Neuronal control of locomotion in C. elegans is modified by a dominant mutation in the GLR-1 ionotropic glutamate receptor

How simple neuronal circuits control behavior is not well understood at the molecular or genetic level. In Caenorhabditis elegans, foraging behavior consists of long, forward movements interrupted by brief reversals. To determine how this pattern is generated and regulated, we have developed novel perturbation techniques that allow us to depolarize selected neurons in vivo using the dominant glutamate receptor mutation identified in the Lurcher mouse. Transgenic worms that expressed a mutated C. elegans glutamate receptor in interneurons that control locomotion displayed a remarkable and unexpected change in their behavior-they rapidly alternated between forward and backward coordinated movement. Our findings suggest that the gating of movement reversals is controlled in a partially distributed fashion by a small subset of interneurons and that this gating is modified by sensory input.     

Motion processing streams in Drosophila are behaviorally specialized

Motion vision is an ancient faculty, critical to many animals in a range of ethological contexts, the underlying algorithms of which provide central insights into neural computation. However, how motion cues guide behavior is poorly understood, as the neural circuits that implement these computations are largely unknown in any organism. We develop a systematic, forward genetic approach using high-throughput, quantitative behavioral analyses to identify the neural substrates of motion vision in Drosophila in an unbiased fashion. We then delimit the behavioral contributions of both known and novel circuit elements. Contrary to expectation from previous studies, we find that orienting responses to motion are shaped by at least two neural pathways. These pathways are sensitive to different visual features, diverge immediately postsynaptic to photoreceptors, and are coupled to distinct behavioral outputs. Thus, behavioral responses to complex stimuli can rely on surprising neural specialization from even the earliest sensory processing stages.     

Persistent thermal input controls steering behavior in Caenorhabditis elegans

Motile organisms actively detect environmental signals and migrate to a preferable environment. Especially, small animals convert subtle spatial difference in sensory input into orientation behavioral output for directly steering toward a destination, but the neural mechanisms underlying steering behavior remain elusive. Here, we analyze a C. elegans thermotactic behavior in which a small number of neurons are shown to mediate steering toward a destination temperature. We construct a neuroanatomical model and use an evolutionary algorithm to find configurations of the model that reproduce empirical thermotactic behavior. We find that, in all the evolved models, steering curvature are modulated by temporally persistent thermal signals sensed beyond the time scale of sinusoidal locomotion of C. elegans. Persistent rise in temperature decreases steering curvature resulting in straight movement of model worms, whereas fall in temperature increases curvature resulting in crooked movement. This relation between temperature change and steering curvature reproduces the empirical thermotactic migration up thermal gradients and steering bias toward higher temperature. Further, spectrum decomposition of neural activities in model worms show that thermal signals are transmitted from a sensory neuron to motor neurons on the longer time scale than sinusoidal locomotion of C. elegans. Our results suggest that employments of temporally persistent sensory signals enable small animals to steer toward a destination in natural environment with variable, noisy, and subtle cues.     

理解运动行为抑制调控的新视角：乙酰胆碱门控氯离子通道受体

Acetylcholine, the first identified neurotransmitter, plays crucial roles in various brain functions. One well-known case is its involvement as an activating neurotransmitter in the regulation of locomotion. However, its inhibitory regulatory role, particularly in locomotion, remains poorly understood. In a study conducted by Polat et al., the authors investigated the inhibitory role of acetylcholine in locomotion in C. elegans. In this organism, the acetylcholine-gated chloride channel receptor consists of four subunits. The authors thoroughly examined the loss-of-function of each subunit in movement regulation. Interestingly, the mutant worms were still capable of performing various movements such as forward, backward crawling, and turning, suggesting that the overall movement was not significantly affected. However, quantitative behavior analysis revealed subtle yet significant differences in the timing and postures of the movement in these mutants. Furthermore, the authors employed optogenetics to stimulate a specific neuron involved in backward crawling and demonstrated that the loss-of-function of the receptors in individual neurons affects the transitioning between locomotion modes. This work provides evidence for the inhibitory regulatory role of acetylcholine in locomotion. The loss-of-function of acetylcholine-gated chloride channel receptors likely disrupts the balance of neuronal and circuit physiology, thereby affecting the regulation of locomotion. Moreover, this study highlights the powerful role of quantitative behavior analysis in discovering and understanding more sophisticated functions of neural circuits.     

