2/8 NADIA U01 Adolescent Alcohol Exposure: Neural Contributors to Sex- and Exposure Timing-Specific Anxiety

2/8 NADIA U01 青少年酒精暴露：性和暴露时间特异性焦虑的神经因素

基本信息

批准号：
10227250
负责人：
ELENA I VARLINSKAYA
金额：
$ 39.14万
依托单位：
STATE UNIVERSITY OF NY,BINGHAMTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-05 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10227250
关键词：
ATAC-seq Acute Address Adolescence Adolescent Adult Affect Affective Agonist Animals Anti-Anxiety Agents Anxiety Attenuated Behavioral Brain Brain region Clustered Regularly Interspaced Short Palindromic Repeats Collaborations DNA Methylation Data Dendritic Spines Dose Epigenetic Process Ethanol FOS gene Female Fluorescent in Situ Hybridization Genes Genome Glutamate Receptor Histones Human Hypothalamic structure Impairment LacZ Genes Lateral Life Mediating Messenger RNA Methylation Molecular Morphology National Institute on Alcohol Abuse and Alcoholism Neurobiology Neuroimmune Neurons Neuropeptides OXT gene Oxytocin Oxytocin Receptor Pathway interactions Peptides Pharmacology Procedures Rattus Regulation Reporting Role Sex Differences Social Facilitation Social Functioning Social Interaction Stimulus System Testing Transgenic Organisms Vertebral column Viral Work adolescent alcohol exposure alcohol effect alcohol exposure alcohol risk alcohol sensitivity anxious brain behavior density design drinking early adolescence early alcohol use emerging adulthood epigenetic regulation ethanol-induced social facilitation improved mRNA Expression male neural patterning neuromechanism neuroregulation protein expression receptor expression recruit relating to nervous system sex social social anxiety social deficits transcriptome sequencing underage drinking

项目摘要

Project Summary Our current work in the NIAAA consortium on the Neurobiology of Adolescent Drinking in Adulthood (NADIA) has revealed that long-lasting behavioral consequences of adolescent intermittent ethanol exposure (AIE) are sex- and exposure timing-dependent. When tested in adulthood, only male rats exposed to ethanol during early-mid adolescence (early AIE) demonstrate social alterations that include social anxiety and enhanced sensitivity to ethanol-induced social facilitation, with exposure to ethanol later in adolescence (late AIE) having no such consequences. Our most important translational finding is that a selective oxytocin receptor (OXTR) agonist reverses the male-specific social anxiety. At the cellular and molecular levels, sex-specific consequences of early AIE are evident as alterations in dendritic spine morphology and decreases in OXTR mRNA and protein expression in the hypothalamus. Our current proposal will address critical gaps arising from this work. Aim 1 will identify socially relevant regions differentially activated in adult males and females by social stimuli following early AIE and will test whether recruitment of neuronal ensembles in identified brain regions is required for male-specific social affective alterations. Aim 2 will further assess AIE-induced alterations of the OXT system contributing to male-specific social anxiety and will investigate neural mechanisms underlying the reversal effects of OXTR pharmacological activation. Aim 3 is designed to test whether AIE selectively disrupts epigenetic regulation of the OXT neuromodulatory peptide system in brain regions critical for normal social functioning.

项目概要我们目前在 NIAAA 联盟关于成年青少年饮酒神经生物学 (NADIA) 的工作研究表明，青少年间歇性乙醇暴露（AIE）的长期行为后果是取决于性别和暴露时间。在成年期进行测试时，只有雄性大鼠在青春期早中期（早期 AIE）表现出社交改变，包括社交焦虑和增强对乙醇引起的社交促进的敏感性，在青春期后期接触乙醇（晚期 AIE）没有这样的后果。我们最重要的转化发现是选择性催产素受体（OXTR）激动剂可以逆转男性特有的社交焦虑。在细胞和分子水平上，性别特异性早期 AIE 的后果很明显，即树突棘形态的改变和 OXTR 的减少下丘脑中的 mRNA 和蛋白质表达。我们当前的提案将解决以下问题所产生的关键差距：这项工作。目标 1 将通过以下方式识别成年男性和女性中差异激活的社会相关区域：早期 AIE 后的社会刺激，并将测试是否在已识别的大脑中招募神经元集合男性特有的社会情感改变需要这些区域。目标 2 将进一步评估 AIE 引起的 OXT 系统的改变导致男性特有的社交焦虑，并将研究神经 OXTR 药理激活逆转作用的潜在机制。目标 3 旨在测试 AIE是否选择性破坏大脑中OXT神经调节肽系统的表观遗传调控对正常社会功能至关重要的区域。