Neuronal Control of Motor State Transitions

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PROJECT SUMMARY Difficulty initiating or executing appropriate movement is characteristic of neurological disorders including Parkinson’s disease and ataxia, while the production of abnormally repetitive movements is seen in neurological and neuropsychiatric disorders such as Tourette Syndrome, OCD and ASD This research is aimed at understanding the neuronal mechanisms by which C. elegans nematodes initiate, execute and stabilize appropriate motor actions, in order to make predictions about how dysregulation of motor action patterns arise. Currently, our understanding of the mechanisms that generate appropriate motor outputs in physiological states and abnormal outputs in pathological states is incomplete. With 302 neurons with known connectivity and numerous genetic tools to target and manipulate individual neurons, the nematode Caenorhabditis elegans offers an excellent system to study the neuronal mechanisms of motor output generation. C. elegans locomotion is composed of a stable of sequence of motor actions/states: from forward locomotion to reversal with or without a turn, then a resumption of forward locomotion. Past studies have associated the C. elegans interneurons AIB, RIM, and AVA with reversals, however the exact neuronal contributions required to initialize, execute and stabilize motor states remain elusive. Based on their connectivity and previous experimental results, I hypothesize that AIB, RIM and AVA primarily initialize, stabilize and execute reversals, respectively, and that these functions will be reflected in their response to optogenetic perturbation, their required temporal windows to drive motor state changes and their response to combinatorial perturbation. In Aim 1, I will express the excitatory optogenetic channel, Chrimson, or inhibitory optogenetic channel, GtACR2, individually in single neurons to understand the state-dependent timing of single neuron activation or deactivation that drives motor state changes. In Aim 2, I will use the bidirectional optogenetic tool BIPOLEs (a Chrimson and a GtACR2 channel in tandem) to determine the precise temporal windows of activity required for reversal-associated interneurons to produce expected motor output. In Aim 3, I will combine optogenetic perturbation with chemogenetic silencing in order to understand the interactions between neurons required to generate stable, flexible motor states. Dissecting motor output changes in C. elegans may elucidate broader themes in motor pattern generation and its dysregulation. This research will take place in a highly supportive, inter-disciplinary laboratory environment. It requires the use of novel genetic tools for neural circuit perturbation and computational behavioral analysis, ideal for my training as a future physician-scientist studying the genetic and circuit mechanisms of behavior in health and disease.