Characterizing motor control and variability at the single-cell level in larval Drosophila

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ABSTRACT Variability in the muscle activations used for movement is a fundamental feature of neural control of movement. Changes to motor variability are associated with aging and motor disease, but motor variability's behavioral consequences are unclear. In order to causally test the role of motor variability in behavior, we need to manipulate sources of motor variability, but few such sources have been empirically identified. The objective of this proposal is to build a new model system for investigating motor variability — Drosophila melanogaster larvae — and use it to experimentally variability in muscle activation timings identify sources of motor variability. I will test the central hypothesis that arises from the motor system's continuous adjustment to feedback from ongoing and recent movements, and that proprioceptive feedback changes motor variability by adjusting muscle activation timings from cycle to cycle. I single out proprioception as a strong candidate source of motor variability, as proprioception is necessary for normal phase relationships and amplitude of the movements used in locomotion. Aim 1 asks “What features of body posture affect variability in muscle activation timings?” Specifically, I will test the working hypothesis that during Drosophila larval crawling, postural variables (e.g., segment lengths and inter-segmental angles) contribute to and will predict stride-by-stride variation in muscle activation timing. This will provide correlative evidence for or against the central hypothesis. This Aim will also test other, non-mutually-exclusive, hypotheses for sources of motor variability, and enable future experimental tests of these hypotheses. Aim 2 asks “How does loss of proprioceptive feedback change timing and variability of muscle activations?” Specifically, I will test the working hypothesis that proprioceptive feedback changes the extent and structure of motor variability by adjusting muscle activation timings from stride to stride. This will causally test the central hypothesis. It will also provide insight into how proprioceptive information informs motor control and regulates motor variability, and into potential behavioral consequences of this variability. In this proposal, I use calcium imaging in intact, crawling larvae; I use precise genetic tools to acutely silence proprioceptive neurons while imaging muscle activity during locomotion; and I model the variability of muscle activation timing as a function of many potentially informative features, including postural variables. Completion of the experiments in this proposal will have two major impacts: 1) I expect to identify a source of variability that will ultimately allow for probing the strategic role of motor variability in behavior. 2) I also expect to establish a tractable model system for motor research in which to manipulate specific cell types or neural circuit architectures and test their functions in control of movement or motor variability. These results have the potential to generalize to other forms of repetitive movement, including human locomotion, and thereby inform therapeutic strategies for functional recovery from injury or treatment of motor disorders.