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: 10093132
• 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/10093132
• 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; 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; Pharmacology; Phenotype; Predisposition; Property; Protein Biosynthesis; Publishing; Regulator Genes; Research; Rewards; Role; Slice; Social Behavior; Social Behavior Disorders; Social Conditions; Specific qualifier value; Synaptic plasticity; Technology; Testing; Therapeutic; Therapeutic Intervention; Transcript; Translating; Treatment Efficacy; Work; autism spectrum disorder; base; 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; 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.

这项修订后的R01申请重点阐明了Fmr1基因在自闭症谱系障碍（ASD）的社会障碍发病机制中的细胞类型特异性功能；这是一个更大项目的第一步，旨在确定基于电路的方法，这种方法可以作为治疗ASD的疗法。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基因功能的丧失导致了通常支持社会奖励学习的机制的破坏，并且社会奖励学习关键期的关闭限制了成年期治疗干预的有效性。我们的假设是基于我们实验室的研究，该研究表明，在向伏隔核（NAc）投射的旁细胞OT神经元中，Fmr1的急性缺失再现了在构成型Fmr1 KO小鼠中观察到的社会奖励学习表型。此外，我们还发现了一个新的社会奖励学习的关键时期，并确定了在成年期恢复社会奖励学习的操作。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，并且只进行了最低限度的探索。基于我们的初步见解，我们建议解决一些关于Fmr1缺失的细胞、突触、电路和发育后果的悬而未决的问题，如下目的1-4所述：目的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。这里我们将