SEPTOHIPPOCAMPAL CHOLINERGIC REGULATION OF DISTINCT HIPPOCAMPAL FUNCTIONS

The dentate gyrus (DG) within the hippocampus houses a unique region in the brain that allows for the continuous addition of new neurons during adulthood in a process known as adult neurogenesis. New neurons enhance the plasticity of surrounding circuits to improve hippocampal-dependent functions such as learning and memory. However, it remains unknown how distinct neural circuits regulate the molecular landscape of the heterogenous DG to regulate these functions. In this study, we report that activation of a cholinergic circuit from the Diagonal Band of Broca (DB) to the DG promotes both adult neural stem cell (aNSC) activation and spatial memory. Furthermore, we employ SPLiT-seq, a single-nuclei sequencing approach to profile the DG, and report broad transcriptomic changes across multiple types of mature and adult-born cells in response to cholinergic circuit activation. Notably, neuronal populations exhibit abundant molecular changes that support synaptic functions crucial for spatial memory. Moreover, adult neural stem cells exhibit molecular changes that support their morphological development and neurogenic proliferation. Interestingly, our electrophysiology and NicheNet analyses reveal granule cells, endothelial cells, and astrocytes as intermediate cell types in cholinergic activity-dependent NSC regulation. Our findings provide cell-type-specific molecular mechanisms underlying cholinergic circuit activity-dependent regulation of distinct DG functions. Lastly, we provide a detailed protocol used to perform several of the studies within our work that aims to interrogate circuit-specific regulation of adult neurogenesis.