DIVERGENT FUNCTIONAL AGING OF MOLECULARLY DEFINED NEURON TYPES IN HUMAN BRAIN

Normal human brain aging is typically associated with cognitive decline. The structural and functional changes in individual neurons leading to cognitive decline remain enigmatic. To address this, we utilize a large cohort of donors undergoing brain surgery (age range 18-83 years). Patch-seq and patch-clamp electrophysiology were performed on cortical resected tissue. We aggregated morphology, electrophysiology, and transcriptomic data for all excitatory and inhibitory subclasses from all cortical layers. We leveraged electrophysiological information from patch-seq to identify transcriptomically defined neurons in patch-clamp recordings. This results in annotating both neuronal datasets to the same transcriptomics taxonomy. In the combined dataset, we find that normal aging of the human brain leads to gradual changes in biophysical features of excitatory pyramidal neurons. These changes are most prominent in intratelencephalic (IT) projecting neurons, and more specifically, the transcriptomic cell type L2/3 IT_12. In contrast, we find that subtypes of inhibitory neurons are resilient to normal brain aging, translating to stable electrophysiological properties throughout adulthood. We conclude that excitatory neurons in the human neocortex are vulnerable to aging and may drive age-related cognitive decline.