Basal Forebrain-Dorsal Hippocampus Cholinergic Circuit Regulates Olfactory Associative Learning

The basal forebrain, an anatomically heterogeneous brain area containing multiple distinct subregions and neuronal populations, innervates many brain regions including the hippocampus (HIP), a key brain region responsible for learning and memory. Although recent studies have revealed that basal forebrain cholinergic neurons (BFCNs) are involved in olfactory associative learning and memory, the potential neural circuit is not clearly dissected yet. Here, using an anterograde monosynaptic tracing strategy, we revealed that BFCNs in different subregions projected to many brain areas, but with significant differentiations. Our rabies virus retrograde tracing results found that the dorsal HIP (dHIP) received heavy projections from the cholinergic neurons in the nucleus of the horizontal limb of the diagonal band (HDB), magnocellular preoptic nucleus (MCPO), and substantia innominate (SI) brain regions, which are known as the HMS complex (HMSc). Functionally, fiber photometry showed that cholinergic neurons in the HMSc were significantly activated in odor-cued go/no-go discrimination tasks. Moreover, specific depletion of the HMSc cholinergic neurons innervating the dHIP significantly decreased the performance accuracies in odor-cued go/no-go discrimination tasks. Taken together, these studies provided detailed information about the projections of different BFCN subpopulations and revealed that the HMSc-dHIP cholinergic circuit plays a crucial role in regulating olfactory associative learning.