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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：
9928606
负责人：
M. CHIARA MANZINI
金额：
$ 44.1万
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/9928606
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 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) 和自闭症谱系障碍自闭症谱系障碍（ASD）在男性中比女性更常见。尽管事实上 NDD 的诊断频率更高男性，这些疾病中性别偏见的分子机制仍然未知。直到最近，性在数据分析中并未常规考虑，并且女性常常被排除在行为之外完全进行实验。与此同时，几十年来大多数 NDD 基因都位于 X 染色体上由于在 X 连锁系谱中识别连锁区域相对容易，导致小鼠模型仅在一种性别中进行了研究。因此，NDD 临床前动物模型中性别差异的测试已被有限的。我们的工作引入了缺乏卷曲螺旋和含有 1a (Cc2d1a) 的 C2 结构域的小鼠作为新型小鼠 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) 突变会导致人类自闭症谱系障碍 (ASD)、智力障碍 (ID) 和癫痫发作，Cc2d1a 敲除 (KO) 雄性小鼠显示人类表型的行为特征，包括认知和社交缺陷、多动和焦虑。相比之下，我们的初步数据表明，雌性 KO 小鼠仅表现出较轻微的认知缺陷。 cc2d1a 由于上游 PKA 失调，KO 雄性还表现出 CREB 激活的性别特异性减少途径。这些发现提出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回路的策略，以及特别导致我们的假设：CC2D1A 以性别特异性方式调节 CREB 信号传导特定性别的行为缺陷。该提案的总体目标是证明我们的假设。在具体目标 1 中，我们将探索形态学、雄性和雌性 Cc2d1a KO 小鼠之间的生理和行为差异与 CREB 信号传导减少。在具体目标 2 中，我们将调节 PKA/CREB 通路以证明所有这些表型通过性别特异性 CREB 信号缺陷连接起来。最后，在具体目标 3 中，我们将探索性别特异性 CC2D1A 信号传导的分子机制。如果我们的研究成功的话确定 CREB 信号调节的新型性别二态性机制并将分子和细胞联系起来行为上的缺陷。我们的研究结果将非常重要，因为它们将建立 ID/ASD 基因 CC2D1A 作为大脑中性别特异性信号传导的关键调节剂。