到完整的大脑 电路，来自未经酒精的小鼠和具有青春期史的DMS射击CL神经元的活性 在逆转学习过程中将测量酒精暴露。这些神经元中的钙动力学将是 使用一般编码的钙指示剂JGCAMP7S通过纤维光度法监测。 AIM中的实验 2将检验以下假设：使用光遗传刺激增加DMS射击CL神经元的活性 将提高暴露于青春期的小鼠的行为灵活性。这些实验的结果 将提供有关青少年酒精暴露如何影响丘脑纹状体电路的重要信息 发展大脑以及酒精诱导的丘脑纹状体生理学的变化与适应不良有关 在成年后导致滥用酒精的行为。发现受到的新电路的发现 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。