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

男性特有的杏仁核依赖性接近和回避行为缺陷的机制

基本信息

批准号：
10593966
负责人：
Sarah L Ferri
金额：
$ 13.72万
依托单位：
UNIVERSITY OF IOWA
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：
2020-04-03 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593966
关键词：
Address Affect Agonist Amygdaloid structure Area Aromatase Aromatase Inhibitors Basal Ganglia Behavior Behavioral Birth Brain Calcium Cell Adhesion Molecules Cell Nucleus Cells Child Cycloserine Data Dendritic Spines Disease Electrophysiology (science)Enzymes Equipment Estradiol Exhibits Female Fiber Fostering Fright Functional disorder Future Genes Genotype Goals Gonadal Hormones Heterozygote Hormones Imaging Techniques Impairment Incidence Lateral Learning Link Masculine Measures Mentors Molecular Molecular Biology Mus N-Methyl-D-Aspartate Receptors Neonatal Neurobiology Neurodevelopmental Disorder Neuroendocrinology Oral Pharmaceutical Preparations Photometry Population Process Property Quality of life Receptor Signaling Reporting Research Research Personnel Rodent Sex Bias Sex Differences Social Behavior Structure Symptoms Synapses System Testing Testosterone Training Transgenic Mice Vertebral column Western Blotting Work Writing approach behavior autism spectrum disorder avoidance behavior base behavior test calcium indicator career career development cell type conditioned fear conditioning density experience experimental study improved in vivo in vivo imaging individuals with autism spectrum disorder insight male mouse model mutant neonatal brain neurophysiology novel patch clamp postnatal pre-clinical prevent protocadherin 10 receptor expression sex skills social social deficits synaptic function treatment strategy

项目摘要

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.

项目概要/摘要目前，六分之一的儿童受到神经发育障碍的影响，但男性受影响的比例更大。这这种强烈的性别差异的原因尚不清楚。神经发育障碍涉及接近和回避行为在很大程度上依赖于杏仁核功能。我们的转基因小鼠缺少一只细胞粘附分子基因 PCDH10 的副本表现出男性特有的行为和杏仁核损害，包括社会方法和威胁调节缺陷，减少了人与人之间的联系杏仁核的外侧核和基底核，基底外侧杏仁核 (BLA) 中的 NMDAR 表达减少， BLA 中的丝状棘密度增加；行为、结构和功能的损伤与神经发育障碍有关。通过这个实验系统，我们将研究其机制男性特有的接近和回避行为缺陷以及行为救援的机制在行为、细胞、分子和电路水平上。我们将控制新生儿的睾酮水平测量社会方法、威胁调节、NMDAR 表达、突触特性和钙活性体内兴奋性 BLA 细胞，使用蛋白质印迹、全细胞膜片钳电生理学和纤维光度测定。我们还将研究 d-环丝氨酸对离体和体内的影响，它被证明可以挽救社交方式。体内 BLA 活性。我们将研究性别、基因型和治疗的主要影响，以帮助揭示以下机制：神经发育障碍男性占主导地位，以便开发新的治疗方法策略。