Vidal-Gadea, Andres G. et al. (2013) International Worm Meeting "Magnetotaxis in C. elegans."

Vidal-Gadea, Andres G., Pierce-Shimomura, Jonathan T., Ward, Kristi A.

[International Worm Meeting, 2013]

The magnetic field of the Earth provides an ancient and continuous source of directional information to organisms able to detect it. While the last half-century has seen the list of species capable of this feat grow steadily (from bacteria to mammals), the mechanisms by which magentosensation is accomplished in animals has remained elusive. Magnetotactic bacteria are known to harvest iron from their environment to build nanometer-sized "compasses" and evidence of magnetite has been reported in many magnetotactic animals. It remains unclear whether and how these putative "biological compasses" are used. This is partly due to the fact that a magnetosensory neuron has never been identified in any animal. We show that the nematode C. elegans readily orients to common magnets in addition to the Earth's magnetic field. Using a custom-built magnetic cage, we tested worms in magnetic fields controlled along three dimensions. Worms migrated at an angle to the field, in what would be the "down" direction. Our findings suggests that the Earth's magnetic field may serve as a better cue than gravity for these tiny animals to orient while burrowing. Through behavioral analysis of mutants as well as cell-specific rescue and ablation, we next identified a pair of amphid sensory neurons as necessary and sufficient to mediate magnetotaxis in C. elegans. Functional calcium imaging performed on these neurons revealed calcium transients induced by magnetic fields. Genes and neurons required for magnetotaxis are distinct from those previously reported to be essential for electrotaxis. Magnetic orientation in C. elegans appears to take place through a light-independent mechanism, and to rely on a cGMP-dependent transduction pathway. To our knowledge, this represents the first report of sensory neurons required for magnetic orientation in any species.

Vidal-Gadea, Andres et al. (2015) International Worm Meeting "Burrowing behavior of C. elegans used to study neuromuscular disorder models."

Vidal-Gadea, Andres, Parikh, Adhishri, Pierce-Shimomura, Jonathan, Cohn, Jesse, Hwang, Grace, Beron, Celia

[International Worm Meeting, 2015]

The nematode Caenorhabditis elegans is a powerful model system for the study of human neuromuscular function and disorders. However, many worm models of human disease only show mild crawling phenotypes. In their natural habitat, C. elegans likely spends much of the time burrowing through the soil matrix. We developed a burrowing assay to challenge motor output by placing worms in agar-filled pipettes of increasing densities. We find that burrowing involves distinct kinematics and turning strategies from crawling that vary with the properties of the substrate. We show that Duchenne muscular dystrophy model (dys-1) mutants crawl normally but are severely impaired in burrowing. In stark contrast with wild-type, muscular degeneration in the dys-1 mutant is hastened and exacerbated by burrowing. We performed a genetic screen and isolated several suppressor mutants with proficient burrowing in a dys-1 mutant background. Further study of burrowing in C. elegans will enhance the study of diseases affecting neuromuscular integrity, and provide insights into the natural behavior of this and other nematodes.

Vidal-Gadea, Andres et al. (2015) International Worm Meeting "Geographical tuning in magnetotactic response across C. elegans wild-type isolates."

Ward, Kristi, Beron, Celia, Vidal-Gadea, Andres, Pierce-Shimomura, Jonathan

[International Worm Meeting, 2015]

Rotation of the earth's liquid core generates a magnetic field used by many organisms to navigate their environment. While some animals such as turtles and birds use the magnetic field to engage in horizontal migrations, other organisms like magnetotactic bacteria use it to guide their migrations vertically. We find that C. elegans readily orients to artificial magnetic fields of earth strength. When assaying responses to the natural magnetic field of the earth, we found that worms appear to use the geomagnetic field to guide vertical migrations via an identified a pair of sensory neurons. Because the orientation of the geomagnetic field differs across the globe, we tested the magnetotactic ability and migratory preference of the standard lab strain (N2), and of wild-type strains isolated from different locations across the planet. We found that different populations displayed an innate preference to migrate at an angle to magnetic fields of earth-strength that would optimize their UP or DOWN direction when burrowing in their native global location. For instance, in England the geomagnetic field pierces the earth at +66 degrees (north points down). We found that well-fed British N2 worms prefer to migrate 120 degrees to an earth-strength artificial magnetic field. This seemingly arbitrary angle corresponds to the optimal angle to orient them upward when burrowing in England. By contrast, starved N2 worms migrated in the opposite direction (i.e. 300 degrees to the field), which would orient them downward in England. Consistent with natural populations adapting to local magnetic fields, we next found that worms isolated from Australia, where the geomagnetic field emanates out of the earth at -66 degrees (north points up), displayed an opposite innate pattern of migratory preference. Similar results were found for wild-type worms from Hawaii. This pattern of optimal natural variation in magnetic orientation in C. elegans serves as an excellent example to relate spatiotemporal genetic variation with a behavioral trait. The breath in number and distribution of wild-type C. elegans populations makes this a promising model for studying the effects of natural and artificial magnetic field variation on the behavior of a genetically tractable animal.