An imbalancing act: gap junctions reduce the backward motor circuit activity to bias C. elegans for forward locomotion

A neural network can sustain and switch between different activity patterns to execute multiple behaviors. By monitoring the decision making for directional locomotion through motor circuit calcium imaging in?behaving Caenorhabditis elegans (C.?elegans), we reveal that C.?elegans determines the directionality of movements by establishing an imbalanced output between the forward and backward motor circuits and that it alters directions by switching between these imbalanced states. We further demonstrate that premotor interneurons modulate endogenous motoneuron activity to establish the output imbalance. Specifically, the UNC-7 and UNC-9 innexin-dependent premotor interneuron-motoneuron coupling prevents a balanced output state that leads to movements without directionality. Moreover, they act as shunts to decrease the backward-circuit activity, establishing a persistent bias for the high forward-circuit output state that results in the inherent preference of C.?elegans for forward locomotion. This study demonstrates that imbalanced motoneuron activity underlies directional movement and establishes gap junctions as critical modulators of the properties and outputs of neural circuits.     

The C. elegans Male Exercises Directional Control during Mating through Cholinergic Regulation of Sex-Shared Command Interneurons

Background

Mating behaviors in simple invertebrate model organisms represent tractable paradigms for understanding the neural bases of sex-specific behaviors, decision-making and sensorimotor integration. However, there are few examples where such neural circuits have been defined at high resolution or interrogated.

Methodology/Principal Findings

Here we exploit the simplicity of the nematode Caenorhabditis elegans to define the neural circuits underlying the male’s decision to initiate mating in response to contact with a mate. Mate contact is sensed by male-specific sensilla of the tail, the rays, which subsequently induce and guide a contact-based search of the hermaphrodite’s surface for the vulva (the vulva search). Atypically, search locomotion has a backward directional bias so its implementation requires overcoming an intrinsic bias for forward movement, set by activity of the sex-shared locomotory system. Using optogenetics, cell-specific ablation- and mutant behavioral analyses, we show that the male makes this shift by manipulating the activity of command cells within this sex-shared locomotory system. The rays control the command interneurons through the male-specific, decision-making interneuron PVY and its auxiliary cell PVX. Unlike many sex-shared pathways, PVY/PVX regulate the command cells via cholinergic, rather than glutamatergic transmission, a feature that likely contributes to response specificity and coordinates directional movement with other cholinergic-dependent motor behaviors of the mating sequence. PVY/PVX preferentially activate the backward, and not forward, command cells because of a bias in synaptic inputs and the distribution of key cholinergic receptors (encoded by the genes acr-18, acr-16 and unc-29) in favor of the backward command cells.

Conclusion/Significance

Our interrogation of male neural circuits reveals that a sex-specific response to the opposite sex is conferred by a male-specific pathway that renders subordinate, sex-shared motor programs responsive to mate cues. Circuit modifications of these types may make prominent contributions to natural variations in behavior that ultimately bring about speciation.     

Central pattern generating networks in insect locomotion

Central pattern generators (CPGs) are neural circuits that based on their connectivity can generate rhythmic and patterned output in the absence of rhythmic external inputs. This property makes CPGs crucial elements in the generation of many kinds of rhythmic motor behaviors in insects, such as flying, walking, swimming, or crawling. Arguably representing the most diverse group of animals, insects utilize at least one of these types of locomotion during one stage of their ontogenesis. Insects have been extensively used to study the neural basis of rhythmic motor behaviors, and particularly the structure and operation of CPGs involved in locomotion. Here, we review insect locomotion with regard to flying, walking, and crawling, and we discuss the contribution of central pattern generation to these three forms of locomotion. In each case, we compare and contrast the topology and structure of the CPGs, and we point out how these factors are involved in the generation of the respective motor pattern. We focus on the importance of sensory information for establishing a functional motor output and we indicate behavior‐specific adaptations. Furthermore, we report on the mechanisms underlying coordination between different body parts. Last but not least, by reviewing the state‐of‐the‐art knowledge concerning the role of CPGs in insect locomotion, we endeavor to create a common ground, upon which future research in the field of motor control in insects can build.     

Flexible navigational computations in the Drosophila central complex

Insects can perform impressive feats of navigation, suggesting a sophisticated sense of direction and an ability to choose appropriate trajectories toward ethological goals. The hypothesized substrate for these navigational abilities is the central complex (CX), a midline brain structure with orderly topology. The circuit transformations performed by the CX are now being concretely described by recent advances in the study of fruit fly neural circuits. An emerging theme is dynamic representation of navigational variables (e.g. heading or travel direction) computed in a manner distributed across specific neuronal populations. These representations are shaped by multimodal inputs whose weights evolve rapidly as surroundings change. Investigation of CX circuits is revealing with precise detail how structured wiring and synaptic plasticity enable neural circuits to flexibly subsample from the currently available sensory and motor cues to build a stable and accurate map of space. Given the sensory richness of natural environments, these findings are encouraging insect neuroscientists to no longer ask which cues insects use to navigate, but instead which cues can insects use, and under which contexts.     

