CRCNS: Mechanisms and Modeling of the Adaptive Modulation of the Intrinsic Properties of Spinal Motoneurons

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The long-term objective of this research is to uncover the cellular mechanisms involved in activity-dependent modification to the excitability of neurons in the spinal cord that control motor function, i.e., spinal motoneurons. Understanding how spinal motoneuron output properties can be modified by increased as well as decreased activity is a fundamental challenge with implications that span from athletic training to rehabilitation and advanced prosthetics. The project serves to generate a quantitative understanding of how persistent activation of motoneurons modulates the neurons' intrinsic excitability and how this effect, in turn, influences the neurons' output to drive muscle contraction. Motoneurons have long been thought to function simply as relays from motor commands to muscle activation. However, growing evidence demonstrates that these neurons can undergo significant modification (plasticity) that can change the relationship between input and output. Recent work with motoneurons demonstrates that plasticity in intrinsic electrical properties might be important for learning in the motor system. The goal of this project is to determine how prolonged activation, as occurs with sustained walking, changes the intrinsic excitability of motorneurons. Alongside experimental studies, the project includes the development of detailed computational models of spinal motoneuron activity before and after persistent activation that are based on but also guide the experimental work. Delaware State University is a Historically-Black, primarily undergraduate institution, with an enrollment that is 75% African-American. Thus, a broader impact of this project is the training of students who are members of under-represented groups. Trainees are exposed to a comprehensive research environment, including technical approaches representing state-of-the-art electrophysiological and computational neuroscience, as well as given career guidance, training in writing and communication, and exposure to grant proposal writing to foster the students' professional development as scientists.Mechanisms of synaptic plasticity have been intensively studied in the central nervous system, but the potential for plasticity in neurons' intrinsic properties has received little attention. The goal of this project is to understand the plasticity of spinal motoneurons and to determine how prolonged activation, as what occurs with sustained walking, changes their intrinsic excitability. The project involves the application of electrophysiological, immunohistochemical, and pharmacological methods in mouse spinal cord slices. The overarching hypothesis is that alteration of KCNQ/Kv7.2 channel function and changes in axonal initial segment properties are the primary mechanisms of adaptation of spinal motoneurons to prolonged network activation, and that activation of excitatory synaptic inputs is required for these changes. The project includes the development of detailed computational models of spinal motoneuron activity before and after persistent activation, exploiting a multi-objective evolutionary algorithm approach capable of matching multiple selection criteria simultaneously and of generating entire collections of neuronal models. The computational models are based on experimental measurements, and the models in turn generate experimentally testable hypotheses. Thus, experiments and simulations are closely intertwined in this project.