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.

抽象的 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能力 日益复杂的高级认知功能，如执行控制、社会认知、注意力和 语言。对这些高级认知功能的研究主要集中在新皮质的部分 以及由与特定认知功能相关的前脑网络组成的相关皮层下区域。最近的 然而，研究表明，每个前脑网络在功能上都与不同的 小脑的区域。令人惊讶的是，进化研究进一步表明，正是小脑的那些部分 与非人类灵长类动物相比，人类的扩张最为显着，甚至在现代也是如此 人类与尼安德特人相比。对于当今的人类来说，尺寸或功能上的个体差异 这些小脑区域的连通性与影响高级认知功能的疾病有关，例如 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 趋同的结果强烈表明，控制发育和发育的分子和细胞机制 人类小脑的功能组织发生了系统性的变化，事实证明 对现代人类具有重要的功能。拟议的研究开始规划这些变化，首先是 一项全基因组关联研究 (GWAS)，使用现有的小脑结构 MRI 图像数据集 对 30,000 名人类参与者进行基因分型，以确定与整体小脑相关的基因和基因组变异 不同区域的体积和相对大小和灰质厚度的个体差异 小脑皮质（目标 1）。一项平行研究（目标 2）将使用人类、猕猴和猕猴的单细胞基因组学。 小鼠小脑研究基因表达 FKURPDWLQ DFFHVVLELOLW\ 和 人类和其他动物之间内在小脑回路的细胞类型组成（目标 2）。一起， 这些研究解决了一个重要但尚未解决的问题，即人类小脑的扩张是否 代表基本小脑电路模块容量的简单增加，该模块在其他方面没有变化 人类，或者小脑扩展区域的局部电路是否发生了功能性变化 重大修改。在本研究的最后部分（目标 3），进化分析将识别特定的 前两个目标中确定的基因内的调控元件显示出加速的替代率 人类进化过程中的积极、净化或平衡选择的证据，以及 自古以来，进化选择是否倾向于增加或减少这些位点的多样性 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具体的监管 小脑相关基因中自然选择目标的元素或其他变体 发育或成人小脑功能，并将进化选择的这些目标与特定的目标进行比较 与现代人类个体差异或主要精神疾病风险增加相关的变异 人口。