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: 10595518
• 负责人: Susan Lin
• 金额: $ 4.77万
• 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/10595518
• 关键词: Action Potentials; Acute; 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; FDA approved; Fellowship; Female; Fibroblast Growth Factor; Genes; Goals; Health; Hippocampus; 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; 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; cocaine related behaviors; cocaine seeking; 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; pharmacologic; 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.

项目摘要 可卡因使用障碍（CUD）造成的过量死亡造成了统一的重大公共卫生负担 州部分原因是缺乏药理治疗。海马是形成的主要大脑区域 并维持与药物相关的上下文记忆。在药理上破坏这些关联， 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 这是由确定海马调节基础的新型分子机制驱动的 可卡因寻求行为。 我的初步发现表明，电压门控钠通道（VGSC）在支持可卡因中的作用 通过VGSC辅助亚基成纤维细胞生长因子13（FGF13）调节的上下文记忆。我 发现成纤维细胞生长因子同源因子13（FGF13）在NNOS+的子集中表达 中间神经元。从这一子集的海马中间神经元中删除FGF13会导致可卡因增加 条件地点偏好（CPP）。我的目的是定义FGF13在控制海马兴奋性中的作用 以及随后在可卡因上下文记忆中的作用。我假设FGF13在编队中起着至关重要的作用 通过调节VGSC功能以及随之而来的神经元兴奋性的子集的可卡因神经内存记忆 NNOS+海马中间神经元。我将通过以下特定目的解决这一假设： 目标1：定义海马中间神经元中钠通道兴奋性的维持。 目标2：测试FGF13在介导可卡因上下文记忆的获取和灭绝时足够。 要执行这些实验，我将使用我们实验室生成的Floxed FGF13鼠标线记录 FGF13+海马中间神经元的电生理特性（AIM 1）响应可卡因暴露 以及评估FGF13在介导可卡因上下文记忆中的作用（AIM 2）。我的奖学金培训 计划概述了我将采取的步骤来获得切片电生理学技术专长（AIM 1） 很少的先前经验，并在研究成瘾的鼠标模型中使用病毒工具（AIM 2），这也是 对我来说是新的技术。威尔神经科学研究生课程的研究环境 康奈尔医学非常适合我完成目标。提出的实验将有助于建立 FGF13控制海马兴奋性的模型，并增强我们对上下文记忆的理解 和吸毒成瘾总体。该提案的目的是将FGF13识别为一种新的药理目标 用于治疗可卡因依赖性。