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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：
9974784
负责人：
Sarah L Ferri
金额：
$ 13.91万
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/9974784
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 Individual 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 autistic base behavior test calcium indicator career career development cell type conditioned fear conditioning density experience experimental study improved in vivo in vivo imaging 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