Hypothalamic melanin-concentrating hormone (MCH) polypeptide contributes to regulating energy homeostasis, sleep, and memory. However, the mechanistic bases of its effects are still unclear. This study found that the physiological mechanism underlying the functional role of MCH signaling in projections to the dorsolateral septum (dLS), which is a region involved in routing hippocampal firing rhythms and encoding spatial memory based on such rhythms. For this study, MCH-Cre and C57BL/6 mice were used for all experiments. The dataset contains electrophysiology, behavioral, and immunohistochemistry data. This study shows a model in which peptidergic signaling within the dLS modulates dorsal hippocampal output and supports memory encoding.