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：
10378510
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378510
关键词：
Address Affect Agonist Amygdaloid structure Area Aromatase Aromatase Inhibitors Basal Ganglia Behavior Behavioral Behavioral Mechanisms 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 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 approach avoidance behavior autism spectrum disorder 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.

项目摘要/摘要神经发育障碍目前影响6个儿童中的1个，但男性受到不成比例的影响。这这种强大的性别差异的原因尚不清楚。神经发育障碍涉及中断方法和回避行为，严重依赖杏仁核功能。我们的转基因小鼠缺少一个细胞粘附分子基因PCDH10的副本表现出男性特异性行为和杏仁核损害，包括社会方法和威胁条件赤字，降低了连通性杏仁核的侧向和基底核，在基底外侧杏仁核（BLA）中降低了NMDAR的表达，并增加BLA中的丝脊柱密度；行为，结构和功能的损害与神经发育障碍有关。使用此实验系统，我们将研究男性在进场和回避行为方面的缺陷以及行为救援的基础机制在行为，细胞，分子和电路水平上。我们将操纵睾丸激素的新生儿水平和测量社会方法，威胁调节，NMDAR表达，突触特性和钙活动使用蛋白质印迹，全细胞贴片钳电生理学和纤维在体内兴奋性BLA细胞光度法。我们还将研究d-胞丝烯的影响，证明是拯救社会方法，对离体和IN的影响体内BLA活性。我们将研究性别，基因型和治疗的主要影响，以帮助发现机制为了开发新的治疗，神经发育障碍的男性优势是策略。