Caudate nucleus aging and its association with brain disorders

Abstract

The caudate nucleus supports cognition and goal-directed behavior, undergoes age-associated changes, and is implicated in substance use, psychiatric, and neurodegenerative disorders. However, how aging alters its diverse cell types and how such changes relate to diseases remains poorly understood. To address these questions, we assembled single nucleus transcriptomic atlases of the caudate tissue, comprising 963,842 nuclei from 178 human donors, including controls and individuals with alcohol use disorder (AUD) or opioid use disorder (OUD), and 83,699 nuclei from six healthy rhesus macaques. We also curated 3,139 bulk RNA-seq profiles from the caudate and other brain regions spanning controls and multiple diagnostic groups, as well as paired RNA and chromatin accessibility profiles from 257,524 caudate nuclei across 161 control and AUD donors. These datasets enabled comparisons across age, species, brain regions, and diagnostic groups. We found shared glial aging features in humans and macaques, whereas neuronal changes were more divergent. Inferred neuron-to-neuron communication declined with age, with greater declines in AUD. Both transcriptional and chromatin accessibility profiles showed nonlinear age-associated patterns, with pronounced changes in later adulthood. In donors with AUD, age-associated changes appeared earlier, with altered trajectories in lipid metabolism, mitochondrial function, and neuronal signaling. Across comparisons involving AUD, OUD, bipolar disorder, schizophrenia, and Alzheimer disease, mitochondrial function and fatty acid metabolism emerged as consensus features linking caudate aging to diseases, although the direction and extent of overlap varied by disorder and brain region. Together, these findings define cellular and regulatory features of primate caudate aging and reveal shared and context-dependent relationships between aging and brain disorders.