Characterization of the role of Fmr1 in oxytocin neuronal subtypes

修订后的R 01应用程序的重点是阐明Fmr 1基因在自闭症谱系障碍（ASD）特征性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，可以作为治疗ASD的治疗方法。基于广泛的初步研究结果，我们的总体假设是，催产素（OT）神经元中Fmr 1基因功能的丧失导致通常有助于社会奖励学习的机制中断，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。我们的假设是根据我们实验室的研究制定的，该研究表明，在投射到丘脑核（NAc）的小细胞OT神经元中，Fmr 1的急性缺失概括了在组成型Fmr 1 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，并且仅进行了最低限度的探索。建立在我们的初步见解，我们建议解决一些悬而未决的问题，有关的细胞，突触，电路，和发展的后果Fmr 1删除，概述如下目标1-4：目标1：确定的分子和细胞的后果Fmr 1删除催产素（OT）神经元亚型。这里我们将 测试小细胞OT神经元的细胞特性将通过Fmr 1基因的缺失而选择性地受到影响的假设。目的2：研究Fmr 1基因缺失对OT依赖性突触可塑性的影响。在这里，我们将测试的假设，删除Fmr 1将导致损害的OT突触可塑性在脑桥核（NAc）。目的3：确定OT神经元亚型的功能选择性。在这里，我们将测试这一假设，即同伴社会奖励学习缺陷将是社会领域的具体消融后，投射到NAc的OT神经元，但不是腹侧被盖区。目的4：确定社会奖励学习的关键期对脆性X染色体治疗方法的影响。在这里，我们将测试的假设，即社会奖励学习缺陷在Fmr 1基因敲除小鼠可以得到纠正，如果治疗干预之前，关闭这个关键时期，或在成年期，如果与操作，重新打开社会奖励学习的关键期。此外，目标1-4中提出的研究将为功能基因组学提供几种新工具。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，拟议的实验将提供新的见解，以了解细胞类型的具体机制，社会奖励行为的基础上，有助于在ASD的社会缺陷的发病机制。

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.