Vidal-Gadea, Andres G et al. (2011) International Worm Meeting "C. elegans selects distinct crawling and swimming gaits via dopamine and serotonin."

Elbel, Erin, Axelrod, Abram, Erbguth, Karen, Topper, Stephen, Brauner, Martin, Vidal-Gadea, Andres G, Crisp, Ashley, Pierce-Shimomura, Jonathan, Young, Layla, Siegel, Dionicio, Maples, Thomas, Kressin, Leah, Gottschalk, Alexander

[International Worm Meeting, 2011]

The ability to select and switch between alternate locomotory gaits is shared among many animals that are required to transition between different environments. Failure to achieve motor transitions is often devastating to the organism as exemplified by patients with advanced Parkinson's disease. The nematode C. elegans is well adapted for locomotion on land and in water and is likely required to transition between these sub-niches in nature. Despite recent advances, it remains controversial if swimming and crawling are distinct gaits in C. elegans, and if so, how transitions between them are accomplished (1-4). Answering these questions could enable the use of this powerful model system to study the mechanisms underlying locomotory transitions. We used a multifaceted approach spanning in depth behavioral assays, mechanic and optogenetic stimulation, laser ablations, mutant analysis, and in vivo photolysis of caged amines to test whether the worm uses distinct gaits and to determine how they transition between them. We show through a series of behavioral assays that in C. elegans crawling and swimming are distinct gaits. Dopamine released by ADE and PDE neurons is necessary and sufficient to initiate and maintain crawling by a pathway activating D1-like receptors. Conversely, serotonin is necessary and sufficient to initiate and maintain transition from crawling to swimming and to inhibit a set of crawl-specific behaviors. We found these transitions to be modulated by the balance between dopamine and serotonin. These amines have been found to play crucial roles in transition between alternate locomotory forms in diverse species stressing the importance locomotor transitions have for survival. Further study of locomotory switching in C. elegans and its dependence on dopamine may provide insight into comparable motor deficits observed in Parkinson's disease. 1) Boyle H et al. N. Front. Behav. Neurosci. 2011 5:10 doi: 10.3389/fnbeh.2011.00010. 2) Mesce KA, Pierce-Shimomura JT. Front. Behav. Neurosci. 2010 4:49 doi: 10.3389/fnbeh.2010.0004 3) Vidal-Gadea AG et al. 2009 Neuroscience 366:17 Calabrese R: Faculty of 1000 Biology, 11 November, 2009. Conference 2009 October 16-21. Available at: http://f1000biology.com/ article/id/1182956/evaluation 4) Fang-Yen C et al. 2010 PNAS 107, 20323-20328.

Hughes, Kiley et al. (2021) International Worm Meeting "C. elegans offers a unique window into the early pathophysiology of Duchenne muscular dystrophy"

Adams, Jessica, Hughes, Kiley, Vidal-Gadea, Andres, Tamrazi, Monica, Rivera, Brittany

[International Worm Meeting, 2021]

Duchenne muscular dystrophy is an x-linked disorder that claims the lives of one in every 3,500 males. The disease is caused by mutations that result in the absence of the dystrophin protein from the membrane of muscle cells where it plays important structural and signaling roles. Without dystrophin, muscle-generated forces are unable to safely exit the cell. This results in cellular injuries, most consequentially to the plasma membrane. Individuals become wheelchair bound between seven to twelve years of age, and typically die in their late teens to twenties. While there is some variability in the rate and the severity of the degeneration, patients suffer a plethora of debilitating symptoms associated with progressive muscle degeneration and loss. There is no cure for Duchenne muscular dystrophy. Lack of progress and understanding of this disorder is largely the result of animal models failing to recapitulate both the genetic and phenotypic severity observed in humans. However, understanding the molecular events that link loss of dystrophin to muscle death remains of paramount importance. This knowledge will help us identify targets amenable to intervention and offer hope to more than one million individuals suffering this disease across the world. Our lab uses dystrophic nematodes to generate insights into the pathophysiology of Duchenne muscular dystrophy, and to identify novel therapeutic avenues. By harnessing the natural burrowing behavior of C. elegans we demonstrated that dystrophic worms recapitulate key aspects of the disease to a greater extent than those observed in most research models currently used. We report a study of the embryonic development of dystrophic animals. Here we show that sarcoplasmic calcium dysregulation associated with dystrophic muscles starts early during development. Furthermore, a suppressor screen, and a comparison of dystrophic strains displaying different severity, both point to muscle calmodulin as a potential therapeutic target. Dystrophic worms provide a unique opportunity for studying the mechanism by which dystrophic cells degenerate, and to identify intervention avenues. To validate findings obtained using our dystrophic animals we are presently developing a human muscle culture system.

