A basal forebrain to midbrain circuit drives exploratory locomotion

Abstract

Locomotion is a fundamental behavior that comprises different specialized neuronal networks. In the basal forebrain, the glutamatergic neurons of the medial septum and diagonal band of Broca (MSDB_glu) can initiate locomotion and control its speed when optogenetically stimulated. MSDB_glu neuronal activity is also linked to hippocampal theta oscillations and codes for aversive salient stimuli. This work aims at investigating the downstream target of the MSDB_glu neurons responsible for the locomotor effect, and the underlying motivation that brings animals to move upon the activation of this circuit. Tracing studies identified the ventral tegmental area (VTA) as a candidate region receiving MSDB_glu inputs. Combining retrograde tracing, slice electrophysiology, <em>in vivo</em> fiberphotometry, pharmacology, and optogenetics, my aim was to understand the role of MSDB_glu projections to VTA during rodents’ behavior in both head-fixed and freely moving tasks. Unsupervised machine learning methods allowed me to extract the animal’s pose dynamics and quantify the effect of the network manipulation on behavior at a sub-second time scale. <br /> Tracing and <em>in vitro</em> patch-clamp data confirmed the existence of a monosynaptic glutamatergic connection between MSDB and VTA, and highlighted how MSDB_glu inputs target a heterogeneous population of VTA neurons. Optogenetic activation of MSDB_glu axons in VTA was sufficient to induce locomotion and to control its speed in a frequency-dependent manner. Lidocaine infusion in the MSDB did not affect the results of the optogenetic stimulation, thus identifying the VTA as a downstream region in the locomotor circuit initiated in the MSDB. These findings were further supported by the increase in calcium signals of MSDB_glu axons in VTA when animals were spontaneously moving. I found that MSDB_glu-VTA circuit activation causes an increase of sniffing and whisking prior to locomotion initiation on the treadmill, and leads to a higher representation of rearing motifs in the open field, all actions classically linked to exploration. <br /> Taken together, in the present work I investigated the MSDB_glu neurons and their projections to VTA, and unveiled a new role for this subcortical network in promoting exploratory and information-seeking behavior.