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

项目总结/摘要 神经发育障碍目前影响六分之一的儿童，但男性受到的影响不成比例。的 这种巨大的性别差异的原因尚不清楚。神经发育障碍包括 接近和回避行为，这在很大程度上依赖于杏仁核的功能。我们的转基因小鼠少了一个 细胞粘附分子基因PCDH 10的拷贝表现出男性特异性的行为和杏仁核 障碍，包括社会途径和威胁条件反射缺陷，减少了 杏仁核的外侧核和基底核，基底外侧杏仁核（BLA）中NMDAR表达减少， BLA中的丝状伪足棘密度增加;行为、结构和功能障碍， 与神经发育障碍有关。利用这一实验系统，我们将研究 男性特有的接近和回避行为缺陷及其行为拯救机制 在行为细胞分子和电路层面上。我们会控制新生儿的睾丸激素水平， 测量社交方式，威胁条件反射，NMDAR表达，突触特性和钙活性， 兴奋性BLA细胞在体内，使用蛋白质印迹，全细胞膜片钳电生理学，和纤维 测光我们还将研究d-环丝氨酸的影响，显示拯救社会的做法，对离体和在 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 神经发育障碍的男性优势，以开发新的治疗方法 战略布局

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.