Cell-Type-Specific Control of Brainstem Locomotor Circuits by Basal Ganglia

Abstract

Summary The basal ganglia (BG) are critical for adaptive motor control, but the circuit principles underlying their pathway-specific modulation of target regions are not well understood. Here, we dissect the mechanisms underlying BG direct- and indirect-pathway-mediated control of the mesencephalic locomotor region (MLR), a brainstem target of the BG that is critical for locomotion. We optogenetically dissect the locomotor function of the three neurochemically-distinct cell types within the MLR: glutamatergic, GABAergic, and cholinergic neurons. We find that the glutamatergic subpopulation encodes locomotor state and speed, is necessary and sufficient for locomotion, and is selectively innervated by BG. We further show activation and suppression, respectively, of MLR glutamatergic neurons by direct and indirect pathways, which is required for bidirectional control of locomotion by BG circuits. These findings provide a fundamental understanding of how the BG can initiate or suppress a motor program through cell-type-specific regulation of neurons linked to specific actions.

Midbrain circuits that set locomotor speed and gait selection

“…The strong inputs to CnF-Vglut2-Ns from PAG (especially the dorsal part), inferior colliculus, and hypothalamus, are in accordance with previous anatomical findings 12 and suggest that CnF-mediated fast locomotion may be generated as part of an escape response independent of the PPN. As previously shown, PPN neurons receive rich projection from basal ganglia nuclei 12,14 , but also from many midbrain and medullary sensory-motor nuclei as well as from motor cortex. This innervation pattern is in accordance with a role of glutamatergic PPN neurons for exploratory locomotor behaviour under the motor action selection of the basal ganglia 30,31,32,33,34,7 .…”

“…No locomotion was induced by stimulation of the local inhibitory neurons in PPN and CnF 14 or the cholinergic cells in PPN while their activation slowed or stopped on-going locomotion (Extended data Fig. 3a–c).…”

“…Electrical stimulation or lesion studies are therefore unable to distinguish the contribution from the various intermingled neuronal populations present in these areas 12,13 . Recently, optogenetic manipulations have showed that stimulation of glutamatergic neurons (GlutNs) in and around PPN induced locomotion in mice 14 . The MLR was regarded as a unity precluding any evaluation of the putative divergent control of locomotion by subpopulations of neurons in CnF and PPN.…”

Locomotion Control: Brainstem Circuits Satisfy the Need for Speed

“…They found that glutamatergic cuneiform nucleus neurons were able to drive the full range of locomotor gaits — walk, trot, bound and gallop — and speed. Glutamatergic pedunculopontine nucleus neurons could only trigger low speed locomotion when stimulated at high intensity, whereas stimulation of cholinergic pedunculopontine nucleus neurons was insufficient to initiate locomotion, as shown by Roseberry et al [9]. …”

“…Roseberry et al [9] pioneered the dissection of mesencephalic locomotor region heterogeneity, by showing that optogenetic activation of glutamatergic neurons was sufficient to transition the mouse from a stationary state to walking, whereas stimulating glutamatergic and cholinergic mesencephalic locomotor region neurons triggered a transition from walking to running; conversely, the inhibition of glutamatergic neuron activation halted or decelerated locomotion.…”