FGF13 Control of Hippocampal Excitability in Cocaine Contextual Memory

项目摘要 可卡因使用障碍（CUD）引起的过量死亡在美国构成了主要的公共卫生负担 部分原因是缺乏药物治疗。海马体是大脑中形成 以及维持与药物相关的情境记忆从药理学上破坏这些关联， 补充现有的心理治疗，可以潜在地降低CUD的健康风险。我的提议 是由这一关键需要，以确定新的分子机制，海马调控， 寻求可卡因的行为 我的初步发现表明电压门控钠通道（VGSC）在支持可卡因 背景记忆，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+ 中间神经元从海马中间神经元的这个子集中缺失FGF13导致可卡因增加。 条件位置偏好（CPP）我的目的是确定FGF13在控制海马兴奋性中的作用， 以及可卡因背景记忆的后续作用。我假设FGF13在形成中起着关键作用， 可卡因背景记忆的调节VGSC功能和随之而来的神经元兴奋性的一个子集， nNOS+海马中间神经元。我将通过以下具体目标来阐述这一假设： 目的1：探讨FGF 13对海马中间神经元钠通道兴奋性的维持作用。 目的2：测试FGF 13在介导可卡因背景记忆获得和消退中的充分性。 为了进行这些实验，我将使用由我们实验室产生的floxed FGF 13小鼠系来记录 FGF13+海马中间神经元（Aim 1）对可卡因暴露的电生理学特性 以及评估FGF 13在介导可卡因背景记忆中的作用（目的2）。我的奖学金训练 计划概述了我将采取的步骤，以获得切片电生理学（目标1）的技术专长，为此，我有 以前的经验很少，并采用病毒工具研究成瘾的小鼠模型（目标2），这也是 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。拟议的实验将有助于建立 FGF13控制海马兴奋性的模型，并增强了我们对背景记忆的理解 和总体毒瘾。该提案的目的是将FGF13鉴定为新的药理学靶点， 用于治疗可卡因依赖。

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.