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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：
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
项目类别：
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

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.

项目总结