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

> **NIH NIH R56** · DUKE UNIVERSITY · 2022 · $368,628

## Abstract

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 ge...

## Key facts

- **NIH application ID:** 10440526
- **Project number:** 5R56MH122819-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** GREGORY E CRAWFORD
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $368,628
- **Award type:** 5
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440526

## Citation

> US National Institutes of Health, RePORTER application 10440526, Genomics, variation, and evolution of cerebellar circuits linked to higher cognitive functions in humans (5R56MH122819-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10440526. Licensed CC0.

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