Molecularly defined and functionally distinct cholinergic subnetworks

Highlights•Molecularly defined and functionally distinct D28K+ and D28K− subnetworks•D28K+ and D28K− subnetworks differ in morphological and physiological properties•D28K+ → VPNs cholinergic subnetwork controls anxiety-like behaviors via Kcnh1•D28K− → DGNs cholinergic subnetwork encodes spatial memory via Cacna1hSummaryCholinergic neurons in the medial septum (MS) constitute a major source of cholinergic input to the forebrain and modulate diverse functions, including sensory processing, memory, and attention. Most studies to date have treated cholinergic neurons as a single population; as such, the organizational principles underling their functional diversity remain unknown. Here, we identified two subsets (D28K+ versus D28K−) of cholinergic neurons that are topographically segregated in mice, Macaca fascicularis, and humans. These cholinergic subpopulations possess unique electrophysiological signatures, express mutually exclusive marker genes (kcnh1 and aifm3 versus cacna1h and gga3), and make differential connections with physiologically distinct neuronal classes in the hippocampus to form two structurally defined and functionally distinct circuits. Gain- and loss-of-function studies on these circuits revealed their differential roles in modulation of anxiety-like behavior and spatial memory. These results provide a molecular and circuitry-based theory for how cholinergic neurons contribute to their diverse behavioral functions.Graphical abstract