Motor Control in the Mesencephalic Locomotor Region: Implications for Action Diversification and Deep Brain Stimulation

The brainstem is an evolutionarily conserved structure in vertebrate species, holding motor centers for the execution of diverse movements essential for the animal’s life, including breathing, orofacial movements permitting nutrient consumption, posture and locomotion. Understanding the organization of motor programs controlling such behaviors and their specific recruitment according to external context and internal needs is an elemental quest in Neuroscience. In the present dissertation, I discuss the brainstem as a continent for neuronal circuitry regulating movement control, at the interface between action-selection forebrain circuits and caudal executive centers in the spinal cord. After an introductory chapter, covering the main topics on the physiology of brainstem locomotor circuits, their possible dysfunction in Parkinson’s Disease and potential relevance as therapeutic targets for deep brain stimulation, I present a review of the current knowledge on supraspinal circuits controlling locomotion selection (and the contextual aspects it entails, such as exploratory, appetitive and escaping) and execution (aligned with the required specific parameters, like speed, limb coordination, postural adjustments and directionality). In a third section, experimental work is presented, describing two glutamatergic subpopulations within the mesencephalic locomotor region (MLR), a spinal cord-projecting and a substantia nigra-projecting population, that segregate not only by projection-specificity but also by tuning to different behaviors and different consequences of their optogenetic manipulation. Using viral vector tools in intersection with mouse genetics, we devised experimental strategies to create local, retrograde and systemic entry-points to these specific neuronal subpopulations. Such access allowed us to map their anatomical organization within the MLR and their axonal projection patterns, to record their in vivo activity using micro-endoscopic calcium imaging, as well as to optogenetically manipulate them. We concluded that the spinally-projecting population regulates body length and, consequently, postural adjustments during behavior, while the substantia nigra-projecting neurons preferentially encode the forelimb movements reaching and grooming and impinge on the basal ganglia circuitry to shape its motor output. The significance of these findings for the fields of MLR basic research and clinical application of PPN-DBS are discussed in the final chapter