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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.

摘要