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.

项目摘要我们目前在NIAAA联盟的成年饮酒神经生物学（NADIA）的工作已经揭示了青少年间歇性乙醇暴露（AIE）的持久行为后果是性和暴露时间依赖性。成年后测试时，只有雄性大鼠在早期青春期（早期AIE）展示了包括社交焦虑和增强的社会改变对乙醇引起的社会促进的敏感性，在青春期后期暴露于乙醇（晚期AIE）没有这样的后果。我们最重要的翻译发现是选择性催产素受体（OXTR）激动剂扭转男性特定的社交焦虑。在细胞和分子水平上，性别特异性早期AIE的后果显而易见，因为树突状脊柱形态的改变并减少OXTR 下丘脑中的mRNA和蛋白质表达。我们目前的建议将解决来自这项工作。 AIM 1将确定在成年男性和女性中差异激活社会相关的地区社交刺激较早AIE，并将测试是否在确定的大脑中募集神经元合奏男性特定的社会情感改变需要区域。 AIM 2将进一步评估AIE引起的 oxt系统的改变，导致男性特定的社交焦虑，并将调查神经 OXTR药理激活的逆转作用的基础机制。 AIM 3旨在测试 AIE是否有选择地破坏大脑中OXT神经调节肽系统的表观遗传调节正常社会功能至关重要的地区。