Alternative forms of axial startle behaviors in fishes

For most aquatic vertebrates, axial movements play key roles in the performance of startle responses. In fishes, these axis-based startle behaviors fall into three distinct categories – the C-start, withdrawal, and S-start – defined by patterns of body bending and underlying motor control. Startle behaviors have been widely studied due to their importance for predator evasion. In addition, the neural circuits that control startles are relatively accessible, compared to other vertebrate circuits, and have provided opportunities to understand basic nervous system function. The C-start neural circuit has long been a model in systems neuroscience and considerable work on neural control of withdrawal response has been conducted in the larval lamprey. The S-start response has only recently been explored from a physiological perspective and we focus here on reviewing S-start motor control and movement in the context of the other two responses. Axial elongation has previously been associated with startle behavior in comparisons of C-starts and withdrawal, with extremely elongate animals performing withdrawals. We suggest that the S-start tends to occur with moderate body elongation, complementing the C-start in animals with this body form. As many larval fishes are moderately elongate, we suggest that the S-start may be common in larvae but may be secondarily lost with body shape change through development.     

Motoring ahead with rodents

How neural circuits underlie the acquisition and control of learned motor behaviors has traditionally been explored in monkeys and, more recently, songbirds. The development of genetic tools for functional circuit analysis in rodents, the availability of transgenic animals with well characterized phenotypes, and the relative ease with which rats and mice can be trained to perform various motor tasks, make rodents attractive models for exploring the neural circuit mechanisms underlying the acquisition and production of learned motor skills. Here we discuss the advantages and drawbacks of this approach, review recent trends and results, and outline possible strategies for wider adoption of rodents as a model system for complex motor learning.     

A Lightweight,Headphones-based System for Manipulating Auditory Feedback in Songbirds

Experimental manipulations of sensory feedback during complex behavior have provided valuable insights into the computations underlying motor control and sensorimotor plasticity¹. Consistent sensory perturbations result in compensatory changes in motor output, reflecting changes in feedforward motor control that reduce the experienced feedback error. By quantifying how different sensory feedback errors affect human behavior, prior studies have explored how visual signals are used to recalibrate arm movements^2,3 and auditory feedback is used to modify speech production^4-7. The strength of this approach rests on the ability to mimic naturalistic errors in behavior, allowing the experimenter to observe how experienced errors in production are used to recalibrate motor output.Songbirds provide an excellent animal model for investigating the neural basis of sensorimotor control and plasticity^8,9. The songbird brain provides a well-defined circuit in which the areas necessary for song learning are spatially separated from those required for song production, and neural recording and lesion studies have made significant advances in understanding how different brain areas contribute to vocal behavior^9-12. However, the lack of a naturalistic error-correction paradigm - in which a known acoustic parameter is perturbed by the experimenter and then corrected by the songbird - has made it difficult to understand the computations underlying vocal learning or how different elements of the neural circuit contribute to the correction of vocal errors¹³.The technique described here gives the experimenter precise control over auditory feedback errors in singing birds, allowing the introduction of arbitrary sensory errors that can be used to drive vocal learning. Online sound-processing equipment is used to introduce a known perturbation to the acoustics of song, and a miniaturized headphones apparatus is used to replace a songbird''s natural auditory feedback with the perturbed signal in real time. We have used this paradigm to perturb the fundamental frequency (pitch) of auditory feedback in adult songbirds, providing the first demonstration that adult birds maintain vocal performance using error correction¹⁴. The present protocol can be used to implement a wide range of sensory feedback perturbations (including but not limited to pitch shifts) to investigate the computational and neurophysiological basis of vocal learning.     

