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: 10314210
• 负责人: Trevor Towner
• 金额: $ 3.12万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314210
• 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 我们的研究小组揭示了与青少年间歇性有关的持久行为障碍 乙醇（AIE）暴露，雄性大鼠在青春期暴露于乙醇中，证明了社会缺陷 通过减少社会偏好和社会调查的索引。我们的初步数据指向预先的数据 （PRL）皮质作为与这种社会抑制相关的区域。据报道，AIE增加了谷氨酸能 PRL中的信号传导，可能是由于GABA能传播的改变。 PRL活动受到严格调节 通过抑制性白蛋白（PV）中间神经元，通常由细胞外基质组件包含 会内神经元网（PNN）。该建议旨在检验以下假设。 PRL是PV Intreneuron抑制性控制的PNN依赖性降低的结果，这是一种可能 直接导致AIE之后成年大鼠明显的社会缺陷。该假设将在AIM 1中通过 确定是否与对社会刺激的反应相关的特定神经集合是否失活 PRL内部可以扭转AIE引起的社会缺陷。在AIM 2中，我们将评估AIE对PNN的影响 PRL中的表达并研究了依赖AIE的PNN改变是否与 谷氨酸能和GABA能在PV中间神经元上的变化。用于评估关系 在PNN上调和AIE之后的社会改变之间，我们将测试是否存在酶促降解 AIE之后的PNN能够逆转暴露于AIE的动物的社会缺陷。这些研究总的来说 表征PRL中特定的神经机制在AIE之后被破坏，进一步 了解这些改变如何导致社会缺陷。通过这种培训机制，我将获得 建立我的技术工具套件，扩展我的理论框架并进一步发展我的技术工具套件的宝贵技能 概念研究技能集，所有这些都将有助于我进入博士后培训，并最终 成为独立研究者。