Activation of Brainstem Neurons During Mesencephalic Locomotor Region-Evoked Locomotion in the Cat

Abstract

The distribution of locomotor-activated neurons in the brainstem of the cat was studied by c-Fos immunohistochemistry in combination with antibody-based cellular phenotyping following electrical stimulation of the mesencephalic locomotor region (MLR) – the anatomical constituents of which remain debated today, primarily between the cuneiform (CnF) and the pedunculopontine tegmental nuclei (PPT). Effective MLR sites were co-extensive with the CnF nucleus. Animals subject to the locomotor task showed abundant Fos labeling in the CnF, parabrachial nuclei of the subcuneiform region, periaqueductal gray, locus ceruleus (LC)/subceruleus (SubC), Kölliker–Fuse, magnocellular and lateral tegmental fields, raphe, and the parapyramidal region. Labeled neurons were more abundant on the side of stimulation. In some animals, Fos-labeled cells were also observed in the ventral tegmental area, medial and intermediate vestibular nuclei, dorsal motor nucleus of the vagus, n. tractus solitarii, and retrofacial nucleus in the ventrolateral medulla. Many neurons in the reticular formation were innervated by serotonergic fibers. Numerous locomotor-activated neurons in the parabrachial nuclei and LC/SubC/Kölliker–Fuse were noradrenergic. Few cholinergic neurons within the PPT stained for Fos. In the medulla, serotonergic neurons within the parapyramidal region and the nucleus raphe magnus were positive for Fos. Control animals, not subject to locomotion, showed few Fos-labeled neurons in these areas. The current study provides positive evidence for a role for the CnF in the initiation of locomotion while providing little evidence for the participation of the PPT. The results also show that MLR-evoked locomotion involves the parallel activation of reticular and monoaminergic neurons in the pons/medulla, and provides the anatomical and functional basis for spinal monoamine release during evoked locomotion. Lastly, the results indicate that vestibular, cardiovascular, and respiratory centers are centrally activated during MLR-evoked locomotion. Altogether, the results show a complex pattern of neuromodulatory influences of brainstem neurons by electrical activation of the MLR.

Deep Brain Stimulation of the Cuneiform Nucleus for Levodopa-Resistant Freezing of Gait in Parkinson’s Disease: Study Protocol for a Prospective, Pilot Trial

“…This aligns with recent optogenetic studies in rodents, which showed that stimulation of glutamatergic neurons in the CnF effectively and speci cally caused locomotor initiation (44, 45) (For review see (46). It also agrees with preclinical electrophysiological studies in the cat, where stimulation of low threshold sites within the MLR primarily showed CnF neuron activation (47). The importance of electrode targeting on e cacy in this region is reinforced by computer modeling studies, demonstrating that targeting errors of 1 mm can signi cantly decrease target activation selectivity (48).…”

Deep imaging in the brainstem reveals functional heterogeneity in V2a neurons controlling locomotion

“…Locomotor stop neurons in the lamprey similarly show increased activity at locomotor onsets ( 40 ), but their direct activation only translates in a down-regulation of locomotion. Nevertheless, whether the V2a population hosts a numerically smaller subtype that may participate, together with other non-V2a neuronal classes ( 5 , 6 , 48 , 49 ), in locomotor initiation remains to be investigated. Furthermore, while V2a neurons may not be exclusively RS ( 22 , 23 ), our methodological approach cannot discriminate the activity of V2a neurons having different projection profiles.…”

Dissecting Brainstem Locomotor Circuits: Converging Evidence for Cuneiform Nucleus Stimulation

“…Historically, two adjacent nuclei have been put forth as putative neuroanatomical correlates of the MLR. Much of the preclinical literature, including Shik et al's original description (Shik et al, 1966), has supported the more dorsally located CnF, where electrical mapping studies consistently show it to promote locomotion ( Figure 1B; Takakusaki et al, 2016;Opris et al, 2019). Conversely, others have favored the more ventral, cholinergic cell-containing PPN (Garcia-Rill et al, 1987), despite its more varied electrical mapping results ( Figure 1B; Takakusaki et al, 2016).…”