FGF13 Control of Hippocampal Excitability in Cocaine Contextual Memory

FGF13 对可卡因情境记忆中海马兴奋性的控制

• 批准号: 10387542
• 负责人: Susan Lin
• 金额: $ 4.68万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10387542
• 关键词: Action Potentials; Acute; Address; Adult; Alternative Splicing; Animals; Antibodies; Behavior; Binding; Brain; Brain region; Cause of Death; Cells; Cocaine; Cocaine Dependence; Cocaine use disorder; Custom; Defect; Dorsal; Down-Regulation; Drug Addiction; Electrophysiology (science); Environment; Excitatory Postsynaptic Potentials; Extinction (Psychology); FDA approved; Fellowship; Female; Fibroblast Growth Factor; Genes; Goals; Health; Hippocampus (Brain); Hospitalization; Hour; In Situ Hybridization; Individual; Interneurons; Knock-out; Knockout Mice; Label; Link; Long-Term Potentiation; LoxP-flanked allele; Maintenance; Measures; Mediating; Medicine; Memory; Mission; Modeling; Molecular; Mus; National Institute of Drug Abuse; Neurons; Neurosciences; Nitric Oxide Synthase Type I; Overdose; Parvalbumins; Performance; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Play; Property; Protein Isoforms; Protocols documentation; Public Health; Pyramidal Cells; Regulation; Reporter; Reporting; Research; Rewards; Risk; Role; Signal Transduction; Slice; Sodium Channel; Somatostatin; Stains; Substance abuse problem; Synaptic plasticity; Tamoxifen; Technical Expertise; Techniques; Testing; Training; United States; Viral; Work; addiction; behavioral phenotyping; behavioral study; cell type; cocaine exposure; conditioned place preference; conditioning; density; differential expression; experience; experimental study; fibroblast growth factor 13; improved; male; memory acquisition; molecular marker; mouse model; mutant; neuronal excitability; novel; overdose death; preference; programs; psychosocial; response; reward circuitry; tool; voltage

Project Summary Overdose deaths caused by cocaine use disorder (CUD) pose a major public health burden in the United States due in part to a lack of pharmacological treatments. The hippocampus is a major brain region for forming and maintaining drug associated contextual memories. Pharmacologically disrupting these associations, in supplement with existing psychosocial treatments, can potentially reduce the health risks of CUD. My proposal is driven by this critical need to identify novel molecular mechanisms underlying hippocampal regulation of cocaine seeking behavior. My preliminary findings suggest a role for voltage-gated sodium channels (VGSCs) in supporting cocaine contextual memory, via regulation by the VGSC auxiliary subunit Fibroblast Growth Factor 13 (FGF13). I discovered that fibroblast growth factor homologous factor 13 (FGF13) is expressed in a subset of nNOS+ interneurons. Deletion of FGF13 from this subset of hippocampal interneurons results in increased cocaine conditioned place preference (CPP). I aim to define the roles of FGF13 in controlling hippocampal excitability and subsequent role in cocaine contextual memory. I hypothesize that FGF13 plays a critical role in the formation of cocaine-contextual memory by regulating VGSC function and consequent neuronal excitability of a subset of nNOS+ hippocampal interneurons. I will address this hypothesis through the following Specific Aims: Aim 1: To define FGF13 maintenance of sodium channel excitability in hippocampal interneurons. Aim 2: To test FGF13 sufficiency in mediating cocaine contextual memory acquisition and extinction. To perform these experiments, I will use a floxed FGF13 mouse line generated by our lab to record electrophysiological properties of FGF13+ hippocampal interneurons (Aim 1) in response to cocaine exposure as well as to evaluate the role of FGF13 in mediating cocaine contextual memory (Aim 2). My fellowship training plan outlines the steps I will take to gain technical expertise in slice electrophysiology (Aim 1), for which I have little prior experience, and to employ viral tools in studying mouse models of addiction (Aim 2), which are also techniques that are new to me. The research environment in the Neuroscience Graduate Program at Weill Cornell Medicine is well suited for me to complete my goals. The proposed experiments will help establish a model by which FGF13 controls hippocampal excitability, and enhance our understanding of contextual memory and drug addiction overall. The objective of this proposal is to identify FGF13 as a novel pharmacological target for treating cocaine dependence.

项目概要 可卡因使用障碍 (CUD) 造成的过量死亡构成了美国的重大公共卫生负担 部分原因是缺乏药物治疗。海马体是大脑形成的主要区域 并维持与药物相关的情境记忆。从药理学上破坏这些关联， 补充现有的社会心理治疗，可以潜在地降低 CUD 的健康风险。我的建议 是由这种迫切需要确定海马调节背后的新分子机制所驱动的 可卡因寻求行为。 我的初步研究结果表明电压门控钠通道 (VGSC) 在支持可卡因方面发挥着作用 情境记忆，通过 VGSC 辅助亚基成纤维细胞生长因子 13 (FGF13) 的调节。我 发现成纤维细胞生长因子同源因子 13 (FGF13) 在 nNOS+ 的一个子集中表达 中间神经元。从海马中间神经元的这个子集中删除 FGF13 会导致可卡因增加 条件性位置偏好（CPP）。我的目的是确定 FGF13 在控制海马兴奋性中的作用 以及可卡因情境记忆中的后续作用。我推测 FGF13 在形成过程中起着关键作用 通过调节 VGSC 功能和随后的一部分神经元兴奋性来控制可卡因情境记忆 nNOS+ 海马中间神经元。我将通过以下具体目标来解决这个假设： 目标 1：确定 FGF13 对海马中间神经元钠通道兴奋性的维持作用。 目标 2：测试 FGF13 在介导可卡因情境记忆获取和消退方面的充分性。 为了进行这些实验，我将使用我们实验室生成的 floxed FGF13 小鼠品系来记录 FGF13+ 海马中间神经元（目标 1）响应可卡因暴露的电生理特性 以及评估 FGF13 在介导可卡因情境记忆中的作用（目标 2）。我的联谊培训 计划概述了我将采取的步骤来获得切片电生理学的技术专业知识（目标 1），为此我有 以前的经验很少，并利用病毒工具来研究小鼠成瘾模型（目标 2），这也是 对我来说是新的技术。威尔神经科学研究生项目的研究环境 康奈尔医学院非常适合我完成我的目标。所提出的实验将有助于建立 FGF13 控制海马兴奋性的模型，增强我们对情境记忆的理解 和整体毒瘾。该提案的目的是将 FGF13 确定为新的药理学靶点 用于治疗可卡因依赖。