Objective: To study the role of excitatory neurons in the ventromedial medulla in gait using Designer Receptors Exclusively Activated by Designer Drugs.

Background: The medial pontomedullary reticular formation (mPMRF) forms an important relay between midbrain and forebrain locomotor regions and spinal networks in the control of locomotion. Cell-type specific loss of function and activation experiments point to a functional anatomical organization within the mPMRF. Loss of vglut2 signaling in the ventromedial medulla results in deficits in skilled movement with only a subtle effect on gait. This indicates that this cell group is not necessary for locomotion, but leaves the question of whether activation of this cluster modulates gait.

Methods: We placed microinjections of the conditional viral vector AAV8-FLEX-hM3Dq-mCherry in the ventral and dorsal mPMRF of vglut2-ires-cre mice, introducing a modified, mCherry tagged, excitatory receptor to vglut2+ neurons. The drug clozapine-N-oxide was injected i.p. to selectively and reversibly activate the receptor. Saline injection served as control treatment. We assessed motor performance using a comprehensive battery of tests, including high-speed video gait analysis and EMG recording of hindlimb muscles. We correlated behavioral data with the location and number of transfected neurons, their axonal projections in the spinal cord, and patterns of cell activation.

Results: Acute excitation of vglut2+ neurons in the ventromedial medulla at the rostral pole of the inferior olive resulted in abnormal gait characterized by decreased speed, stance and swing duration, and stride length. Transfected neurons in this region projected via the ipsilateral dorsolateral funiculus to terminations in the dorsal intermediate zone throughout the length of the spinal cord. Activation in two nearby regions resulted in decreased speed without qualitative changes in speed dependent spatial-temporal gait parameters. These nearby regions projected most heavily to the cervical cord, in line with their role in neck and postural control.

Conclusions: Activation of each of three excitatory cell clusters in the mPMRF results in slowing of gait. Speed dependent analysis of spatial-temporal gait parameters shows that one of these clusters truly modulates the quality of gait, whereas slowing mediated by the remaining regions has no accompanying qualitative change.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/selective-activation-of-excitatory-cell-groups-in-the-medial-medulla-differentially-affects-spatial-temporal-gait-parameters/