Cohen N et al. (2014) Curr Opin Neurobiol "Nematode locomotion: dissecting the neuronal-environmental loop."

Cohen N, Sanders T

[Curr Opin Neurobiol, 2014]

With a fully reconstructed and extensively characterized neural circuit, the nematode Caenorhabditis elegans is a promising model system for integrating our understanding of neuronal, circuit and whole-animal dynamics. Fundamental to addressing this challenge is the need to consider the tight neuronal-environmental coupling that allows the animal to survive and adapt to changing conditions. Locomotion behaviors are affected by environmental variables both at the biomechanical level and via adaptive sensory responses that drive and modulate premotor and motor circuits. Here we review significant advances in our understanding of proprioceptive control of locomotion, and more abstract models of spatial orientation and navigation. The growing evidence of the complexity of the underlying circuits suggests that the intuition gained is but the first step in elucidating the secrets of neural computation in this relatively simple system.

Denham, J. et al. (2017) International Worm Meeting "An integrated neuro-mechanical model of C. elegans forward locomotion."

Ranner, T., Denham, J., Cohen, N.

[International Worm Meeting, 2017]

Behavioural responses in C. elegans can be observed through changes in locomotive patterns. It is therefore important to consider the role of the physics in computational models of the neural circuit for motor behaviours. We present a dynamical systems model of C. elegans forward locomotion in which the neural circuit is divided into a series of repeating identical units, coupled via posterior stretch receptor feedback. Each unit includes cholinergic, bistable B-type motor neurons (modelled after bistable RMD neurons, Mellem et al. 2008, Boyle et al. 2012), implicit GABAergic D-type motor neurons (Boyle et al. 2012) and nonlinear viscoelastic muscle forcing along the body (Boyle et. al. 2012). The neural model incorporates proprioceptive feedback as the mechanism for producing sustained oscillations. Integrating the neural model with a recent continuum mechanical body model (Cohen and Ranner 2017) provides this feedback and is also the method for incorporating environmental drag from the surrounding fluid, closing the neuronal-environmental loop. Biophysically realistic parameters are used to obtain sustained travelling waves in muscle activation which respond to changes in environmental viscoelasticity. To explore the pattern generation mechanism, we present results from bifurcation analysis performed in the isolated neural framework and in the fully integrated neuro-mechanical model. We show how these results are modulated by changes in the external drag and internal material properties of the passive and active body. References [1] Boyle JH, Berri S, Cohen N: Gait modulation in c. elegans: an integrated neuro-mechanical model. Frontiers in computational neuroscience 2012, 6:10. [2] Mellem JE, Brockie PJ, Madsen DM, Maricq AV: Action potentials contribute to neuronal signaling in C. elegans, Nature Neuroscience 2008, 11:865-867 [3] Cohen N, Ranner T: A new computational method for a model of C. elegans biomechanics: Insights into elasticity and locomotion performance, arXiv:1702.04988, 20

Ghosh, D. D. et al. (2015) International Worm Meeting "Neuroendocrine reinforcement of a dynamic multisensory decision."

Nitabach, M.N., Sanders, T., Cohen, N., Hong, S., Koelle, M.R., Chase, D.L., Ghosh, D. D.

[International Worm Meeting, 2015]

To navigate complex natural environments containing both dangerous and valuable items, animals must make economic decisions on the basis of information transduced by multiple senses. However, detailed underlying neural mechanisms of multisensory decision making remain poorly understood. Here we confronted worms with a multisensory decision in which the reward of food must be balanced with the threat of desiccation imposed by a hyperosmotic barrier intervening between the worm and a source of food odor. We find that this decision is modulated by food deprivation. To identify neural substrates underlying this decision, we focused on the RIM interneuron, which is advantageously positioned to transduce integrated multisensory information into locomotor outputs. Consistent with this hypothesis, we find that the activation of a neuropeptide receptor in RIM sets the balance of threat and reward in this decision, with greater receptor activation biasing the worm against crossing the dangerous barrier. Unexpectedly, however, RIM controls the decision not by synaptic signaling to the downstream premotor command circuit, but rather by extrasynaptic aminergic signaling directly onto the primary osmosensory neuron to tune its sensitivity. Additionally, our results suggest that this neuromodulator relay is suppressed in food deprived states, thereby providing a link between internal state, neural network activity, and decision making. Finally, to characterize the complex and dynamic interplay between neuromodulator activity, neuron state, and behavior in the decision making arena, we reproduced the paradigm in silico [1]. Computational modeling revealed how non-linear sensory integration in RIM modulates neuromodulator circuit activity to implement the decision. Taken together, these studies reveal a cellular and molecular mechanism for a dynamic multisensory decision. Intriguingly, our results identified organizational circuit principles conserved between mammalian and C. elegans multisensory decision making. Therefore our studies have broad implications for understanding principles underlying multisensory decision making in Metazoans.1Sanders, T., Ghosh, D.D., Nitabach, M.N., and Cohen, N. "Nonlinear sensory integration in C. elegans: a computational model." International C. elegans meeting.

