Genomics, variation, and evolution of cerebellar circuits linked to higher cognitive functions in humans

与人类高级认知功能相关的小脑回路的基因组学、变异和进化

• 批准号: 10375139
• 负责人: GREGORY E CRAWFORD
• 金额: $ 40.2万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375139
• 关键词: Address; Adolescent; Adult; Affect; Animals; Area; Attention; Attention deficit hyperactivity disorder; Brain; Brain region; Cell Nucleus; Cells; Cercopithecidae; Cerebellar Cortex; Cerebellum; Chromatin; Cognition; Cognitive; Complex; Data; Data Set; Development; Disease; Equilibrium; Evolution; Freezing; Gene Expression; Gene Expression Profile; Genes; Genomics; Genotype; Growth; Human; Image; Individual; Individual Differences; Language; Link; Macaca; Macaca mulatta; Magnetic Resonance Imaging; Mammals; Maps; Mediating; Mental disorders; Methods; Modernization; Modification; Molecular; Mus; Natural Selections; Neocortex; Pan Genus; Participant; Pathway interactions; Pongidae; Population; Prefrontal Cortex; Primates; Property; Prosencephalon; Regulatory Element; Research; Risk; Schizophrenia; Series; Site; Structure; Testing; Thick; Time; Tissues; Variant; autism spectrum disorder; biobank; cell type; cognitive development; cognitive function; design; executive function; genetic variant; genome wide association study; genomic data; genomic variation; gray matter; imaging study; individual variation; neocortical; nonhuman primate; relating to nervous system; single-cell RNA sequencing; social cognition; trait; transcriptomics

ABSTRACT Growing cognitive demands over the course of human evolution have shaped the adaptation of human brains for increasingly complex higher cognitive functions, like executive control, social cognition, attention, and language. Research on those higher cognitive functions has focused predominantly on parts of the neocortex and related subcortical areas that comprise forebrain networks linked to specific cognitive functions. Recent research makes it clear, however, that each of those forebrain networks is functionally connected to distinct regions of the cerebellum. Surprisingly, evolutionary studies show further that it is those parts of the cerebellum that show the most dramatic expansion in humans compared to non-human primates, and even in modern humans compared to Neanderthals. In humans living today, individual variation in the size or functional connectivity of those cerebellar regions has been linked to disorders affecting higher cognitive functions, such as autism spectrum disorder (ASD), attention-deficit/hyperactive disorder (ADHD), and schizophrenia. These converging results suggest strongly that molecular and cellular mechanisms controlling the development and functional organization of the human cerebellum have undergone systematic changes that have proven functionally important in modern humans. The proposed studies begin to map out those changes, beginning with a genome-wide association study (GWAS) using an existing dataset of structural MRI images of cerebellum from 30,000 genotyped human participants to identify genes and genomic variants associated with overall cerebellar volume and individual differences in relative size and gray matter thickness across different regions of the cerebellar cortex (Aim 1). A parallel study (Aim 2) will use single-cell genomics of human, macaque, and mouse cerebellum to investigate possible differences in gene expression FKURPDWLQ DFFHVVLELOLW\ and the cell type composition of intrinsic cerebellar circuits between humans and other animals (Aim 2). Together, those studies address an essential but unresolved issue, whether expansion of the cerebellum in humans represents a simple increase in capacity of a basic cerebellar circuit module that is otherwise unchanged in humans, or whether the local circuitry in expanded regions of the cerebellum has undergone functionally significant modifications. In the final part of this research (Aim 3), evolutionary analysis will identify specific regulatory elements within the genes identified in the first two aims that show accelerated rates of substitution in humans or evidence of positive, purifying, or balancing selection over the course of human evolution, and whether evolutionary selection has tended to increase or decrease diversity at these sites in since the divergence of modern humans from other primates. These studies will allow us to identify specific regulatory elements or other variants that have been targets of natural selection within the genes involved in cerebellar development or adult cerebellar functions, and to compare those targets of evolutionary selection to specific variants associated with individual variation or increased risk for major psychiatric disorders in modern human populations.

摘要 人类进化过程中不断增长的认知需求塑造了人类大脑的适应性 对于越来越复杂的高级认知功能，如执行控制，社会认知，注意力， 语言对这些高级认知功能的研究主要集中在新皮层的部分 以及相关的皮层下区域，这些区域包括与特定认知功能相关的前脑网络。最近 然而，研究清楚地表明，这些前脑网络中的每一个在功能上都与不同的神经网络相连接。 小脑的区域。令人惊讶的是，进化研究进一步表明， 与非人类灵长类动物相比，人类的扩张最为剧烈， 与尼安德特人相比。在今天生活的人类中，个体在大小或功能上的差异 这些小脑区域的连通性与影响高级认知功能的疾病有关， 如自闭症谱系障碍（ASD）、注意力缺陷/多动障碍（ADHD）和精神分裂症。这些 聚合结果强烈表明，分子和细胞机制控制的发展， 人类小脑的功能组织经历了系统性的变化， 在现代人类中具有重要功能。拟议的研究开始绘制这些变化，首先是 一项全基因组关联研究（GWAS），使用了来自 对30，000名人类参与者进行基因分型，以确定与整个小脑相关的基因和基因组变异 在脑的不同区域，相对大小和灰质厚度的体积和个体差异 小脑皮质（Aim 1）。一项平行研究（目标2）将使用人类、猕猴和 小鼠小脑，以研究基因表达FKURPDWLQ DFFHVVLELOLW\和 人类和其他动物之间固有小脑回路的细胞类型组成（目的2）。在一起， 这些研究解决了一个重要但尚未解决的问题， 代表了一个简单的增加能力的基本小脑电路模块，否则不变， 人类，或者小脑扩展区域的局部电路是否在功能上经历了 重大修改。在本研究的最后一部分（目标3），进化分析将确定具体的 在前两个目标中确定的基因内的调节元件显示出加速的替换速率 在人类或证据的积极，净化，或平衡选择在人类进化的过程中， 进化选择是否倾向于增加或减少这些地点的多样性， 现代人类与其他灵长类动物的差异。这些研究将使我们能够确定特定的监管 元件或其他变异体，这些元件或其他变异体是参与小脑发育的基因内自然选择的目标。 发展或成人小脑功能，并比较这些目标的进化选择，以具体 与个体变异或现代人重大精神疾病风险增加相关的变异 人口。