Novel signaling pathways driving experience-dependent maturation in dentate gyrus granule cells: a deep-sequencing approach

Abstract

The granule cells in the dentate gyrus of the hippocampus are a cell type that is critical for learning and memory ability. Dentate gyrus granule cells exhibit the unique capacity to differentiate and mature throughout an individual's lifetime. Decades of dedicated research has revealed many transcription factors that facilitate the differentiation of granule cells from neural progenitors. The goal of this research project is to identify key molecular and transcriptional pathways that contribute to the maturation of dentate gyrus granule cells. We performed single-cell RNA sequencing and multiomic single-nuclei RNA and ATAC sequencing in an activity-dependent mouse reporter model to examine the influence of neuronal activity on the transcriptome and chromatin accessibility within individual granule cells. These experiments were performed between postnatal day 14 and postnatal day 24 due to the increased abundance of developing granule cells. We implemented an environmental enrichment paradigm where mice were reared in complex, dynamic, and socially-enriched housing. This paradigm allowed us to examine the impact of chronically increased circuit activity on granule cell maturation. This study reveals novel heterogeneity in the maturing granule cell population that is associated with previous neuronal activity and synaptic function. A follow-up investigation identifies new transcription factor candidates that appear to orchestrate the transition between maturity stages. We propose a new model where granule cell identity is established through an activity-independent transcriptional network. The subsequent experience of neuronal activity appears to drive the emergence of a distinct transcriptional network that is poised to facilitate long-lasting granule cell maturity.