Iwanir S et al. (2019) Nat Commun "Addendum: Irrational behavior in C. elegans arises from asymmetric modulatory effects within single sensory neurons."

Itskovits E, Ruach R, Bokman E, Iwanir S, Pritz CO, Zaslaver A

[Nat Commun, 2019]

We would like to make our readers aware of the publication by Cohen et al., which reports irrational behaviour in C. elegans olfactory preference[1] . These complementary studies establish C. elegans as a model system to explore the neural mechanisms of decision making.

Boyle JH et al. (2008) Biosystems "Caenorhabditis elegans body wall muscles are simple actuators."

Cohen N, Boyle JH

[Biosystems, 2008]

Over the past four decades, one of the simplest nervous systems across the animal kingdom, that of the nematode worm Caenorhabditis elegans, has drawn increasing attention. This system is the subject of an intensive concerted effort to understand the behaviour of an entire living animal, from the bottom up and the top down. C. elegans locomotion, in particular, has been the subject of a number of models, but there is as yet no general agreement about the key (rhythm generating) elements. In this paper we investigate the role of one component of the locomotion subsystem, namely the body wall muscles, with a focus on the role of inter-muscular gap junctions. We construct a detailed electrophysiological model which suggests that these muscles function, to a first approximation, as mere actuators and have no obvious rhythm generating role. Furthermore, we show that within our model inter-muscular coupling is too weak to have a significant electrical effect. These results rule out muscles as key generators of locomotion, pointing instead to neural activity patterns. More specifically, the results imply that the reduced locomotion velocity observed in unc-9 mutants is likely to be due to reduced neuronal rather than inter-muscular coupling.

Bryden J et al. (2008) Biol Cybern "Neural control of Caenorhabditis elegans forward locomotion: the role of sensory feedback."

Cohen N, Bryden J

[Biol Cybern, 2008]

This paper presents a simple yet biologically-grounded model for the neural control of Caenorhabditis elegans forward locomotion. We identify a minimal circuit within the C. elegans ventral cord that is likely to be sufficient to generate and sustain forward locomotion in vivo. This limited subcircuit appears to contain no obvious central pattern generated control. For that subcircuit, we present a model that relies on a chain of oscillators along the body which are driven by local and proximate mechano-sensory input. Computer simulations were used to study the model under a variety of conditions and to test whether it is behaviourally plausible. Within our model, we find that a minimal circuit of AVB interneurons and B-class motoneurons is sufficient to generate and sustain fictive forward locomotion patterns that are robust to significant environmental perturbations. The model predicts speed and amplitude modulation by the AVB command interneurons. An extended model including D-class motoneurons is included for comparison.

Ranner, T. et al. (2017) International Worm Meeting "A new biomechanical model links material properties with locomotion behaviors and predicts that gait modulation is a form of speed optimisation in C. elegans."

Cohen, N., Ranner, T.

[International Worm Meeting, 2017]

An organism's ability to move freely is a fundamental behaviour across the animal kingdom. We present a biomechanical model of C. elegans locomotion together with a novel computational approach. We model the body as a flexible elastic shell, subject to muscle forcing along the body walls of the body. All parameters are grounded in behavioral, anatomical or physiological data. Our numerical approach allows us to solve for arbitrary body shapes. Our model replicates behaviours across a wide range of environments. We use it to study forward locomotion undulation gaits, linking between the animal's material properties and its performance across a range of viscoelastic environments. The model makes strong predictions on the viable range of the worm's Young's modulus and suggests that animals can control speed via the known mechanism of gait modulation that is observed across different media.

Sanders, Tom et al. (2015) International Worm Meeting "Nonlinear sensory integration in C. elegans: a computational model."

Cohen, Netta, Ghosh, D.D., Sanders, Tom, Nitabach, M.N.

