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

基本信息

批准号：
10354795
负责人：
Kari Johnson
金额：
$ 18.11万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10354795
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 Electrophysiology (science)Exposure to Female Fiber Glutamates Goals Health Heavy Drinking Impairment Intervention Knowledge Lead 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 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 high risk human imaging imaging study improved in vivo insight maladaptive behavior male neuroadaptation novel optogenetics patch clamp response socioeconomics underage drinking vapor

项目摘要

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.

项目概要酒精使用障碍 (AUD) 是一种慢性疾病，会对健康和社会经济产生重大影响。青春期饮酒会增加出现 AUD 相关症状的风险该项目的首要目标是确定成年期的功能适应。由青少年酒精暴露引起的大脑回路，并确定这些适应的作用行为灵活性缺陷（即改变行为的能力受损）先前的研究表明，该行为结果的变化与药物和酒精滥用有关。青春期的酒精暴露会降低成年啮齿动物的行为灵活性。探讨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神经元的影响投射到背内侧纹状体 (DMS) 的丘脑中央外侧核 (CL)。这些神经元的减少会导致常用任务中行为灵活性的缺陷，包括逆向学习和这些缺陷与青少年酒精暴露后观察到的类似。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尚未得到探讨，核心假设是青少年酗酒。 DMS 投射的 CL 神经元的暴露活动减少，并且 CL 神经元活动的减少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。未接触酒精的小鼠和暴露于汽化酒精的小鼠的 CL 神经元脑切片电生理学实验将测量 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。未接触过酒精的小鼠和有青少年史的小鼠的 DMS 投射 CL 神经元的回路、活性在逆转学习期间将测量酒精暴露，这些神经元中的钙动态将被测量。使用基因编码的钙指示剂 jGCaMP7s 通过光纤光度法进行监测。 2 将检验以下假设：使用光遗传学刺激增加 DMS 投射 CL 神经元的活性这些实验的结果将提高青春期接触酒精的小鼠的行为灵活性。将提供有关青少年酒精暴露如何影响丘脑纹状体回路的重要信息大脑发育以及酒精引起的丘脑纹状体生理学变化如何与适应不良相关发现导致成年后滥用酒精的行为。青少年酒精暴露将为控制回路活动以减少酒精滥用的策略提供信息。