ABSTRACTIn Parkinson’s disease (PD), the loss of midbrain dopaminergic cells results in severe locomotor deficits such a gait freezing and akinesia. Growing evidence indicates that these deficits can be attributed to decreased activity in the Mesencephalic Locomotor Region (MLR), a brainstem region controlling locomotion. Clinicians are exploring deep brain stimulation of the MLR as a treatment option to improve locomotor function. The results are variable, from modest to promising. However, within the MLR, clinicians have targeted the pedunculopontine nucleus exclusively, while leaving the cuneiform nucleus unexplored. To our knowledge, the effects of cuneiform nucleus stimulation have never been determined in parkinsonian conditions in any animal model. Here, we addressed this issue in a mouse model of Parkinson’s disease based on bilateral striatal injection of 6-hydroxydopamine (6-OHDA), which damaged the nigrostriatal pathway and decreased locomotor activity. We show that selective optogenetic stimulation of glutamatergic neurons in the cuneiform nucleus in mice expressing channelrhodopsin in a Cre-dependent manner in Vglut2-positive neurons (Vglut2-ChR2-EYFP mice) increased the number of locomotor initiations, increased the time spent in locomotion, and controlled locomotor speed. Using deep learning-based movement analysis, we found that limb kinematics of optogenetic-evoked locomotion in pathological conditions were largely similar to those recorded in freely moving animals. Our work identifies the glutamatergic neurons of the cuneiform nucleus as a potentially clinically relevant target to improve locomotor activity in parkinsonian conditions. Our study should open new avenues to develop targeted stimulation of these neurons using deep brain stimulation, pharmacotherapy or optogenetics.SIGNIFICANCE STATEMENTIn Parkinson’s disease, alleviating locomotor deficits is a challenge. Clinicians are exploring deep brain stimulation of the Mesencephalic Locomotor Region, a brainstem region controlling locomotion, but results are mixed. However, the best target in this region in Parkinson’s disease remains unknown. Indeed, this region which comprises the pedunculopontine and cuneiform nuclei, contains different cell types with opposing effects on locomotor output. Here, using a mouse model where midbrain dopaminergic cells were damaged by a neurotoxin, we demonstrate that optogenetic activation of glutamatergic neurons in the cuneiform nucleus increases locomotion, controls speed, and evokes limb movements similar to those observed during spontaneous locomotion in intact animals. Our study identifies a potentially clinically relevant target to improve locomotor function in Parkinson’s disease.
Histone deacetylase inhibitors, glutamatergic drugs and deep brain stimulation rescue resistance to fear extinction in a genetic mouse model
