Neuronal Control of Motor State Transitions

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.

Grant Number: 5F31NS132477-04
NIH Institute/Center: NIH
Principal Investigator: Friederike Buck