Periodic Reporting for period 2 - InterAct (Shaping Body Movements through Interactions with Brainstem Neurons)
Período documentado: 2024-01-01 hasta 2025-06-30
Understanding how neuronal circuits regulate the enormous repertoire of movements is a key outstanding question in neuroscience. Providing answers to this question will also improve our ability to design therapies for disorders of the nervous system or injuries, leading to severe impairments in body movement such as observed for example in patients with Parkinson’s disease or spinal cord injury. Neurons contributing to execution and learning of body movements are distributed throughout the nervous system. Control of body movements entails the engagement of connected brain motor centers to generate action commands, providing instructions for execution to the spinal cord. The brainstem is the most caudal part of the brain and represents a switchboard between frontal motor centers involved in movement planning, and caudal motor centers in the spinal cord implementing the execution of body movements through the control of muscles. Recent technological advances have led to the identification of brainstem neurons regulating diverse forms of body movement, including locomotion and skilled forelimb movements, both engaging limbs but for very distinct purposes. The goal of this project is to understand how brainstem populations involved in specific body movements are endowed with their behavior-specific fingerprints through interactions within the broader motor system. We aim to determine how key synaptic inputs to specific brainstem neurons shape their activity patterns in synchrony with the regulated behavior. We hypothesize that the emergence of action-specific neuronal ensembles in the brainstem requires control by their driver, gating and modulatory elements, with the function to promote the recruitment of specific brainstem neurons during desired actions and to suppress them when no or alternative actions are planned. We build on our know-how on brainstem neurons and use sophisticated combinatorial viral-genetic targeting strategies, state of the art neuronal recording and activity-pattern modifying technologies, combined with precise quantitative behavioral readouts in mice to address this question. Together, our project will elucidate circuit mechanisms by which brainstem neurons interact in the motor system to control the generation of body movements, thereby uncovering principles of how the nervous system generates diverse actions. These findings will also provide insight into how movement control can be reconfigured or reinstalled in cases of disorders or injuries impairing the ability to move.
We have made significant progress in understanding the organization of synaptic input to key brainstem centers involved in the control of movement. The most caudal part of the brainstem is the medulla, containing dedicated neuronal populations for the control of body movements. We have studied the control of skilled forelimb movement and found that within the lateral rostral medulla (latRM), distinct populations of neurons encode different behavioral phases. We have studied the organization of cortical input to these different neurons (Yang et al., Cell, 2023) and found that reaching tuned latRM neurons receive input from the medial anterior cortex (MAC) while handling tuned neurons receive input from the lateral anterior cortex (LAC). This work defines the precise matrix with which upper motor centers, here exemplified by the cortex, communicate with dedicated populations of neurons in the brainstem, and through these influence the generation of body movements at a very high level of specificity.
Through gained knowledge, predicted interference with and changing of animal behavior through targeted interventions should be possible in the longer run. Our studies should therefore also be able to contribute to and guide future studies on reestablishing motor function in neurodegenerative disorders such as Parkinson’s disease, or after spinal cord injury. Revealing principles of motor circuit organization and function will also contribute to our understanding of how circuits work outside the motor system and in evolutionarily higher species than mice. We suspect that the insight emerging through our work will be widely applicable.