@article {48299, title = {The multilayer connectome of Caenorhabditis elegans.}, journal = {PLoS Computational Biology}, volume = {12}, year = {2016}, month = {2016 Dec 16}, pages = {e1005283}, abstract = {

Connectomics has focused primarily on the mapping of synaptic links in the brain; yet it is well established that extrasynaptic volume transmission, especially via monoamines and neuropeptides, is also critical to brain function and occurs primarily outside the synaptic connectome. We have mapped the putative monoamine connections, as well as a subset of neuropeptide connections, in C. elegans based on new and published gene expression data. The monoamine and neuropeptide networks exhibit distinct topological properties, with the monoamine network displaying a highly disassortative star-like structure with a rich-club of interconnected broadcasting hubs, and the neuropeptide network showing a more recurrent, highly clustered topology. Despite the low degree of overlap between the extrasynaptic (or wireless) and synaptic (or wired) connectomes, we find highly significant multilink motifs of interaction, pinpointing locations in the network where aminergic and neuropeptide signalling modulate synaptic activity. Thus, the C. elegans connectome can be mapped as a multiplex network with synaptic, gap junction, and neuromodulator layers representing alternative modes of interaction between neurons. This provides a new topological plan for understanding how aminergic and peptidergic modulation of behaviour is achieved by specific motifs and loci of integration between hard-wired synaptic or junctional circuits and extrasynaptic signals wirelessly broadcast from a small number of modulatory neurons.

}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1005283}, author = {Bentley, Barry and Branicky, Robyn and Barnes, Christopher L and Chew, Yee Lian and Yemini, Eviatar and Bullmore, Edward T and V{\'e}rtes, Petra E and Schafer, William R} } @article {45854, title = {A consistent muscle activation strategy underlies crawling and swimming in Caenorhabditis elegans.}, journal = {Journal of the Royal Society Interface}, volume = {12}, year = {2015}, month = {2015 Jan 6}, pages = {20140963}, abstract = {

Although undulatory swimming is observed in many organisms, the neuromuscular basis for undulatory movement patterns is not well understood. To better understand the basis for the generation of these movement patterns, we studied muscle activity in the nematode Caenorhabditis elegans. Caenorhabditis elegans exhibits a range of locomotion patterns: in low viscosity fluids the undulation has a wavelength longer than the body and propagates rapidly, while in high viscosity fluids or on agar media the undulatory waves are shorter and slower. Theoretical treatment of observed behaviour has suggested a large change in force-posture relationships at different viscosities, but analysis of bend propagation suggests that short-range proprioceptive feedback is used to control and generate body bends. How muscles could be activated in a way consistent with both these results is unclear. We therefore combined automated worm tracking with calcium imaging to determine muscle activation strategy in a variety of external substrates. Remarkably, we observed that across locomotion patterns spanning a threefold change in wavelength, peak muscle activation occurs approximately 45{\textdegree} (1/8th of a cycle) ahead of peak midline curvature. Although the location of peak force is predicted to vary widely, the activation pattern is consistent with required force in a model incorporating putative length- and velocity-dependence of muscle strength. Furthermore, a linear combination of local curvature and velocity can match the pattern of activation. This suggests that proprioception can enable the worm to swim effectively while working within the limitations of muscle biomechanics and neural control.

}, issn = {1742-5662}, author = {Butler, Victoria J and Branicky, Robyn and Yemini, Eviatar and Liewald, Jana F and Gottschalk, Alexander and Kerr, Rex A and Chklovskii, Dmitri B and Schafer, William R} } @article {5460, title = {Proprioceptive coupling within motor neurons drives C. elegans forward locomotion.}, journal = {Neuron}, volume = {76}, year = {2012}, month = {2012 Nov 21}, pages = {750-61}, abstract = {

Locomotion requires coordinated motor activity throughout an animal{\textquoteright}s body. In both vertebrates and invertebrates, chains of coupled central pattern generators (CPGs) are commonly evoked to explain local rhythmic behaviors. In C.\ elegans, we report that proprioception within the motor circuit is responsible for propagating and coordinating rhythmic undulatory waves from head to tail during forward movement. Proprioceptive coupling between adjacent body regions transduces rhythmic movement initiated near the head into bending waves driven along the body by a chain of reflexes. Using optogenetics and calcium imaging to manipulate and monitor motor circuit activity of moving C.\ elegans held in microfluidic devices, we found that the B-type cholinergic motor neurons transduce the proprioceptive signal. In C.\ elegans, a sensorimotor feedback loop operating within a specific type of motor neuron both drives and organizes body movement.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2012.08.039}, author = {Wen, Quan and Po, Michelle D. and Hulme, Elizabeth and Chen, Sway and Liu, Xinyu and Kwok, Sen Wai and Gershow, Marc and Leifer, Andrew M. and Butler, Victoria and Fang-Yen, Christopher and Kawano, Taizo and Schafer, William R and Whitesides, George and Wyart, Matthieu and Chklovskii, Dmitri B and Samuel, Aravinthan D. T.} } @article {46630, title = {Guidelines on nicotine dose selection for in vivo research.}, journal = {Psychopharmacology (Berl)}, volume = {190}, year = {2007}, month = {2007 Feb}, pages = {269-319}, abstract = {

