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...