Mechanisms of male-specific amygdala-dependent deficits in approach and avoidance behaviors

项目摘要/摘要 目前，每6名儿童中就有1名患有神经发育障碍，但男性受影响的比例更大。这个 这种明显的性别差异的原因尚不清楚。神经发育障碍涉及大脑中 接近和回避行为，严重依赖杏仁核功能。我们的转基因小鼠少了一个 复制的细胞黏附分子基因PCDH10表现出男性特有的行为和杏仁核 障碍，包括社交方法和威胁条件化缺陷，降低了 杏仁核外侧核和基底核，杏仁基底外侧核NMDAR表达减少， 以及BLA中丝状棘密度的增加；行为、结构和功能方面的损害 与神经发育障碍有关。利用这一实验系统，我们将研究其机制。 男性在接近和回避行为上的缺陷及其行为救援机制 在行为、细胞、分子和电路层面上。我们将控制新生儿的睾丸素水平和 测量社交方式、威胁条件作用、NMDAR表达、突触特性和钙活性 体内兴奋性BLA细胞，采用Western blotts、全细胞膜片钳电生理学和纤维 测光学。我们还将研究d-环丝氨酸对体外和体内的影响，这种方法被证明是拯救社会的方法。 体内BLA活性。我们将研究性别、基因型和治疗的主要影响，以帮助揭示 为神经发育障碍的男性优势奠定基础，以开发新的治疗方法 战略。

Project Summary/Abstract Neurodevelopmental disorders currently affect 1 in 6 children but males are disproportionately affected. The cause of this robust sex difference is not known. Neurodevelopmental disorders involve disruptions in approach and avoidance behaviors, which rely heavily on amygdala function. Our transgenic mice missing one copy of the cell-adhesion molecule gene, PCDH10, exhibit male-specific behavioral and amygdalar impairments, including social approach and threat conditioning deficits, decreased connectivity between the lateral and basal nuclei of the amygdala, decreased NMDAR expression in the basolateral amygdala (BLA), and increased filopodial spine density in the BLA; impairments in behavior, structure, and function that are relevant to neurodevelopmental disorders. With this experimental system, we will study the mechanisms of male-specific deficits in approach and avoidance behaviors and the mechanisms underlying behavioral rescue on behavioral, cellular, molecular, and circuit levels. We will manipulate neonatal levels of testosterone and measure social approach, threat conditioning, NMDAR expression, synaptic properties, and calcium activity in excitatory BLA cells in vivo, using Western blots, whole-cell patch-clamp electrophysiology, and fiber photometry. We will also study the effects of d-cycloserine, shown to rescue social approach, on ex vivo and in vivo BLA activity. We will study main effects of sex, genotype, and treatment to help uncover mechanisms that underlie the male preponderance of neurodevelopmental disorders in order to develop novel treatment strategies.