RATIONALE: This review provides insight for the judicious selection of nicotine dose ranges and routes of administration for in vivo studies. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. In many cases, such discrepancies could be attributed to the complex variables comprising species-specific in vivo responses to acute or chronic nicotine exposure.

OBJECTIVES: This review capitalizes on the authors{\textquoteright} collective decades of in vivo nicotine experimentation to clarify the issues and to identify the variables to be considered in choosing a dosaging regimen. Nicotine dose ranges tolerated by humans and their animal models provide guidelines for experiments intended to extrapolate to human tobacco exposure through cigarette smoking or nicotine replacement therapies. Just as important are the nicotine dosaging regimens used to provide a mechanistic framework for acquisition of drug-taking behavior, dependence, tolerance, or withdrawal in animal models.

RESULTS: Seven species are addressed: humans, nonhuman primates, rats, mice, Drosophila, Caenorhabditis elegans, and zebrafish. After an overview on nicotine metabolism, each section focuses on an individual species, addressing issues related to genetic background, age, acute vs chronic exposure, route of administration, and behavioral responses.

CONCLUSIONS: The selected examples of successful dosaging ranges are provided, while emphasizing the necessity of empirically determined dose-response relationships based on the precise parameters and conditions inherent to a specific hypothesis. This review provides a new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine.

}, keywords = {Animals, Behavioral Research, Dose-Response Relationship, Drug, Ganglionic Stimulants, Guidelines as Topic, Humans, Models, Biological, Nicotine, Species Specificity}, issn = {0033-3158}, doi = {10.1007/s00213-006-0441-0}, author = {Matta, Shannon G and Balfour, David J and Benowitz, Neal L and Boyd, R Thomas and Buccafusco, Jerry J and Caggiula, Anthony R and Craig, Caroline R and Collins, Allan C and Damaj, M Imad and Donny, Eric C and Gardiner, Phillip S and Grady, Sharon R and Heberlein, Ulrike and Leonard, Sherry S and Levin, Edward D and Lukas, Ronald J and Markou, Athina and Marks, Michael J and McCallum, Sarah E and Parameswaran, Neeraja and Perkins, Kenneth A and Picciotto, Marina R and Quik, Maryka and Rose, Jed E and Rothenfluh, Adrian and Schafer, William R and Stolerman, Ian P and Tyndale, Rachel F and Wehner, Jeanne M and Zirger, Jeffrey M} } @article {2014, title = {In vivo imaging of C. elegans mechanosensory neurons demonstrates a specific role for the MEC-4 channel in the process of gentle touch sensation.}, journal = {Neuron}, volume = {39}, year = {2003}, month = {2003 Sep 11}, pages = {1005-17}, abstract = {

In the nematode C. elegans, genes encoding components of a putative mechanotransducing channel complex have been identified in screens for light-touch-insensitive mutants. A long-standing question, however, is whether identified MEC proteins act directly in touch transduction or contribute indirectly by maintaining basic mechanoreceptor neuron physiology. In this study, we used the genetically encoded calcium indicator cameleon to record cellular responses of mechanosensory neurons to touch stimuli in intact, behaving nematodes. We defined a gentle touch sensory modality that adapts with a time course of approximately 500 ms and primarily senses motion rather than pressure. The DEG/ENaC channel subunit MEC-4 and channel-associated stomatin MEC-2 are specifically required for neural responses to gentle mechanical stimulation but do not affect the basic physiology of touch neurons or their in vivo responses to harsh mechanical stimulation. These results distinguish a specific role for the MEC channel proteins in the process of gentle touch mechanosensation.

}, keywords = {Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Calcium Channels, Cells, Cellular, Cultured, L-Type, Mechanoreceptors, Mechanotransduction, Membrane Potentials, Membrane Proteins, Neurons, Touch}, issn = {0896-6273}, author = {Suzuki, Hiroshi and Kerr, Rex and Bianchi, Laura and Fr{\o}kjaer-Jensen, Christian and Slone, Dan and Xue, Jian and Gerstbrein, Beate and Driscoll, Monica and Schafer, William R} }