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

基本信息

批准号：
10440526
负责人：
GREGORY E CRAWFORD
金额：
$ 36.86万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10440526
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

项目摘要

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.

抽象的在人类进化过程中，认知需求越来越多，已经塑造了人类大脑的适应对于越来越复杂的更高认知功能，例如执行控制，社会认知，注意力和语言。对这些较高认知功能的研究主要集中在新皮层的一部分上以及构成与特定认知功能相关的前脑网络的相关皮层区域。最近的但是，研究清楚地表明，这些前脑网络在功能上都连接到不同小脑区域。令人惊讶的是，进化研究进一步表明，这是小脑的那些部分与非人类灵长类动物相比，这显示了人类最戏剧性的扩张，甚至在现代与尼安德特人相比。在今天生活的人类中，大小或功能的个人变化这些小脑区域的连通性与影响较高认知功能的疾病有关作为自闭症谱系障碍（ASD），注意力缺陷/多动症（ADHD）和精神分裂症。这些融合结果强烈表明，控制发育的分子和细胞机制人小脑的功能组织经历了已证明的系统变化在现代人类中功能很重要。拟议的研究开始绘制出这些变化，从全基因组关联研究（GWAS）使用现有的小脑结构MRI图像数据集 30,000个基因分型的人参与者鉴定与整体小脑相关的基因和基因组变异相对大小和灰质厚度的个人差异和个体差异小脑皮层（目标1）。并行研究（AIM 2）将使用人类，猕猴的单细胞基因组学小鼠小脑研究基因表达的可能差异fkurpdwlq dffhvvlelolw \和人类与其他动物之间内在小脑回路的细胞类型组成（AIM 2）。一起，这些研究解决了一个基本但尚未解决的问题，是否扩展人类小脑代表基本小脑电路模块的容量的简单增加，否则人类，或小脑扩展区域中的本地电路是否在功能上经历了重大修改。在这项研究的最后部分（AIM 3），进化分析将确定特定的前两个目的中确定的基因中的调节元素显示出加速替代率在人类或在人类进化过程中进行积极，净化或平衡选择的证据，以及由于现代人类与其他灵长类动物的分歧。这些研究将使我们能够确定特定的监管在小脑中涉及的基因中自然选择的元素或其他变体开发或成人小脑功能，并将进化选择的那些靶标与特定与个人变异或现代人类重大精神疾病的风险增加相关的变体人群。