[International Worm Meeting, 2015]

Animal survival depends on a combination of often conflicting demands such as foraging and evading of dangers. To navigate effectively in such unknown and changing conditions, animals must continuously integrate over a variety of sensory cues, and adapt their decision making strategy in a context dependent manner. Here, we examine the neural control of a sensory integration task in the nematode C. elegans. The task involves an ASH-triggered aversive response to high osmolarity fructose and an AWA-triggered attractive response to diacetyl [1]. In the assay, worms are placed in the center of a ring of fructose; two drops of diacetyl are located outside the ring. We present a computational model, consisting of point worms, situated in a virtual arena that closely mimics this experimental assay, and endowed with a sensory motor pathway of two sensory neurons, a neural integration pathway and two motor programs (pirouettes and steering). A monoamine (PDF-2 and tyramine) modulation circuit involving RIM and ASH is overlaid on the synaptic circuit, in line with molecular data [1]. Model parameters were constrained by behavioral data for wild type and mutant animals for a range of stimulus concentrations. Based on our simulation results, we reject a null hypothesis of a linear sensory integration mechanism in RIM and present results that are consistent with the data for a sensory "coincidence detector" like process in RIM.[1] Ghosh, D.D., Sanders, T., Hong, S., Chase, D.L., Cohen, N., Koelle, M.R., and Nitabach, M.N. "Neuroendocrine reinforcement of a dynamic multisensory decision." International C. elegans meeting.

Ge YL et al. (2002) Anticancer Res "Effects of adenoviral gene transfer of C. elegans n-3 fatty acid desaturase on the lipid profile and growth of human breast cancer cells."

Kang ZB, Chen Z, Leaf A, Kang JX, Cluette-Brown J, Laposata M, Ge YL

[Anticancer Res, 2002]

Background: Current evidence from both experimental and human studies indicates that omega-6 polyunsaturated fatty acids (n-6 PUFAs) promote breast tumor development, whereas long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) exert suppressive effects. The ratio of n-6 to n-3 fatty acids appears to be an important factor in controlling tumor development. Human cells usually have a very high n-6/n-3 fatty acid ratio because they cannot convert n-6 PUFAs to n-3 PUFAs due to lack of an n-3 desaturase found in C. elegans. Materials and Methods: Adenoviral strategies were used to introduce the C. elegans fat-1 gene encoding an n-3 fatty acid desaturase into human breast cancer cells followed by examination of the n-6/n-3 fatty acid ratio and growth of the cells. Results: Infection of MCF-7 cells with an adenovirus carrying the fat-1 gene resulted in a high expression of the n-3 fatty acid desaturase. Lipid analysis indicated a remarkable increase in the levels of n-3 PUFAs accompanied with a large decrease in the contents of n-6 PUFAs, leading to a change of the n-6/n-3 ratio from 12.0 to 0.8. Accordingly, production of the eicosanoids derived from n-6 PUFA was reduced significantly in cells expressing the fat-1 gene. Importantly, the gene transfer induced mass cell death and inhibited cell proliferation. Conclusion: The gene transfer of the n-3 fatty acid desaturase, as a novel approach, can effectively modify the n-6/n-3 fatty acid ratio of human tumor cells and provide an anticancer effect, without the need of exogenous n-3 PUFA supplementation. These data also increase the understanding of the effects of n-3 fatty acids and the n-6/n-3 ratio on cancer prevention and treatment.

Denham JE et al. (2018) Philos Trans R Soc Lond B Biol Sci "Signatures of proprioceptive control in Caenorhabditis elegans locomotion."

Cohen N, Denham JE, Ranner T

[Philos Trans R Soc Lond B Biol Sci, 2018]

Animal neuromechanics describes the coordinated self-propelled movement of a body, subject to the combined effects of internal neural control and mechanical forces. Here we use a computational model to identify effects of neural and mechanical modulation on undulatory forward locomotion of <i>Caenorhabditis elegans</i>, with a focus on proprioceptively driven neural control. We reveal a fundamental relationship between body elasticity and environmental drag in determining the dynamics of the body and demonstrate the manifestation of this relationship in the context of proprioceptively driven control. By considering characteristics unique to proprioceptive neurons, we predict the signatures of internal gait modulation that contrast with the known signatures of externally or biomechanically modulated gait. We further show that proprioceptive feedback can suppress neuromechanical phase lags during undulatory locomotion, contrasting with well studied advancing phase lags that have long been a signature of centrally generated, feed-forward control.This article is part of a discussion meeting issue 'Connectome to behaviour: modelling <i>C. elegans</i> at cellular resolution'.