Professor, Department of Biology
Ph.D. University of California, San Diego
Research Interests: Neuronal basis of behavior
Overview: We study how the nervous system controls behavior by analyzing the neural networks for decision making, focusing on spatial exploration behaviors, and food choice involving trade-offs that mimic human economic decisions. We investigate how these networks function using a combination of experimental and theoretical approaches. We track the movements of worms at high spatiotemporal resolution in complex naturalistic environments to determine the underlying behavioral strategies. Neuronal function is assessed by investigating changes in behavior caused by genetic mutations, neuronal ablations, and optogenetic manipulations. We also make optical recordings in freely moving animals to correlate neuronal activity patterns and behavior; these experiments are facilitated by microfluidic devices to control the worm's local sensory environment. Patch-clamp electrophysiological recordings are made from normal and mutant animals to determine how the electrical properties of neurons influence network function. Experimental data are synthesized in predictive theoretical models. Predictions are tested experimentally and the results are used to improve our theoretical understanding of the function of biological networks. These results provide new insights into the cellular and molecular mechanisms of information processing underlying animal behavior.
Anthelmintic drug actions in resistant and susceptible C. elegans revealed by electrophysiological recordings in a multichannel microfluidic device.
Int J Parasitol Drugs Drug Resist. 2018 Dec;8(3):607-628
Authors: Weeks JC, Robinson KJ, Lockery SR, Roberts WM
Many anthelmintic drugs used to treat parasitic nematode infections target proteins that regulate electrical activity of neurons and muscles: ion channels (ICs) and neurotransmitter receptors (NTRs). Perturbation of IC/NTR function disrupts worm behavior and can lead to paralysis, starvation, immune attack and expulsion. Limitations of current anthelmintics include a limited spectrum of activity across species and the threat of drug resistance, highlighting the need for new drugs for human and veterinary medicine. Although ICs/NTRs are valuable anthelmintic targets, electrophysiological recordings are not commonly included in drug development pipelines. We designed a medium-throughput platform for recording electropharyngeograms (EPGs)-the electrical signals emitted by muscles and neurons of the pharynx during pharyngeal pumping (feeding)-in Caenorhabditis elegans and parasitic nematodes. The current study in C. elegans expands previous work in several ways. Detecting anthelmintic bioactivity in drugs, compounds or natural products requires robust, sustained pharyngeal pumping under baseline conditions. We generated concentration-response curves for stimulating pumping by perfusing 8-channel microfluidic devices (chips) with the neuromodulator serotonin, or with E. coli bacteria (C. elegans' food in the laboratory). Worm orientation in the chip (head-first vs. tail-first) affected the response to E. coli but not to serotonin. Using a panel of anthelmintics-ivermectin, levamisole and piperazine-targeting different ICs/NTRs, we determined the effects of concentration and treatment duration on EPG activity, and successfully distinguished control (N2) and drug-resistant worms (avr-14; avr-15; glc-1, unc-38 and unc-49). EPG recordings detected anthelmintic activity of drugs that target ICs/NTRs located in the pharynx as well as at extra-pharyngeal sites. A bus-8 mutant with enhanced permeability was more sensitive than controls to drug treatment. These results provide a useful framework for investigators who would like to more easily incorporate electrophysiology as a routine component of their anthelmintic research workflow.
PMID: 30503202 [PubMed - in process]