Portal de Periódicos da CAPES

Sensorimotor Integration for Decision Making: How the Worm Steers

2018; Cell Press; Volume: 97; Issue: 2 Linguagem: Inglês

10.1016/j.neuron.2017.12.042

1097-4199

Harris S. Kaplan, Manuel Zimmer,

Circadian rhythm and melatonin

Animals' movements actively shape their perception and subsequent decision making. In this issue of Neuron, Liu et al., 2018Liu H. Yang W. Wu T. Duan F. Soucy E. Jin X. Zhang Y. Cholinergic sensorimotor integration regulates olfactory steering.Neuron. 2018; 97 (this issue): 390-405Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar show how C. elegans nematodes steer toward an odorant: a dedicated interneuron class integrates oscillatory olfactory signals, generated by head swings, with corollary discharge motor signals. Animals' movements actively shape their perception and subsequent decision making. In this issue of Neuron, Liu et al., 2018Liu H. Yang W. Wu T. Duan F. Soucy E. Jin X. Zhang Y. Cholinergic sensorimotor integration regulates olfactory steering.Neuron. 2018; 97 (this issue): 390-405Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar show how C. elegans nematodes steer toward an odorant: a dedicated interneuron class integrates oscillatory olfactory signals, generated by head swings, with corollary discharge motor signals. Our sensory systems are in continuous interaction with the environment and are directly shaped by our own movements. Decision making crucially relies on the proper integration of both sensory inputs themselves and the state (e.g., position, velocity) of neuronal sensors receiving those inputs. For example, if you smell something burning, you might turn your head left and right to determine whether the smell is coming from the kitchen or the fireplace. Whether or not you subsequently turn off the oven and prevent disaster depends on your ability to simultaneously measure the strength of the odor and the direction your head is turned and to use those measurements to decide your next move. How two such measurements can be integrated to guide decision making is the subject of Liu et al., 2018Liu H. Yang W. Wu T. Duan F. Soucy E. Jin X. Zhang Y. Cholinergic sensorimotor integration regulates olfactory steering.Neuron. 2018; 97 (this issue): 390-405Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar's study. Liu et al., 2018Liu H. Yang W. Wu T. Duan F. Soucy E. Jin X. Zhang Y. Cholinergic sensorimotor integration regulates olfactory steering.Neuron. 2018; 97 (this issue): 390-405Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar take advantage of the numerically compact nervous system, genetic manipulations, and neural activity recording techniques available in C. elegans to trace both inputs, from sensory neurons and motor neurons, to convergence onto an interneuron class termed RIA. They show how RIA integrates both inputs to generate the appropriate output back onto the same motor neurons, which subsequently steer the worm toward an appetitive odor (Figure 1A). RIA neurons, like many other neurons in the worm, each possess a single unbranched neurite projecting into the nerve ring located in the animal's head (Figure 1B, bottom). The nerve ring encompasses most of the synaptic connections between sensory neurons, interneurons, and many motor neurons found in the worm brain. In previous work, Yun Zhang's lab showed that, despite its simple anatomy, the RIA neurite exhibits intriguing sub-cellular functional specializations. Three compartmentalized Ca2+ domains process different inputs and outputs: a loop domain receives input from sensory circuits and thus generates sensory-evoked calcium signals. Two domains further in the nerve ring, termed nrD (nerve ring Dorsal) and nrV (nerve ring Ventral), receive inputs from dorsal and ventral head motor neurons, respectively, and therefore show calcium transients associated with dorsal or ventral head bending (Hendricks et al., 2012Hendricks M. Ha H. Maffey N. Zhang Y. Compartmentalized calcium dynamics in a C. elegans interneuron encode head movement.Nature. 2012; 487: 99-103Crossref PubMed Scopus (102) Google Scholar). In the lab, worms are typically studied crawling on a two-dimensional agar surface; in this environment, the worm lies on its left or right side and bends its head and body between dorsal and ventral extremes, in a sinusoidal manner, to generate movement. An odor gradient across the agar surface could therefore be perceived by the worm's sensors as different odor concentrations during dorsal versus ventral head swings (Figure 1B, top), unless the worm is headed directly toward or away from the odor source. These inputs potentially could lead to a navigational behavior by changing the head-swing bias, enabling the worm to consistently steer toward the side where the attractive odor concentration is increasing. Work from other groups has shown that worms indeed use such a navigation strategy, in addition to other strategies, when performing chemotaxis in sensory gradient landscapes (Iino and Yoshida, 2009Iino Y. Yoshida K. Parallel use of two behavioral mechanisms for chemotaxis in Caenorhabditis elegans.J. Neurosci. 2009; 29: 5370-5380Crossref PubMed Scopus (164) Google Scholar). It's worth noting that this type of strategy is used by many animals, including humans, in odor localization tasks (Porter et al., 2007Porter J. Craven B. Khan R.M. Chang S.