Shawn Lockery

Professor, Department of Biology
Member, ION

Ph.D. University of California, San Diego 
B.A. Yale

Office:
305 Huestis
541-346-4590 

 

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.

RECENT PUBLICATIONS

Related Articles

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 12;8(3):607-628

Authors: Weeks JC, Robinson KJ, Lockery SR, Roberts WM

Abstract
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 - indexed for MEDLINE]

Related Articles

Microfluidic platform for electrophysiological recordings from host-stage hookworm and Ascaris suum larvae: A new tool for anthelmintic research.

Int J Parasitol Drugs Drug Resist. 2016 12;6(3):314-328

Authors: Weeks JC, Roberts WM, Robinson KJ, Keaney M, Vermeire JJ, Urban JF, Lockery SR, Hawdon JM

Abstract
The screening of candidate compounds and natural products for anthelmintic activity is important for discovering new drugs against human and animal parasites. We previously validated in Caenorhabditis elegans a microfluidic device ('chip') that records non-invasively the tiny electrophysiological signals generated by rhythmic contraction (pumping) of the worm's pharynx. These electropharyngeograms (EPGs) are recorded simultaneously from multiple worms per chip, providing a medium-throughput readout of muscular and neural activity that is especially useful for compounds targeting neurotransmitter receptors and ion channels. Microfluidic technologies have transformed C. elegans research and the goal of the current study was to validate hookworm and Ascaris suum host-stage larvae in the microfluidic EPG platform. Ancylostoma ceylanicum and A. caninum infective L3s (iL3s) that had been activated in vitro generally produced erratic EPG activity under the conditions tested. In contrast, A. ceylanicum L4s recovered from hamsters exhibited robust, sustained EPG activity, consisting of three waveforms: (1) conventional pumps as seen in other nematodes; (2) rapid voltage deflections, associated with irregular contractions of the esophagus and openings of the esophogeal-intestinal valve (termed a 'flutter'); and (3) hybrid waveforms, which we classified as pumps. For data analysis, pumps and flutters were combined and termed EPG 'events.' EPG waveform identification and analysis were performed semi-automatically using custom-designed software. The neuromodulator serotonin (5-hydroxytryptamine; 5HT) increased EPG event frequency in A. ceylanicum L4s at an optimal concentration of 0.5 mM. The anthelmintic drug ivermectin (IVM) inhibited EPG activity in a concentration-dependent manner. EPGs from A. suum L3s recovered from pig lungs exhibited robust pharyngeal pumping in 1 mM 5HT, which was inhibited by IVM. These experiments validate the use of A. ceylanicum L4s and A. suum L3s with the microfluidic EPG platform, providing a new tool for screening anthelmintic candidates or investigating parasitic nematode feeding behavior.

PMID: 27751868 [PubMed - indexed for MEDLINE]

Related Articles

Dopamine receptor DOP-4 modulates habituation to repetitive photoactivation of a C. elegans polymodal nociceptor.

Learn Mem. 2016 10;23(10):495-503

Authors: Ardiel EL, Giles AC, Yu AJ, Lindsay TH, Lockery SR, Rankin CH

Abstract
Habituation is a highly conserved phenomenon that remains poorly understood at the molecular level. Invertebrate model systems, like Caenorhabditis elegans, can be a powerful tool for investigating this fundamental process. Here we established a high-throughput learning assay that used real-time computer vision software for behavioral tracking and optogenetics for stimulation of the C. elegans polymodal nociceptor, ASH. Photoactivation of ASH with ChR2 elicited backward locomotion and repetitive stimulation altered aspects of the response in a manner consistent with habituation. Recording photocurrents in ASH, we observed no evidence for light adaptation of ChR2. Furthermore, we ruled out fatigue by demonstrating that sensory input from the touch cells could dishabituate the ASH avoidance circuit. Food and dopamine signaling slowed habituation downstream from ASH excitation via D1-like dopamine receptor, DOP-4. This assay allows for large-scale genetic and drug screens investigating mechanisms of nociception modulation.

PMID: 27634141 [PubMed - indexed for MEDLINE]

Related Articles

A stochastic neuronal model predicts random search behaviors at multiple spatial scales in C. elegans.

Elife. 2016 Jan 29;5:

Authors: Roberts WM, Augustine SB, Lawton KJ, Lindsay TH, Thiele TR, Izquierdo EJ, Faumont S, Lindsay RA, Britton MC, Pokala N, Bargmann CI, Lockery SR

Abstract
Random search is a behavioral strategy used by organisms from bacteria to humans to locate food that is randomly distributed and undetectable at a distance. We investigated this behavior in the nematode Caenorhabditis elegans, an organism with a small, well-described nervous system. Here we formulate a mathematical model of random search abstracted from the C. elegans connectome and fit to a large-scale kinematic analysis of C. elegans behavior at submicron resolution. The model predicts behavioral effects of neuronal ablations and genetic perturbations, as well as unexpected aspects of wild type behavior. The predictive success of the model indicates that random search in C. elegans can be understood in terms of a neuronal flip-flop circuit involving reciprocal inhibition between two populations of stochastic neurons. Our findings establish a unified theoretical framework for understanding C. elegans locomotion and a testable neuronal model of random search that can be applied to other organisms.

PMID: 26824391 [PubMed]

Related Articles

Even-Skipped(+) Interneurons Are Core Components of a Sensorimotor Circuit that Maintains Left-Right Symmetric Muscle Contraction Amplitude.

