MCH enables synchronized firing in the hippocamposeptal circuit to facilitate spatial memory

Neuropeptide melanin-concentrating hormone (MCH) plays important roles in the brain including control of energy homeostasis, sleep, learning and memory. However, the synaptic and circuitry mechanisms underlying MCH-mediated regulations remain largely unknown. Here, we uncover that MCH modulates the hippocampo (HP)-dorsal lateral septum (dLS)-lateral hypothalamus neural circuit to facilitate spatial learning and memory. MCH achieves this function by enhancing both excitatory and inhibitory synaptic transmission via presynaptic mechanisms. The dLS neuronal spiking activity in response to HP CA3 excitatory inputs is strongly controlled by feed-forward inhibition (FFI) mediated by both GABAA and GABAB receptors. Endogenous MCH signaling enhances Signal/Noise (S/N) ratio of dLS neurons by increase the excitatory strengths, meanwhile decrease the overall dLS excitability by enhance inhibition which reduces dLS FFI, and consequentially enables dLS neurons to fire with high fidelity with HP synaptic inputs. Our data unravel the multifaceted synaptic mechanisms of MCH in the defined HP-dLS circuitry which may contribute to learning and memory.