Neurogenetics and the "fly-stampede": dissecting neural circuits involved in visual behaviors

A central goal of systems neuroscience is to understand how neural circuits represent quantitative aspects of the outside world and transform these signals into the motor code for behavior. By contrast to olfactory perception in which odors are encoded by a population of ligand-binding receptors at the input stage, the visual system extracts complex information about color, form and movement from just a few types of photoreceptor inputs. The algorithms for many of these transformations are poorly understood. We designed a high throughput real-time quantitative testing system, the "fly-stampede", to evaluate behavioral responses to light and motion cues in Drosophila. With this system, we identified a neural circuit that does not participate in sensing light but is crucial for computing visual motion. When neurons of this circuit are genetically inactivated, the flies show normal walking phototaxis, but are completely motion blind. Using neurogenetics to study the circuits mediating sophisticated animal behaviors is currently a field of intense study. This extra view attempts to summarize our work within historical background of fly biocybernetics and other recent advances.     

Monoaminergic Orchestration of Motor Programs in a Complex C. elegans Behavior

Monoamines provide chemical codes of behavioral states. However, the neural mechanisms of monoaminergic orchestration of behavior are poorly understood. Touch elicits an escape response in Caenorhabditis elegans where the animal moves backward and turns to change its direction of locomotion. We show that the tyramine receptor SER-2 acts through a Gα_o pathway to inhibit neurotransmitter release from GABAergic motor neurons that synapse onto ventral body wall muscles. Extrasynaptic activation of SER-2 facilitates ventral body wall muscle contraction, contributing to the tight ventral turn that allows the animal to navigate away from a threatening stimulus. Tyramine temporally coordinates the different phases of the escape response through the synaptic activation of the fast-acting ionotropic receptor, LGC-55, and extrasynaptic activation of the slow-acting metabotropic receptor, SER-2. Our studies show, at the level of single cells, how a sensory input recruits the action of a monoamine to change neural circuit properties and orchestrate a compound motor sequence.     

Sensorimotor integration: locating locomotion in neural circuits

Neural components of the circuits that transform sensory cues into changes in motor activities are largely unknown. Several recent studies have now functionally mapped the sensorimotor circuits responsible for locomotion behaviors under defined environmental conditions in the nematode Caenorhabditis elegans.     

Optical silencing of C. elegans cells with arch proton pump

BACKGROUND: Optogenetic techniques using light-driven ion channels or ion pumps for controlling excitable cells have greatly facilitated the investigation of nervous systems in vivo. A model organism, C. elegans, with its small transparent body and well-characterized neural circuits, is especially suitable for optogenetic analyses. METHODOLOGY/PRINCIPAL FINDINGS: We describe the application of archaerhodopsin-3 (Arch), a recently reported optical neuronal silencer, to C. elegans. Arch::GFP expressed either in all neurons or body wall muscles of the entire body by means of transgenes were localized, at least partially, to the cell membrane without adverse effects, and caused locomotory paralysis of worms when illuminated by green light (550 nm). Pan-neuronal expression of Arch endowed worms with quick and sustained responsiveness to such light. Worms reliably responded to repeated periods of illumination and non-illumination, and remained paralyzed under continuous illumination for 30 seconds. Worms expressing Arch in different subsets of motor neurons exhibited distinct defects in the locomotory behavior under green light: selective silencing of A-type motor neurons affected backward movement while silencing of B-type motor neurons affected forward movement more severely. Our experiments using a heat-shock-mediated induction system also indicate that Arch becomes fully functional only 12 hours after induction and remains functional for more than 24 hour. CONCLUSIONS/SGNIFICANCE: Arch can be used for silencing neurons and muscles, and may be a useful alternative to currently widely used halorhodopsin (NpHR) in optogenetic studies of C. elegans.     

Olfactory networks: from sensation to perception

Olfactory networks, comprised of sensory neurons and interneurons, detect and process changes in the chemical environment to drive animal behavior. Recent studies combining genetics with behavioral analyses and imaging in worms, flies and mice have revealed new insights into the mechanisms of olfaction. In this discussion, we focus on three interesting findings. First, sensory neuron responses to odor are modulated by neuropeptides. This modulation might serve to extend the range of responses of the sensory neurons and also to integrate internal state information into the chemosensory circuit. Second, genetic tracing studies in mice and flies have shown that the first layer of connections in chemosensory circuits from olfactory epithelium to the glomeruli are stereotyped, while the subsequent connections to higher order sensory processing regions are not. Distributed connectivity to the higher order sensory processing regions has profound implications for how odors are represented in those regions. Third, recent work has revealed that odors are surprisingly sparsely represented in the piriform cortex. The sparse coding in the higher brain centers implies a much greater role for experience and learning in mediating responses to olfactory cues. Analyzing olfactory network function in various species provides us with fascinating clues about how sensory information is acquired, processed and represented at multiple levels within the nervous system.