Neural circuit and brain system alterations underlying social recognition memory deficits

摘要 社交缺陷是几种精神和神经发育障碍的标志性特征， 自闭症谱系障碍的症状。到目前为止，行为疗法是治疗糖尿病的第一线干预措施。 社会行为受损，而药物治疗在解决这一问题方面无效 症状域为了告知治疗目标，迫切需要了解病理生理学 潜在的社会赤字。已经确定了几种与社会行为有关的神经回路和激素 并且在物种间是保守的，例如，下丘脑室旁核与催产素的释放 肽。尽管大量的行为学和药理学研究表明室旁核 和催产素在社会行为中的作用，关于自闭症相关突变对催产素的影响知之甚少。 系统以及该系统的故障是否是自闭症社会缺陷的基础。 催产素主要由下丘脑室旁核和视上核的神经元合成 并在外周释放以调节生理功能和在中枢释放以调节社会行为。 谷氨酸能信号参与催产素的释放过程。值得注意的是，Shank3基因的突变， 自闭症的高危基因，扰乱海马体和纹状体中的神经递质信号。不过效果 Shank3突变对室旁核中催产素释放和催产素能信号传导的影响从未被证实。 以前被研究过。在这项提议中，我们研究了Shank3突变对催产素系统的影响， 大鼠Shank3突变如何影响催产素神经元的活性， 室旁核，以及社会行为大脑区域催产素的释放。我们也调查 Shank3突变对催产素系统的影响是否是社会行为缺陷的基础。我们的中央 假设Shank3突变损害了室旁核和脑内催产素的释放 区域的社会识别电路（目的1）通过干扰的神经元能信号和神经活动， 室旁核的催产素神经元（目的2），导致社会识别缺陷（目的3）。本 最后，我们将利用Shank3突变的大鼠模型，并采用分子，行为和体内成像 捕捉催产素神经元的神经活动变化并识别催产素神经元损伤的实验 在行为中释放。我们还将采用基于病毒的方法和化学遗传学工具， 操纵以确定催产素系统的改变和社会行为缺陷之间的因果关系， 是由Shank3突变引起的这项研究将有助于更清楚地了解Shank3在 下丘脑催产素系统，这是一个更大的社会大脑回路的一部分， 遗传学或通过特定回路的非侵入性干预来治疗社会行为缺陷 在SHANK3突变个体和自闭症个体中，表现出类似的大脑改变。

Abstract Social deficits are a hallmark feature of several psychiatric and neurodevelopmental disorders and are a core symptom of autism spectrum disorder. To date, behavioral therapies are the first line of intervention for treating impaired social behaviors, whereas pharmacological treatments have been ineffective at addressing this symptom domain. To inform treatment targets, there is an urgent need to understand the pathophysiology underlying social deficits. Several neural circuits and hormones involved in social behaviors have been identified and are conserved across species, e.g., the hypothalamic paraventricular nucleus and the release of the oxytocin peptide. Despite the wealth of behavioral and pharmacological studies implicating the paraventricular nucleus and oxytocin in social behavior, little is known about the effect of autism-associated mutations on the oxytocin system and whether malfunction in this system underlies social deficits in autism. Oxytocin is primarily synthesized by neurons in the paraventricular and supraoptic nuclei of the hypothalamus and is released peripherally to regulate physiological functions and centrally to modulate social behavior. Glutamatergic signaling is involved in the process of oxytocin release. Notably, mutations in the Shank3 gene, a high-risk gene for autism, perturb glutamatergic signaling in the hippocampus and striatum. However, the effect of Shank3 mutations on glutamatergic signaling and oxytocin release in the paraventricular nucleus has never been studied before. In this proposal, we study the effect of Shank3 mutations on the oxytocin system to ask how a Shank3 mutation in rats affect the activity of oxytocin neurons, glutamatergic signaling in the paraventricular nucleus, and the release of oxytocin at brain regions of social behavior. We also investigate whether the effect of Shank3 mutations on the oxytocin system underlies social behavior deficits. Our central hypothesis is that Shank3 mutations impair oxytocin release within the paraventricular nucleus and at brain regions of the social recognition circuit (Aim 1) by interfering with glutamatergic signaling and neural activity of oxytocin neurons in the paraventricular nucleus (Aim 2), leading to social recognition deficits (Aim 3). To this end, we will utilize a rat model with a Shank3 mutation and employ molecular, behavioral, and in vivo imaging experiments to capture alterations in neural activity of oxytocin neurons and identify impairments in oxytocin release during behavior. We will also employ viral-based approaches and chemo-genetic tools for neural-specific manipulations to determine causality between alteration in the oxytocin system and deficits in social behavior, caused by a Shank3 mutation. This study will lead to a clearer understanding of Shank3 function in the hypothalamic oxytocin system, which is part of a larger social brain circuit that could be targeted pharmacologically, genetically, or via circuit-specific non-invasive interventions to treat social behavior deficits in individuals with SHANK3 mutations and in individuals with autism that present similar brain alterations.