Professor, Department of Biology
Ph.D. University of California, San Diego
B.S. Massachusetts Institute of Technology
Upcoming Seminar: 4/7/2016
Office: 209 Huestis
Research Interests: Technology development for drug screening platforms, including anthelmintic (anti-nematode worm) drugs for human and animal health; nematode neurobiology and genetics; synaptic physiology; neural circuits for behavior; insect neurobiology; tropical infectious and parasitic diseases; research and education capacity building in Africa.
Overview: Traditionally, research in the Weeks lab investigated hormonal regulation of the structure, function and survival of neurons and neural circuits, using methods including electrophysiology, biophysics, genetics, genomics and behavioral analysis. This work focused on an extreme example of natural neural plasticity: insect metamorphosis in the moth, Manduca sexta, and fruit fly, Drosophila melanogaster, when neural circuits are reorganized to accommodate different life stages. Hormones similarly influence the vertebrate nervous system with relevance to human health such as Alzheimer's Disease and stress-induced cognitive decline.
Since the mid-1990s, Weeks has increasingly been involved with research and education in Africa, and the study of tropical parasitic and infectious diseases. Infection with parasitic nematodes causes chronic, debilitating disease in humans and animals in many resource-limited regions of the world. Existing anthelmintic (anti-nematode) drugs are losing potency due to increasing drug resistance in the parasites, and new drugs are critically needed. Within this context, the Weeks lab turned its focus to the small roundworm, Caenorhabditis elegans, a powerful model organism for biological inquiry. The Weeks lab is using combined microfluidic and electrophysiological platforms developed with Shawn Lockery to accelerate the screening process for new anthelmintic drugs, using C. elegans. The ScreenChip platform is also useful for C. elegans models of human aging and disease. Recently, the Bill & Melinda Gates Foundation funded the successful modification of this technology for use with human parasites such as hookworm (Ancylostoma spp.) and roundworm (Ascaris). In 2011, Weeks and Lockery founded a UO spin-off company, NemaMetrix Inc., to enhance commercialization of these devices.
Weeks has taught in and organized advanced neuroscience courses throughout Africa (e.g., Senegal, Egypt, Kenya, Democratic Republic of Congo, South Africa, Ghana) for graduate and medical students, and neuroscience faculty, under the auspices of the International Brain Research Organization. A member of the African Studies Program, Weeks performs healthcare fieldwork in Zimbabwe and is a student and performer of Zimbabwean music. At UO, she teaches courses in global health [“Tropical Diseases in Africa” (Bi309) and “HIV/AIDS in Africa” (CHC434)] and helps direct a global-health-focused study abroad and internship program in Accra, Ghana, for undergraduates.
Microfluidic platform for electrophysiological recordings from host-stage hookworm and Ascaris suum larvae: a new tool for anthelmintic research. Weeks JC, Roberts WM, Robinson KJ, Keaney M, Vermeire JJ, Urban Jr., JF, Lockery SR, Hawdon JM.. International Journal for Parasitology: Drugs and Drug Resistance, in press.
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
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]
Sertraline, Paroxetine, and Chlorpromazine Are Rapidly Acting Anthelmintic Drugs Capable of Clinical Repurposing.
Sci Rep. 2018 01 17;8(1):975
Authors: Weeks JC, Roberts WM, Leasure C, Suzuki BM, Robinson KJ, Currey H, Wangchuk P, Eichenberger RM, Saxton AD, Bird TD, Kraemer BC, Loukas A, Hawdon JM, Caffrey CR, Liachko NF
Parasitic helminths infect over 1 billion people worldwide, while current treatments rely on a limited arsenal of drugs. To expedite drug discovery, we screened a small-molecule library of compounds with histories of use in human clinical trials for anthelmintic activity against the soil nematode Caenorhabditis elegans. From this screen, we found that the neuromodulatory drugs sertraline, paroxetine, and chlorpromazine kill C. elegans at multiple life stages including embryos, developing larvae and gravid adults. These drugs act rapidly to inhibit C. elegans feeding within minutes of exposure. Sertraline, paroxetine, and chlorpromazine also decrease motility of adult Trichuris muris whipworms, prevent hatching and development of Ancylostoma caninum hookworms and kill Schistosoma mansoni flatworms, three widely divergent parasitic helminth species. C. elegans mutants with resistance to known anthelmintic drugs such as ivermectin are equally or more susceptible to these three drugs, suggesting that they may act on novel targets to kill worms. Sertraline, paroxetine, and chlorpromazine have long histories of use clinically as antidepressant or antipsychotic medicines. They may represent new classes of anthelmintic drug that could be used in combination with existing front-line drugs to boost effectiveness of anti-parasite treatment as well as offset the development of parasite drug resistance.