Fernandez, Eliana Mailen et al. (2021) International Worm Meeting "C. elegans as tool to study chronic stress implications"

Adams, Jessica, Vidal-Gadea, Andres, Monteleone, Melisa, Brocco, Marcela, Fernandez, Eliana Mailen

[International Worm Meeting, 2021]

Chronic stress is one of the main risk factors for depression and other neuropsychiatric diseases. Long exposure to chronic stress results in changes in brain gene expression that are deleterious for organisms. Due its relevance to human health, our goal is to investigate the molecular pathways disrupted by chronic stress to understand how this leads to such diseases. Using rodent models of chronic stress, we found that stress alters neuronal protein GPM6A. GPM6A participates in neuronal differentiation and morphology establishment and human GPM6A has been linked to schizophrenia, bipolar disorder, claustrophobia and suicide patients. This links GPM6A to the stress phenomenon and depression. Nevertheless, there is a gap between the cellular GPM6A functions and its role in systemic stress response. To fill this gap, we use the nematode Caenorhabditis elegans as model due to shared features between nematode and mammal nervous system and because of the genetic tools available. C. elegans exhibits a GPM6A ortholog, the neuronal membrane glycoprotein 1 (NMGP-1), thus, here we used C. elegans as a simpler model to study NMGP-1 participation in stress response. First, worms expressing GFP under the nmgp-1 promoter indicated us that nmgp-1 expresses in sensory amphid and phasmid neurons and in the egg-laying apparatus. Second, we have characterized NMGP-1 functions using RNAi knockdown and two non-null, hypomorphic mutant alleles. Analysis of dsRNA (nmgp-1)-treated or mutant alleles showed an increased recovering time from the stress-resistant dauer stage and a reduced egg-laying rate with respect to control worms. In addition, defects in egg-laying induced egg retention (bag of worms) in nmgp-1-deficient worms. Also, worms lacking NMGP-1 showed a normal response to the attractant diacetyl, but an altered repulsive response to SDS. Moreover, morphologically, nmgp-1(RNAi) worms showed alterations on ASJ chemosensory neurons located at the nerve ring, responsible of dauer exit. Altogether these results suggest that NMGP-1 is involved in the stress response in C. elegans. To move forward, we will present and discuss a battery of experiments to score stress response: Temperature acute and chronic exposure, oxidative and osmotic stress. The characterization of stress response in worms lacking nmgp-1 will allow us to deepen on the stress molecular bases and mental diseases.

Topper, Stephen M. et al. (2013) International Worm Meeting "Ethanol induces state-dependent behavioral transition."

Vidal-Gadea, Andres, Pierce-Shimomura, Jonathan, Topper, Stephen M., Aguilar, Sara, Young, Layla

[International Worm Meeting, 2013]

Alcohol, the most widely abused drug in the world, has a wide range of effect on individuals and there are many factors that predispose one to addiction. Chief among them are stress, depression, and anxiety, all of which include altered monoamine signaling. It remains unclear how behavioral states differentially influence responses to ethanol. C. elegans displays distinct behavioral states associated with locomotion (crawling and swimming) that are mediated by dopamine and serotonin respectively. We found that ethanol-induced responses in C. elegans depended on crawl or swim behavioral state. Whereas alcohol non-specifically impaired locomotion and feeding in crawling worms on land, alcohol induced a specific transition from swim to crawl state in worms submerged in ethanol. This response was dependent on dopamine. Loss of the D1-like dopamine receptor DOP-4 impaired the EtOH-induced transition to crawl, while optogenetic inhibition of DOP-4 receptor-expressing neurons via the Arch chloride pump recovered the swim state. These results suggest that alterations of dopamine-dependent behavioral states can drastically influence EtOH-induced behaviors with implications for prevention of addiction. Acknowledgements: CGC and the Knockout Consortium for strains, Bruce/Jones Award for Alcohol and Addiction Research, Karl Deisseroff for reagents.

