Hippocampal Output to the Septum Regulates Locomotion and Exploration

The cognitive maps are established in the dorsal hippocampus (DH) when the animal explores the environment. During exploration, the DH combined extrinsic inputs from multiple sensory and motor-related structures to generate locomotion-dependent activity; however, the hippocampal mechanisms of locomotion and exploratory behavior remain controversial and unclear. By using optogenetics and chemogenetics, we selectively manipulated the DH pan-inhibitory interneurons (INs) and revealed that disrupting the DH inhibitory circuit is sufficient to acutely induce hyperlocomotion. Furthermore, we found that the DH-septum inhibitory pathway is critical for regulation of locomotion and exploratory behavior. Activation of the DH inhibitory output to the medial septum complex (MSc) decreased animals' distance traveled and increased immobility in the open field. Alternatively, inhibition of the DH inhibitory output to the MSc increased maximum speed and exploratory behavior. Moreover, activation of the septum-projecting DH INs is sufficient to decrease locomotion and exploratory behavior. On the other hand, activation of a subset of retrosplenial cortex-specific projecting DH INs or the entorhinal cortex-projecting DH neurons did not change animal locomotion. For the clinical application, targeting the DH-MSc inhibitory pathway can help us to determine the neuronal mechanisms of locomotion in animal models. Therefore, we may be able to ameliorate spatial processing deficits and motor symptoms in patients with memory impairment or psychosis and find therapeutic treatments for them.