Glutamatergic Septal Inputs to VTA Modulate Movement Onset and Speed

Petra Mocellin1, Pavol Bauer1, Dennis Dalügge1, Falko Fuhrmann1, HiroshiGerman Center for Neurodegenerative Diseases (DZNE), Bonn, Germany Kaneko1, Christina Müller1, Stefan Remy2

1 Neuronal Networks Group, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
2 Department of Cellular Neuroscience, Leibniz Institute for Neurobiology (LIN), Magdeburg, Germany

The Ventral Tegmental Area (VTA) neurons are classically studied for their function in reward, addiction and goal-directed behavior. Recent studies are also pointing to a role of VTA during locomotion: VTA neurons are active at movement onset, fire during movement, and send inputs to the dorsal striatum in an acceleration-dependent pattern. On the other side, locomotion onset and speed are controlled by the glutamatergic (VGluT2+) population of the Medial Septum/Diagonal Band of Broca (MSDB). When optogenetically stimulated, these neurons initiate locomotion and modulate the animal’s speed in a frequency-dependent manner. However, the MSDB has no direct projections to any motor-related area. It stands to reason, that MSDB VGluT2+ neurons could send inputs to VTA, which in turn projects to the brain areas responsible for movement execution.

A multidisciplinary approach including slice electrophysiology, in vivo fiberphotometry, and optogenetics was used to test if MSDB VGluT2+ inputs to VTA play a role during locomotion. Preliminary in vivo results show that optogenetic activation of VGluT2+ MSDB projections in VTA is sufficient to induce locomotion onset and to control the speed in a frequency-dependent manner. These findings are supported by the increase in calcium signal of the VGluT2+ MSDB axons in VTA when the animal moves spontaneously. In vitro patch-clamp data confirmed the existence of a monosynaptic glutamatergic connection between MSDB and VTA and highlighted how VGluT2+ MSDB inputs preferentially target VGluT2+ VTA neurons. Finally, in vivo optogenetic stimulation of VTA VGluT2+ neurons reliably induced locomotion, recapitulating the effect of MSDB VGluT2+ axon stimulation.