Moon, K. et al. (2019) International Worm Meeting "Gait selection of Caenorhabditis elegans is regulated by mechanosensitive DEG/ENaC channels."

Moon, K., Kim, K., Kim, J., Yeon, J.

[International Worm Meeting, 2019]

Animals change their locomotion or gaits in response to environmental condition. In vertebrates, gait transition has been shown to be mediated by monoamines, which is conserved across many species including the nematode Caenorhabditis elegans (Vidal-Gadea et al., 2011). However, molecular mechanisms of gait transition are still unclear. C. elegans exhibits two gaits, swimming in liquids and crawling on dense gels. C. elegans genome contains evolutionarily conserved 28 DEG/ENaC channels, of which functions may be involved in mechanosensory transduction and locomotion (Goodman and Schwarz, 2003). We first hypothesized that mechanosensitive channels could act as a gait transition initiator and examined crawl-to-swim transition phenotype in DEG/ENaC mutants. We found that while acd-5 mutants show normal crawling, transition from crawling to swimming upon liquid exposure is defective, suggesting roles of ACD-5 in gait transition. We are currently generating acd-5 rescue lines and examining expression pattern of acd-5.

Bainbridge, Chance et al. (2017) International Worm Meeting "Investigation of the behavioral and cellular basis for magnetotaxis in C. elegans."

Benefield, Zachary, Bainbridge, Chance, McDonald, Jocelyn, Jackson, Janelle, Nguyen, Ken, Padia, Samantha, Hall, David, Vidal-Gadea, Andres, Barickman, Lucas

[International Worm Meeting, 2017]

The magnetic field of the Earth provides directional information to organisms across many taxa (from bacteria to mammals). However, the cellular and molecular mechanisms necessary for magnetic field detection in animals remain poorly understood, in part, because of the genetic, behavioral, and neurological intractability of the species studied. We previously showed that C. elegans readily orients to magnetic fields of earth-strength through a pair of identified sensory neurons (AFDs). This opens the door for the use of this behaviorally and genetically tractable species in the study of magnetotransduction. Much remains to be understood regarding how C. elegans transduces magnetic information, how this information is encoded, and how it ultimately affects the animal's behavior. Our lab studies the behavioral, cellular, and molecular basis of magnetotransduction in C. elegans. By recording animals orienting to magnetic stimuli, we determined that C. elegans orients to magnetic fields by modulating the frequency of deep bends during locomotion. We found that the integrity and number of AFD sensory villi are critical for magnetic orientation in C. elegans. Magnetotransduction and magnetic orientation in C. elegans function light-independently. We used streptavidin coated magnetic beads and atomic force microscopy to track the potential presence of endogenous magnetic particles in C. elegans. The behavioral, cellular, and genetic tractability of C. elegans offer a unique valuable opportunity to elucidate the mechanism through which animals harness the magnetic field of the earth to enhance their survival.

Topper, Stephen M. et al. (2013) International Worm Meeting "Dopaminergic control of gait switching in C. elegans."

Pierce-Shimomura, Jonathan, Aguilar, Sara, Topper, Stephen M., Young, Layla

[International Worm Meeting, 2013]

The ability to switch between different forms of locomotion is critical to many aspects of survival, whether it is switching from walking to running to evade predators, or switching to a slower gait to obtain food. However, the neuronal mechanisms of gait switching are not well understood. We recently showed C. elegans, displays distinct crawl and swim gaits, mediated by dopamine and serotonin, respectively (Vidal-Gadea et al., 2011). Further investigation into the role of dopamine signaling in the transition to crawl has indicated the D1-like dopamine receptor dop-4 as a key component. Laser microablation of dop-4-expressing neurons has revealed single neurons that are required for the transition to crawl. Optogenetic activation of dop-4-expressing neurons via the light-activated GPCR optoXRB2 induces crawl-like behavior in swimming worms. Finally, expression of dop-4 in specific subsets of dop-4 neurons is sufficient to rescue the swim to crawl transition. We are now combining noninvasive imaging of these neurons in freely moving worms with optogenetics to dissect how dopamine controls gait switching at the circuit level. A genetic analysis dopaminergic locomotory in C. elegans may reveal fundamental principles on gait switching with implications for many fields, including the study of human ailments such as Parkinson's disease.