PMID: 29343694 [PubMed - indexed for MEDLINE]
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
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]
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
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]
Steroid-triggered, cell-autonomous death of a Drosophila motoneuron during metamorphosis.
Neural Dev. 2011 Apr 27;6:15
Authors: Winbush A, Weeks JC
BACKGROUND: The metamorphosis of Drosophila melanogaster is accompanied by elimination of obsolete neurons via programmed cell death (PCD). Metamorphosis is regulated by ecdysteroids, including 20-hydroxyecdysone (20E), but the roles and modes of action of hormones in regulating neuronal PCD are incompletely understood.
RESULTS: We used targeted expression of GFP to track the fate of a larval motoneuron, RP2, in ventral ganglia. RP2s in abdominal neuromeres two through seven (A2 to A7) exhibited fragmented DNA by 15 hours after puparium formation (h-APF) and were missing by 20 h-APF. RP2 death began shortly after the 'prepupal pulse' of ecdysteroids, during which time RP2s expressed ecdysteroid receptors (EcRs). Genetic manipulations showed that RP2 death required the function of EcR-B isoforms, the death-activating gene, reaper (but not hid), and the apoptosome component, Dark. PCD was blocked by expression of the caspase inhibitor p35 but unaffected by manipulating Diap1. In contrast, aCC motoneurons in neuromeres A2 to A7, and RP2s in neuromere A1, expressed EcRs during the prepupal pulse but survived into the pupal stage under all conditions tested. To test the hypothesis that ecdysteroids trigger RP2's death directly, we placed abdominal GFP-expressing neurons in cell culture immediately prior to the prepupal pulse, with or without 20E. 20E induced significant PCD in putative RP2s, but not in control neurons, as assessed by morphological criteria and propidium iodide staining.
CONCLUSIONS: These findings suggest that the rise of ecdysteroids during the prepupal pulse acts directly, via EcR-B isoforms, to activate PCD in RP2 motoneurons in abdominal neuromeres A2 to A7, while sparing RP2s in A1. Genetic manipulations suggest that RP2's death requires Reaper function, apoptosome assembly and Diap1-independent caspase activation. RP2s offer a valuable 'single cell' approach to the molecular understanding of neuronal death during insect metamorphosis and, potentially, of neurodegeneration in other contexts.
PMID: 21521537 [PubMed - indexed for MEDLINE]
Segment-specific muscle degeneration is triggered directly by a steroid hormone during insect metamorphosis.
J Neurobiol. 2005 Feb 05;62(2):164-77
Authors: Hazelett DJ, Weeks JC
During metamorphosis of the hawkmoth, Manduca sexta, some larval muscles degenerate while others are respecified for new functions. In larvae, accessory planta retractor muscles (APRMs) are present in abdominal segments 1 to 6 (A1 to A6). APRMs serve as proleg retractors in A3 to A6 and body wall muscles in A1 and A2. At pupation, all APRMs degenerate except those in A2 and A3, which are respecified to circulate hemolymph in pupae. The motoneurons that innervate APRMs, the APRs, likewise undergo segment-specific programmed cell death (PCD), as a direct, cell-autonomous response to the prepupal peak of ecdysteroids. The segment-specific patterns of APR and APRM death differ. The present study tested the hypothesis that APRM death is a direct, cell-autonomous response to the prepupal peak of ecdysteroids. Prevention of the prepupal peak prevented APRM degeneration, and replacement of the peak by infusion of 20-hydroxyecdysone restored the correct segment-specific pattern of APRM degeneration. Surgical denervation of APRMs did not perturb their segment-specific degeneration at pupation, indicating that signals from APRs are not required for the muscles' segment-specific responses to ecdysteroids. The possibility that instructive signals originate from APRMs' epidermal attachment points was tested by treating the epidermis with a juvenile hormone analog to prevent pupal development. This manipulation likewise did not alter APRM fate. We conclude that both the muscles and motoneurons in this motor system respond directly and cell-autonomously to prepupal ecdysteroids to produce a segment-specific pattern of PCD that is matched to the functional requirements of the pupal body.
