Persistent Firing Neurons in the Medial Septum Drive Arousal and Locomotion

Abstract The medial septum and diagonal band of Broca (MSDB) serve as a central hub in an ascending brainstem pathway that conveys sensory and motor signals to the limbic system. However, the cellular and circuit mechanisms underlying these functions remain unclear. Here, we show that transient optogenetic activation of MSDB VGluT2⁺ neurons initiates a structured arousal sequence - beginning with facial movements, followed by pupil dilation and locomotion. Neuropixels recordings reveal persistent MSDB neuronal activity that strongly correlates with arousal-related behaviors. We demonstrate that persistent firing (PF) is an intrinsic property of a subset of MSDB neurons, independent of ongoing synaptic input. PF neurons and putative GABAergic theta-bursting neurons predicted movement initiation, with population activity scaling with initiation magnitude, unlike other MSDB populations. These findings identify PF in the MSDB as a central neural mechanism that orchestrates the transition from preparatory movements to full behavioral engagement, bridging sensory input with locomotor arousal and supporting state transitions within the limbic system.