Context Dependent Sensorimotor Processing in C. elegans: Linking Behavioral State, Circuit, and Molecular Mechanisms

Abstract

Understanding how the nervous system flexibly responds to sensory stimuli to generate behav­ior is a major goal in neuroscience. In this thesis, I investigated the mechanosensory circuit of Caenorhabditis elegans to understand how sensory processing is dynamically modulated at the level of behaviors, neuronal circuits, and receptors. I began by investigating the response to a mechanosensory stimulus during turning behavior, as the worm is less likely to reverse in response to a touch stimulus presented during a turn than during a forward behavior. I developed a closed­-loop high­-throughput optogenetic delivery system, capable of delivering optogenetic stimulation to worms triggered on specific behaviors, enabling precise perturbation of neural circuits in behaving animals.I investigated the circuit mechanism underlying turning­ dependent gating of the touch­ evoked reversals. I showed that turning neurons RIV, SMB, and SAA inhibit the reversal neurons upstream of neuron AVA, revealing a mechanism through which turning behavior modulates sensorimotor response. I further identified that heteromeric acetylcholine receptors LGC­-47 and ACC­-1 mediate this context-­dependent mechanosensory response, thus revealing the underlying molecular mecha­nism. I also showed that these heteromeric acetylcholine receptors are involved in the termination of reversal behaviors. I also focused on understanding how opposing sensory stimuli are integrated in the nervous system. To answer this question, I employed the high­throughput optogenetic delivery setup and split­-GAL4 intersectional genetic strategy. When only the anterior touch neurons are activated, a worm responds by slowing down. However, the worm responds by speeding up if only the posterior touch neurons are activated. My investigation showed that the worm’s nervous system linearly integrates the anterior­posterior mechanosensory information to generate motor behaviors. A single­-cell RNA sequencing study identified the tail touch neuron, PLM, as a sexually dimor­phic neuron. My optogenetic interrogation supported this finding by showing that when both the anterior and posterior touch neurons are activated simultaneously, the behavioral response in males and hermaphrodites is significantly different. Together, these studies introduce technological and methodological advances for circuit and molecular level interrogations, and contribute to novel insights into how behavioral and internal states of an animal flexibly gate sensory processing.