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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要我们的研究小组揭示了与青少年间歇性行为障碍相关的长期行为障碍乙醇（AIE）暴露，青春期暴露于乙醇的雄性大鼠表现出社交缺陷通过社会偏好和社会调查的减少来索引。我们的初步数据指向前边缘 (PrL) 皮层是与这种社交抑制相关的区域。据报道，AIE 可增加谷氨酸能 PrL 中的信号传导，可能是由于 GABA 能传输的改变所致。 PrL 活动受到严格监管通过抑制性小清蛋白（PV）中间神经元，这些中间神经元通常被细胞外基质成分包围，神经周围网（PNN）。该提案旨在检验 AIE 引起的功能障碍这一假设 PrL 是 PNN 依赖性 PV 中间神经元抑制控制减少的结果，这种神经改变可能会导致直接导致成年大鼠 AIE 后明显的社交缺陷。该假设将在目标 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相关 PrL 内的可以逆转 AIE 引起的社会缺陷。在目标 2 中，我们将评估 AIE 对 PNN 的影响 PrL 内的表达并研究 AIE 依赖性 PNN 改变是否与 PV 中间神经元的谷氨酸能和 GABA 能输入的变化。用于评估关系在 PNN 上调和 AIE 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 能够扭转 AIE 暴露动物的社会缺陷。总的来说，这些研究将描述 PrL 中在 AIE 后被破坏的特定神经机制，并进一步我们的研究了解这些改变如何导致社会赤字。通过这个训练机制我将收获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宝贵技能概念研究技能，所有这些都将有助于我进入博士后培训并最终成为一名独立调查员。