Characterization of the role of Fmr1 in oxytocin neuronal subtypes

Fmr1 在催产素神经元亚型中作用的表征

• 批准号: 10531611
• 负责人: Gul Dolen
• 金额: $ 46.67万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531611
• 关键词: Ablation; Acute; Address; Adult; Behavior; Behavioral; Brain; Cell Count; Cell model; Cells; Characteristics; Child; Chronic; Clinical; Development; Disease; Electrophysiology (science); Exhibits; FMR1; FMRP; Fragile X Syndrome; Functional disorder; Genetic; High Prevalence; Human; Hypothalamic structure; Impairment; Individual; Knockout Mice; Laboratories; Learning; Link; Literature; Long-Term Depression; Measurement; Modeling; Modernization; Molecular; Mutation; Neurons; Nucleus Accumbens; Oxytocin; Pathogenesis; Pathogenicity; Patients; Phenotype; Predisposition; Property; Protein Biosynthesis; Proteins; Publishing; Regulator Genes; Research; Rewards; Role; Slice; Social Behavior; Social Behavior Disorders; Social Conditions; Specific qualifier value; Synapses; Synaptic plasticity; Technology; Testing; Therapeutic; Therapeutic Intervention; Transcript; Translating; Treatment Efficacy; Work; autism spectrum disorder; behavioral impairment; behavioral phenotyping; cell type; conditioned place preference; critical period; design; effective therapy; experimental study; functional genomics; gene function; genetic manipulation; improved; information processing; insight; learned behavior; neural circuit; neuropsychiatric disorder; novel; optogenetics; parvocellular; patch clamp; peer; pharmacologic; risk variant; social; social cognition; social deficits; therapeutic target; tool; treatment duration

This revised R01 application focuses on elucidating the cell type specific functions of the Fmr1 gene in the pathogenesis of social impairments that characterize autism spectrum disorder (ASD); a first step in a larger project aimed at identifying circuit based approaches which could act as therapeutics for treating ASD. Based on extensive preliminary findings, our overall hypothesis is that the loss of Fmr1 gene function in oxytocin (OT) neurons leads to disruption of mechanisms that normally subserve social reward learning, and that closure of the social reward learning critical period limits the efficacy of therapeutic interventions delivered in adulthood. Our hypothesis was formulated based on research in our laboratory demonstrating that acute deletion of Fmr1 in parvocellular OT neurons projecting to the nucleus accumbens (NAc) recapitulates social reward learning phenotypes observed in constitutive Fmr1 KO mice. In addition, we have discovered a novel critical period for social reward learning, and identified manipulations to reinstate social reward learning in adulthood. Despite our important preliminary findings, the importance of subtypes of OT neurons in ASD relevant phenotypes is unknown and only minimally been explored. Building on our preliminary insights, we propose to address a number of outstanding questions concerning the cellular, synaptic, circuit, and developmental consequences of Fmr1 deletion, outlined below in Aims 1-4: Aim 1: To determine the molecular and cellular consequences of Fmr1 deletion in oxytocin (OT) neuronal subtypes. Here we will test the hypothesis that cellular characteristics of parvocellular OT neurons will be selectively impacted by deletion of the Fmr1 gene. Aim 2: To determine the consequences of Fmr1 deletion on OT dependent synaptic plasticity. Here we will test the hypothesis that deletion of Fmr1 will lead to an impairment of OT synaptic plasticity in the nucleus accumbens (NAc). Aim 3: To determine the functional selectivity of OT neuronal subtypes. Here we will test the hypothesis that peer-peer social reward learning deficits will be social domain specific following ablation of OT neurons projecting to the NAc, but not the VTA. Aim 4: To determine the impact of the critical period for social reward learning on the therapeutic approach to Fragile X. Here we will test the hypothesis that social reward learning deficits in Fmr1 KO mice can be corrected if therapeutic interventions are delivered either before the closure of this critical period, or in adulthood if given in conjunction with manipulations that reopen the social reward learning critical period. In addition, the studies proposed in Aims 1-4 will deliver several novel tools for functional genomics. These tools will allow us to perform sophisticated molecular, synaptic and circuit level manipulations. It is our hope that the proposed experiments will provide new insight into how cell type specific mechanisms underlying social reward behavior contribute to the pathogenesis of social deficits in ASD.

这一修订的R01应用侧重于阐明Fmr1基因在以自闭症谱系障碍(ASD)为特征的社会障碍的发病机制中的细胞类型特定功能；这是旨在确定可用作治疗自闭症谱系障碍的治疗方法的基于电路的方法的更大项目的第一步。基于广泛的初步发现，我们的总体假设是，催产素(OT)神经元中Fmr1基因功能的丧失会导致正常的社会奖赏学习机制的破坏，社会奖赏学习关键期的关闭限制了成年后提供的治疗干预的有效性。我们的假说是基于我们实验室的研究表明，投射到伏隔核(NAC)的微小细胞OT神经元中Fmr1的急性缺失概括了在构成Fmr1KO小鼠中观察到的社会奖励学习表型。此外，我们发现了一个新的社会回报学习的关键期，并确定了在成年后恢复社会回报学习的操作。尽管我们有重要的初步发现，但OT神经元亚型在ASD相关表型中的重要性尚不清楚，仅有最低限度的探索。在我们初步见解的基础上，我们建议解决以下目标1-4中概述的关于Fmr1缺失的细胞、突触、回路和发育后果的一些悬而未决的问题：目标1：确定Fmr1缺失在催产素(OT)神经元亚型中的分子和细胞后果。在这里，我们将 验证Fmr1基因缺失将选择性地影响微小细胞OT神经元细胞特性的假设。目的：研究Fmr1基因缺失对OT依赖突触可塑性的影响。在这里，我们将检验Fmr1基因缺失将导致伏隔核(NAC)OT突触可塑性受损的假设。目的3：测定OT神经元亚型的功能选择性。在这里，我们将检验这一假设，即在消融投射到NAC的OT神经元后，同龄人的社会奖赏学习缺陷将是特定于社会领域的，但不是VTA。目的4：确定社会奖赏学习的关键期对脆性X的治疗方法的影响。在这里，我们将测试这样的假设，即如果在这一关键期关闭之前提供治疗干预，或在成年后结合重新打开社会奖赏学习关键期的操作，Fmr1 KO小鼠的社会奖赏学习缺陷可以得到纠正。此外，AIMS 1-4中提出的研究将为功能基因组学提供几种新的工具。这些工具将允许我们执行复杂的分子、突触和电路级别的操作。我们希望所提出的实验将提供新的见解，以了解潜在的社会奖励行为的细胞类型特定机制如何有助于ASD社会缺陷的发病机制。