Neuron. 2015 Oct 21;88(2):314-29

Authors: Heckscher ES, Zarin AA, Faumont S, Clark MQ, Manning L, Fushiki A, Schneider-Mizell CM, Fetter RD, Truman JW, Zwart MF, Landgraf M, Cardona A, Lockery SR, Doe CQ

Abstract
Bilaterally symmetric motor patterns--those in which left-right pairs of muscles contract synchronously and with equal amplitude (such as breathing, smiling, whisking, and locomotion)--are widespread throughout the animal kingdom. Yet, surprisingly little is known about the underlying neural circuits. We performed a thermogenetic screen to identify neurons required for bilaterally symmetric locomotion in Drosophila larvae and identified the evolutionarily conserved Even-skipped(+) interneurons (Eve/Evx). Activation or ablation of Eve(+) interneurons disrupted bilaterally symmetric muscle contraction amplitude, without affecting the timing of motor output. Eve(+) interneurons are not rhythmically active and thus function independently of the locomotor CPG. GCaMP6 calcium imaging of Eve(+) interneurons in freely moving larvae showed left-right asymmetric activation that correlated with larval behavior. TEM reconstruction of Eve(+) interneuron inputs and outputs showed that the Eve(+) interneurons are at the core of a sensorimotor circuit capable of detecting and modifying body wall muscle contraction.

PMID: 26439528 [PubMed - indexed for MEDLINE]

Related Articles

Characterization of Drosophila larval crawling at the level of organism, segment, and somatic body wall musculature.

J Neurosci. 2012 Sep 05;32(36):12460-71

Authors: Heckscher ES, Lockery SR, Doe CQ

Abstract
Understanding rhythmic behavior at the developmental and genetic levels has important implications for neurobiology, medicine, evolution, and robotics. We studied rhythmic behavior--larval crawling--in the genetically and developmentally tractable organism, Drosophila melanogaster. We used narrow-diameter channels to constrain behavior to simple, rhythmic crawling. We quantified crawling at the organism, segment, and muscle levels. We showed that Drosophila larval crawling is made up of a series of periodic strides. Each stride consists of two phases. First, while most abdominal segments remain planted on the substrate, the head, tail, and gut translocate; this "visceral pistoning" moves the center of mass. The movement of the center of mass is likely powered by muscle contractions in the head and tail. Second, the head and tail anchor while a body wall wave moves each abdominal segment in the direction of the crawl. These two phases can be observed occurring independently in embryonic stages before becoming coordinated at hatching. During forward crawls, abdominal body wall movements are powered by simultaneous contraction of dorsal and ventral muscle groups, which occur concurrently with contraction of lateral muscles of the adjacent posterior segment. During reverse crawls, abdominal body wall movements are powered by phase-shifted contractions of dorsal and ventral muscles; and ventral muscle contractions occur concurrently with contraction of lateral muscles in the adjacent anterior segment. This work lays a foundation for use of Drosophila larva as a model system for studying the genetics and development of rhythmic behavior.

PMID: 22956837 [PubMed - indexed for MEDLINE]

Related Articles

Neuronal microcircuits for decision making in C. elegans.

Curr Opin Neurobiol. 2012 Aug;22(4):580-91

Authors: Faumont S, Lindsay TH, Lockery SR

Abstract
The simplicity and genetic tractability of the nervous system of the nematode Caenorhabditis elegans make it an attractive system in which to seek biological mechanisms of decision making. Although work in this area remains at an early stage, four basic types paradigms of behavioral choice, a simple form of decision making, have now been demonstrated in C. elegans. A recent series of pioneering studies, combining genetics and molecular biology with new techniques such as microfluidics and calcium imaging in freely moving animals, has begun to elucidate the neuronal mechanisms underlying behavioral choice. The new research has focussed on choice behaviors in the context of habitat and resource localization, for which the neuronal circuit has been identified. Three main circuit motifs for behavioral choice have been identified. One motif is based mainly on changes in the strength of synaptic connections whereas the other two motifs are based on changes in the basal activity of an interneuron and the sensory neuron to which it is electrically coupled. Peptide signaling seems to play a prominent role in all three motifs, and it may be a general rule that concentrations of various peptides encode the internal states that influence behavioral decisions in C. elegans.

PMID: 22699037 [PubMed - indexed for MEDLINE]

Related Articles

A microfluidic device for whole-animal drug screening using electrophysiological measures in the nematode C. elegans.

Lab Chip. 2012 Jun 21;12(12):2211-20

Authors: Lockery SR, Hulme SE, Roberts WM, Robinson KJ, Laromaine A, Lindsay TH, Whitesides GM, Weeks JC

Abstract
This paper describes the fabrication and use of a microfluidic device for performing whole-animal chemical screens using non-invasive electrophysiological readouts of neuromuscular function in the nematode worm, C. elegans. The device consists of an array of microchannels to which electrodes are attached to form recording modules capable of detecting the electrical activity of the pharynx, a heart-like neuromuscular organ involved in feeding. The array is coupled to a tree-like arrangement of distribution channels that automatically delivers one nematode to each recording module. The same channels are then used to perfuse the recording modules with test solutions while recording the electropharyngeogram (EPG) from each worm with sufficient sensitivity to detect each pharyngeal contraction. The device accurately reported the acute effects of known anthelmintics (anti-nematode drugs) and also correctly distinguished a specific drug-resistant mutant strain of C. elegans from wild type. The approach described here is readily adaptable to parasitic species for the identification of novel anthelmintics. It is also applicable in toxicology and drug discovery programs for human metabolic and degenerative diseases for which C. elegans is used as a model.

PMID: 22588281 [PubMed - indexed for MEDLINE]