Role of Neural Activity and Perineuronal Nets in Adolescent Intermittent Ethanol-Induced Social Anxiety

神经活动和神经周围网络在青少年间歇性乙醇引起的社交焦虑中的作用

• 批准号: 10434676
• 负责人: Trevor Towner
• 金额: $ 2.89万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434676
• 关键词: Adolescence; Adolescent; Adult; Alcohols; Animals; Behavioral; Brain; Data; Development; Ethanol; Ethanol dependence; Evaluation; Exposure to; Extracellular Matrix; Foundations; Functional disorder; Glutamates; Goals; Histocytochemistry; Histology; Image Analysis; Insula of Reil; Interneurons; Investigation; Knowledge; Label; LacZ Genes; Medial; Microscopy; Neurobiology; Neurons; Operative Surgical Procedures; Parvalbumins; Pattern; Play; Population; Positioning Attribute; Postdoctoral Fellow; Prefrontal Cortex; Procedures; Process; Rattus; Regulation; Reporting; Research; Research Personnel; Risk Factors; Rodent; Role; Social Behavior; Stimulus; Substance abuse problem; Synapses; Techniques; Testing; Three-Dimensional Image; Time; Training; Transgenic Organisms; United States; Up-Regulation; Water; adolescent alcohol exposure; alcohol exposure; alcohol measurement; alcohol use disorder; alcohol use initiation; anxiety-like behavior; anxious; behavioral impairment; behavioral outcome; binge drinking; career; chemical genetics; design; developmental plasticity; drinking; drug of abuse; emerging adulthood; experimental study; genetic manipulation; glutamatergic signaling; high school; hippocampal pyramidal neuron; indexing; insight; male; neural circuit; neurobiological mechanism; neuromechanism; neuronal cell body; peer; post-doctoral training; pre-clinical research; preference; presynaptic; relating to nervous system; skills; social; social anxiety; social deficits; tool; transmission process; underage drinking

Project Summary Our research group has revealed long-lasting behavioral impairments associated with adolescent intermittent ethanol (AIE) exposure, with male rats exposed to ethanol during adolescence demonstrating social deficits indexed via decreases in social preference and social investigation. Our preliminary data point to the prelimbic (PrL) cortex as a region associated with this social inhibition. AIE has been reported to increase glutamatergic signaling in the PrL, potentially due to alterations in GABAergic transmission. PrL activity is heavily regulated by inhibitory parvalbumin (PV) interneurons that are often encompassed by extracellular matrix components, perineuronal nets (PNNs). This proposal is designed to test the hypothesis that AIE-induced dysfunction of the PrL is a result of PNN-dependent decreases of PV interneuron inhibitory control, a neural alteration that might directly contribute to social deficits evident in adult rats following AIE. This hypothesis will be tested in Aim 1 by determining whether inactivation of specific neural ensembles associated with responding to a social stimulus within the PrL can reverse AIE-induced social deficits. In Aim 2, we will assess the impact of AIE on PNN expression within the PrL and investigate whether AIE-dependent PNN alterations are associated with changes in glutamatergic and GABAergic inputs onto PV interneurons. For evaluation of the relationship between PNN upregulation and social alterations after AIE, we will test whether an enzymatic degradation of PNNs following AIE is able to reverse social deficits in AIE-exposed animals. Collectively, these studies will characterize specific neural mechanisms in the PrL that are disrupted following AIE and further our understanding of how these alterations contribute to social deficits. Through this training mechanism I will gain invaluable skills to build my technical tool kit, expand my theoretical framework, and further develop my conceptual research skillset, all of which will aid in my progression into postdoctoral training and eventually becoming an independent investigator.

项目摘要 我们的研究小组发现了与青少年间歇性行为障碍有关的长期行为障碍 酒精暴露(AIE)，青春期暴露于乙醇的雄性大鼠表现出社会缺陷 通过社会偏好和社会调查的减少来索引。我们的初步数据显示 (PRL)大脑皮层作为与这种社会抑制相关的区域。据报道，AIE可增加谷氨酸能 PRL中的信号，可能是由于GABA能传递的改变。PRL活动受到严格监管 通过通常被细胞外基质成分包围的抑制性小白蛋白(PV)中间神经元， 周围神经网(PNNS)。这一建议旨在检验以下假设：AIE导致的脑功能障碍 PRL是PNN依赖的PV神经元间抑制控制减少的结果，这种神经改变可能 直接导致AIE后成年大鼠明显的社会缺陷。这一假设将在目标1中通过 确定特定神经群的失活是否与对社会刺激的反应有关 在PRL内可以扭转由AIE引起的社会赤字。在目标2中，我们将评估AIE对PNN的影响 并研究AIE依赖的PNN改变是否与 谷氨酸和GABA能传入PV中间神经元的变化。对两国关系的评估 在AIE后PNN上调和社会变化之间，我们将测试PNN的酶降解 AIE后的PNNS能够逆转暴露于AIE的动物的社会缺陷。总的来说，这些研究将 描述AIE后PRL中被破坏的特定神经机制 了解这些变化如何导致社会赤字。通过这种培训机制，我将获得 构建我的技术工具包，扩展我的理论框架，并进一步发展我的 概念研究技能，所有这些都将帮助我进入博士后培训，并最终 成为一名独立调查员。