Defining the molecular mechanisms of sex differences in cognitive function

定义认知功能性别差异的分子机制

基本信息

批准号：
9974594
负责人：
M. CHIARA MANZINI
金额：
$ 41.3万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9974594
关键词：
Adult Affect Animal Model Anxiety Behavior Behavioral Binding Brain C2 Domain CREB1 gene Cognitive Cognitive deficits Coiled-Coil Domain Complex Cyclic AMP-Dependent Protein Kinases Cytoskeleton Data Data Analyses Defect Dendritic Spines Diagnosis Disease Dorsal Electrophysiology (science)Embryonic Development Event Extinction (Psychology)Female Fright Genes Goals Hippocampus (Brain)Human Hyperactive behavior Intellectual functioning disability Knock-out Knockout Mice Lead Learning Link Long-Term Potentiation Memory Memory impairment Modeling Molecular Morphology Mus Mutation Neurodevelopmental Disorder Neurons Pathway interactions Pharmacology Phenotype Phosphorylation Physiological Physiology Prosencephalon Proteins Regulation Scaffolding Protein Seizures Sex Bias Sex Differences Signal Pathway Signal Transduction Social Functioning Specificity Stream Synapses Testing Vertebral column Western Blotting Work X Chromosome autism spectrum disorder base behavioral phenotyping cognitive function density emotional behavior experimental study genetic pedigree loss of function loss of function mutation male molecular modeling mouse model neuronal circuitry novel pre-clinical response scaffold sex sexual dimorphism social deficits spatial memory tandem mass spectrometry theories therapy development

项目摘要

Abstract Neurodevelopmental disorders (NDDs), such as Intellectual Disability (ID) and Autism Spectrum Disorder (ASD) are more prevalent in males than females. Despite the fact the NDDs are diagnosed more frequently in males, the molecular mechanisms underlying sex bias in these disorders are still unknown. Until recently, sex had not been routinely considered in data analysis, and females were often excluded from behavioral experiments altogether. In parallel, for decades most genes identified for NDDs were on the X chromosome because of the relative ease to identify linkage regions in X-linked pedigrees, leading to mouse models that were studied only in one sex. Thus, testing of sex differences in preclinical animal models of NDDs has been limited. Our work introduces mice deficient for Coiled-coil and C2 domain containing 1a (Cc2d1a) as a novel mouse model for molecular and behavioral sex-specific deficits in NDDs. We found that CC2D1A loss of function (LOF) mutations cause ASD, ID and seizures in humans, and that Cc2d1a knock-out (KO) male mice display behavioral features of the human phenotype, including cognitive and social deficits, hyperactivity and anxiety. In contrast, our preliminary data show that female KO mice only present with milder cognitive deficits. Cc2d1a KO males also display a sex-specific reduction in CREB activation due a disregulation of the upstream PKA pathway. These findings raise the possibility that males and females may use different molecular strategies for encoding information and building neuronal circuits for the same behaviors, and in particular lead to our hypothesis that CC2D1A regulates CREB signaling in a sex-specific manner leading to sex-specific behavioral deficits. The overall goal of this proposal is to prove our hypothesis. In Specific Aim 1 we will explore morphological, physiological and behavioral differences between male and female Cc2d1a KO mice which correlate with reduction in CREB signaling. In Specific Aim 2 we will modulate the PKA/CREB pathway to demonstrate that all these phenotypes are connected by a sex-specific CREB signaling defect. Finally, in Specific Aim 3 we will explore the molecular mechanisms underlying sex-specific CC2D1A signaling. If successful our studies will identify a novel sexually dimorphic mechanisms for CREB signaling regulation and link molecular and cellular deficits to behavior. Our findings will be highly significant as they will establish the ID/ASD gene CC2D1A as a critical regulator of sex-specific signaling in the brain.

抽象的神经发育障碍（NDD），例如智力障碍（ID）和自闭症谱系障碍（ASD）在男性中比女性更普遍。尽管事实上，NDD被更频繁地诊断雄性，这些疾病中性偏见的分子机制仍然未知。直到最近，性爱在数据分析中没有常规考虑，并且通常将女性排除在行为之外实验完全。同时，数十年来，大多数针对NDD的基因都在X染色体上由于相对易于识别X连锁血统中的连锁区域，导致了鼠标模型仅以一种性别进行研究。因此，在NDD的临床前动物模型中的性别差异测试已经有限的。我们的工作介绍了缺乏盘绕螺旋的小鼠和包含1a（CC2D1A）的C2域的小鼠 NDD中分子和行为性别特异性缺陷的模型。我们发现CC2D1A功能丧失（LOF）突变导致人类的ASD，ID和癫痫发作，而CC2D1A敲除（KO）雄性小鼠显示人类表型的行为特征，包括认知和社会缺陷，多动症和焦虑。相比之下，我们的初步数据表明，雌性KO小鼠仅出现较温和的认知缺陷。 CC2D1A KO雄性还显示出上游PKA的CREB激活的特定性别降低路径。这些发现增加了男性和女性可能使用不同分子的可能性编码信息和构建相同行为的神经元电路的策略，特别导致我们的假设，即CC2D1A以性别特异性的方式调节CREB信号传导特定性行为的行为缺陷。该提案的总体目标是证明我们的假设。在特定目标1中，我们将探索形态学，男性和雌性CC2D1A KO小鼠之间的生理和行为差异，与降低CREB信号传导。在特定目标2中，我们将调节PKA/CREB途径以证明所有这些表型通过性别特异性的CREB信号传导缺陷连接。最后，在特定的目标3中，我们将探索性别特异性CC2D1A信号传导的分子机制。如果成功的话，我们的学习将确定一种新型的性二态机制，用于CREB信号调节并连接分子和细胞行为的赤字。我们的发现将非常重要，因为它们将建立ID/ASD基因CC2D1A 作为大脑中性别特异性信号的关键调节剂。