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

基本信息

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
项目类别：
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

项目摘要

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.

此修订后的R01应用的重点是阐明FMR1基因在表征自闭症谱系障碍（ASD）的社会障碍的发病机理中的细胞类型特异性功能；较大项目的第一步旨在识别基于电路的方法，该方法可以用作治疗ASD的治疗方法。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破坏通常可以得到社会奖励学习的机制，并且社交奖励学习的关闭关键时期限制了在幻想中提供的治疗干预措施的功效。我们的假设是根据实验室的研究提出的，表明投射到伏隔核（NAC）的副细胞神经元中FMR1的急性缺失概括了在本构型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颖的社会奖励学习关键时期，并确定了在成年后恢复社会奖励学习的操纵。尽管我们重要的初步发现，但OT神经元在ASD相关表型中的亚型的重要性尚不清楚，并且仅探讨了最少。在我们的初步见解的基础上，我们建议解决有关FMR1删除的细胞，突触，电路和发育后果的许多杰出问题，以下在AIMS 1-4：AIM 1：确定FMR1删除的分子和细胞后果（OT）中（OT）（OOT）神经元中的分子和细胞后果。我们会在这里测试假说，即受FMR1基因的缺失选择性影响副细胞神经元的细胞特征。目标2：确定FMR1删除对IT依赖性突触可塑性的后果。在这里，我们将检验以下假设：FMR1的缺失将导致伏隔核（NAC）中OT突触可塑性受损。目标3：确定OT神经元亚型的功能选择性。在这里，我们将检验以下假设：在将OT神经元投射到NAC但不是VTA之后，对等点的社会奖励学习缺陷将是社会领域的特定于社会领域。目的4：确定社会奖励学习的关键时期对脆弱X的治疗方法的影响。我们将测试以下假设：如果在此关键时期结束之前，或者在与Maniplection conjunction conjunction fice nip fict nig fict and ficte n.如果与Manip的社交奖励时，则可以纠正FMR1 KO小鼠中的社会奖励学习缺陷，如果进行治疗干预措施，则可以纠正。此外，AIMS 1-4中提出的研究将为功能基因组学提供几种新型工具。这些工具将使我们能够执行复杂的分子，突触和电路水平的操作。我们希望拟议的实验将提供有关社会奖励行为背后的细胞类型特定机制如何有助于ASD中社会缺陷的发病机制的新见解。