An animal’s ability to navigate through its natural environment is critical to its survival. Navigation can be slow and methodical such as an annual migration, or purely reactive such as an escape response. How sensory input is translated into a fast behavioral output to execute goal oriented locomotion remains elusive. In this dissertation, I aimed to investigate escape response behavior in the nematode C. elegans. It has been shown that the biogenic amine tyramine is essential for the escape response. A tyramine-gated chloride channel, LGC-55, has been revealed to modulate suppression of head oscillations and reversal behavior in response to touch. Here, I discovered key modulators of the tyraminergic signaling pathway through forward and reverse genetic screens using exogenous tyramine drug plates. ser-2, a tyramine activated G protein-coupled receptor mutant, was partially resistant to the paralytic effects of exogenous tyramine on body movements, indicating a role in locomotion behavior. Further analysis revealed that ser-2 is asymmetrically expressed in the VD GABAergic motor neurons, and that SER-2 inhibits neurotransmitter release along the ventral nerve cord. Although overall locomotion was normal in ser-2 mutants, they failed to execute omega turns by fully contracting the ventral musculature. Omega turns allow the animal to reverse and completely change directions away from a predator during the escape response. Furthermore, my studies developed an assay to investigate instantaneous velocity changes during the escape response using machine based vision. We sought to determine how an animal accelerates in response to a mechanical stimulus, and subsequently decelerates to a basal locomotion rate. Mutant analysis using this assay revealed roles for both dopamine and tyramine signaling. During my doctoral work, I have further established the importance for tyramine in the nematode, as I have demonstrated two additional roles for tyramine in modulating escape response behavior in C. elegans.

Despite the current understanding that sensorimotor circuits function through the action of transmitters and modulators, we have a limited understanding of how the nervous system directs the flow of information necessary to orchestrate complex behaviors. In this dissertation, I aimed to uncover how the nervous system coordinates these behaviors using the escape response of the soil nematode, Caenorhabditis elegans, as a paradigm. C. elegans exhibits a robust escape behavior in response to touch. The worm typically moves forward in a sinusoidal pattern, which is accompanied by exploratory head movements. During escape, the worm quickly retreats by moving backward from the point of stimulus while suppressing its head movements. It was previously shown that the biogenic amine tyramine played an important role in modulating the suppression of these head movmemetns in response to touch. We identified a novel tyramine-gated chloride channel, LGC-55, whose activation by tyramine coordinates motor programs essential for escape. Furthermore, we found that changing the electrical nature of a synapse within the neural circuit for escape behavior can reverse its behavioral output, indicating that the C. elegans connectome is established independent of the nature of synaptic activity or behavioral output. Finally, we characterized a unique mutant, zf35 , which is hyperactive in reversal behavior. This mutant was identified as a gain of function allele of the C. elegans P/Q/N-type voltage-gated calcium channel, UNC-2. Taken together, this work defines tyramine as a genuine neurotransmitter and completes the neural circuit that controls the initial phases of the C. elegans escape response. Additionally, this research further advances the understanding of how the interactions between transmitters and ion channels can precisely regulate neural circuit activity in the execution of a complex behavior.