PMID: 15452849 [PubMed - indexed for MEDLINE]
Thinking globally, acting locally: steroid hormone regulation of the dendritic architecture, synaptic connectivity and death of an individual neuron.
Prog Neurobiol. 2003 Aug;70(5):421-42
Authors: Weeks JC
Steroid hormones act via evolutionarily conserved nuclear receptors to regulate neuronal phenotype during development, maturity and disease. Steroid hormones exert 'global' effects in organisms to produce coordinated physiological responses whereas, at the 'local' level, individual neurons can respond to a steroidal signal in highly specific ways. This review focuses on two phenomena-the loss of dendritic processes and the programmed cell death (PCD) of neurons-that can be regulated by steroid hormones (e.g. during sexual differentiation in vertebrates). In insects such as the moth, Manduca sexta, and fruit fly, Drosophila melanogaster, ecdysteroids orchestrate a reorganization of neural circuits during metamorphosis. In Manduca, accessory planta retractor (APR) motoneurons undergo dendritic loss at the end of larval life in response to a rise in 20-hydroxyecdysone (20E). Dendritic regression is associated with a decrease in the strength of monosynaptic inputs, a decrease in the number of contacts from pre-synaptic neurons, and the loss of a behavior mediated by these synapses. The APRs in different abdominal segments undergo segment-specific PCD at pupation and adult emergence that is triggered directly and cell-autonomously by a genomic action of 20E, as demonstrated in cell culture. The post-emergence death of APRs provides a model for steroid-mediated neuroprotection. APR death occurs by autophagy, not apoptosis, and involves caspase activation and the aggregation and ultracondensation of mitochondria. Manduca genes involved in segmental identity, 20E signaling and PCD are being sought by suppressive subtractive hybridization (SSH) and cDNA microarrays. Experiments utilizing Drosophila as a complementary system have been initiated. These insect model systems contribute toward understanding the causes and functional consequences of dendritic loss and neurodegeneration in human neurological disorders.
PMID: 14511700 [PubMed - indexed for MEDLINE]
Steroid-induced dendritic regression reduces anatomical contacts between neurons during synaptic weakening and the developmental loss of a behavior.
J Neurosci. 2003 Feb 15;23(4):1406-15
Authors: Gray JR, Weeks JC
Steroid hormones alter dendritic architecture in many animals, but the exact relationship between dendritic anatomy, synaptic strength, and behavioral expression is typically unknown. In larvae of the moth Manduca sexta, the tip of each abdominal proleg (locomotory appendage) bears an array of mechanosensory hairs, each innervated by a planta hair sensory neuron (PH-SN). In the CNS, PH-SN axons make monosynaptic, excitatory nicotinic cholinergic connections with accessory planta retractor (APR) motoneurons. These synapses mediate a proleg withdrawal reflex behavior that is lost at pupation. The prepupal peak of ecdysteroids (molting hormones) triggers the regression of APR dendrites and a >80% reduction in the amplitude of EPSPs produced in APRs by PH-SNs that innervate posterior planta hairs. The present study tested the hypothesis that a decrease in the number of synaptic contacts from PH-SNs to APRs contributes to this synaptic weakening. Pairs of PH-SNs and APRs were fluorescently labeled in larvae and pupae, and the number of indistinguishably close anatomical contacts (putative synapses) was counted by confocal laser scanning microscopy. During APR dendritic regression, the mean number of contacts from posterior PH-SNs decreased by approximately 80%, whereas the size of individual contacts did not change detectably and the axonal arbors of PH-SNs did not regress. These results suggest that the steroid-induced regression of motoneuron dendrites physically disconnects the motoneurons from the synaptic terminals of sensory neurons, producing synaptic weakening and the developmental loss of the proleg withdrawal reflex behavior at pupation.
PMID: 12598629 [PubMed - indexed for MEDLINE]