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

• 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
• 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

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.

摘要 神经发育障碍（NDD），如智力障碍（ID）和自闭症谱系障碍 (ASD)男性比女性更常见。尽管NDD在美国被诊断出的频率更高， 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 在数据分析中没有常规考虑，女性经常被排除在行为研究之外。 全部实验与此同时，几十年来，大多数被鉴定为NDD的基因都位于X染色体上 因为在X连锁的谱系中识别连锁区域相对容易，导致小鼠模型， 只在一种性别中进行研究。因此，在NDD的临床前动物模型中测试性别差异已经被证明是可行的。 有限公司 本工作介绍了一种新的小鼠Cc 2d 1a（Coiled-coil and C2 domain containing 1a） NDD中分子和行为性别特异性缺陷的模型。我们发现CC 2D 1A功能丧失 (LOF)突变导致人类ASD，ID和癫痫发作，并且Cc 2d 1a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，我们的初步数据显示，雌性KO小鼠仅表现出较轻的认知缺陷。Cc2d1a KO雄性还显示出CREB激活的性别特异性降低，这是由于上游PKA的失调。 通路这些发现增加了男性和女性可能使用不同的分子 为相同的行为编码信息和建立神经元回路的策略， 特别是导致我们的假设，CC 2D 1A调节CREB信号在性别特异性的方式，导致 性别特异性行为缺陷 这个提案的总体目标是证明我们的假设。在具体目标1中，我们将探讨形态学， 雄性和雌性Cc 2d 1a KO小鼠之间的生理和行为差异， 减少CREB信号传导。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信号传导缺陷连接。在第三章中，我们将 探索性别特异性CC 2D 1A信号转导的分子机制。如果我们的研究成功， 确定CREB信号调节和连接分子和细胞一种新的性二态性机制 行为缺陷。我们的研究结果将是非常重要的，因为他们将建立ID/ASD基因CC 2D 1A 作为大脑中性别特异性信号的关键调节器。