Grant: Project Grant

The hippocampus integrates information from distributed cortical and subcortical regions to support memory formation and spatial navigation. This depends on interplay between excitatory pyramidal cells and inhibitory GABAergic interneurons. Interneurons are themselves inhibited by other interneurons, forming "disinhibitory" microcircuits that gate principal cell activity and shape information flow. Understanding these pathways is key to revealing how the hippocampus selects and processes inputs for memory formation. Our prior work identified vasoactive intestinal peptide-expressing (VIP) interneurons in CA1 as central modulators of inhibitory networks. This heterogeneous population includes subtypes with distinct properties, connectivity, and recruitment. Some VIP subtypes may be selectively vulnerable in Alzheimer's, epilepsy, and schizophrenia. A specialized subset in the stratum lacunosum moleculare - SLM-VIPs - sits at the gateway for top-down brain inputs, yet their diversity, connections, and function remain poorly understood. This project will define the cellular diversity, connectivity, and mnemonic roles of SLM-VIP interneurons. Specifically, we will (1) characterize their morphology, molecular markers, and electrophysiology; (2) identify afferent pathways and postsynaptic targets via dual recordings and optogenetics; and (3) determine their in vivo activity during memory encoding and test their causal role in shaping network dynamics in freely moving mice. Using genetic targeting, patch-clamp, high-res reconstructions, patch-sequencing, and miniaturized microscopy, we will provide the first comprehensive description of this disinhibitory node. These findings will advance understanding of hippocampal top-down integration and may reveal targets to restore circuit balance in neurological disorders.