-J. Kang I. Judkewitz B. Volpe J. Settles G. Sobel N. Mechanisms of scent-tracking in humans.Nat. Neurosci. 2007; 10: 27-29Crossref PubMed Scopus (233) Google Scholar). Liu et al., 2018Liu H. Yang W. Wu T. Duan F. Soucy E. Jin X. Zhang Y. Cholinergic sensorimotor integration regulates olfactory steering.Neuron. 2018; 97 (this issue): 390-405Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar set out to test a tantalizingly simple mechanism by which the worm's nervous system might achieve this goal: the RIA loop domain receives sensory inputs that modulate the calcium changes evoked by motor neuron inputs to nrD and nrV; head bends sampling different odor concentrations would therefore cause asymmetric nrD and nrV activities, which would feed back onto the same motor neurons to bias the worm's head bends toward the appetitive odor. Hendricks et al., 2012Hendricks M. Ha H. Maffey N. Zhang Y. Compartmentalized calcium dynamics in a C. elegans interneuron encode head movement.Nature. 2012; 487: 99-103Crossref PubMed Scopus (102) Google Scholar showed that sensory inputs indeed modulate nrD and nrV dynamics and that these motor-related dynamics serve to reduce head bending. Still, a confirmation of the steering mechanism awaited an exploration of RIA dynamics during gradient navigation. First, Liu et al., 2018Liu H. Yang W. Wu T. Duan F. Soucy E. Jin X. Zhang Y. Cholinergic sensorimotor integration regulates olfactory steering.Neuron. 2018; 97 (this issue): 390-405Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar confirmed that RIA aids in navigation toward the appetitive odor isoamyl alcohol (IAA): specific RIA expression of tetanus toxin, which prevents synaptic vesicle release, lowered the efficiency with which worms reached the odor source. Next, Liu et al., 2018Liu H. Yang W. Wu T. Duan F. Soucy E. Jin X. Zhang Y. Cholinergic sensorimotor integration regulates olfactory steering.Neuron. 2018; 97 (this issue): 390-405Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar used a setup in which worms are constrained in a microfluidic device, free to move their heads, but not their bodies. This device allows controlled delivery of IAA during imaging of both head-swing behavior and RIA calcium dynamics. A 0.5-Hz on-off oscillation of IAA revealed clear, separable representations of both motor and sensory dynamics in nrD and nrV: nrD showed higher activity levels during dorsal bends and nrV during ventral bends, while both domains showed synchronous activity changes correlated with the 0.5-Hz odor pulses. This setup elegantly enabled dissection of the independent motor and sensory inputs to RIA. As previously shown, the muscarinic acetylcholine receptor GAR-3 is required for the motor inputs to RIA; gar-3 mutants lacked RIA head-bend correlations but retained the 0.5-Hz IAA responses that are synchronous across nrD and nrV. On the sensory side, tetanus toxin expression in the IAA-responsive sensory neuron AWC (Figure 1B, top) led to a loss of sensory-evoked RIA responses, while head-bend-correlated activities were spared. AWC signals to RIA via AIY, an interneuron that also showed activity changes locked to 0.5-Hz IAA pulses (Figure 1B, middle). Tetanus toxin expression in AIY also specifically prevented RIA sensory responses. Because AIY gives cholinergic input to RIA, and because IAA-on periods inhibited RIA, Liu et al., 2018Liu H. Yang W. Wu T. Duan F. Soucy E. Jin X. Zhang Y. Cholinergic sensorimotor integration regulates olfactory steering.Neuron. 2018; 97 (this issue): 390-405Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar examined animals with a deletion mutation in the acetylcholine-gated chloride channel gene acc-2, previously shown to be expressed in RIA. acc-2 mutants lacked sensory-related synchronous changes across nrD and nrV but retained head-swing-related signals. These results established the pathways to RIA from both sensory and motor inputs and laid the groundwork for examining RIA activity in freely moving animals. To pin down the steering mechanism, Liu et al., 2018Liu H. Yang W. Wu T. Duan F. Soucy E. Jin X. Zhang Y. Cholinergic sensorimotor integration regulates olfactory steering.Neuron. 2018; 97 (this issue): 390-405Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar next examined RIA calcium dynamics in freely moving worms. They found that RIA nrD and nrV domains behaved as in the restrained condition: nrD was active during dorsal head bends, nrV during ventral head bends, and both nrD and nrV showed reduced calcium levels in the presence of IAA. Imaging in gar-3 and acc-2 mutants also recapitulated the results seen in restrained worms. To determine how RIA activity looks during steering, Liu et al., 2018Liu H. Yang W. Wu T. Duan F. Soucy E. Jin X. Zhang Y. Cholinergic sensorimotor integration regulates olfactory steering.Neuron. 2018; 97 (this issue): 390-405Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar examined the data separately for worms steering only ventrally, with IAA on their ventral side, compared to worms steering only dorsally, with IAA on their dorsal side. This showed the expected sensorimotor integration: worms steering ventrally toward IAA on their ventral side showed weaker nrV activity than nrD activity, because higher IAA concentration (and therefore stronger RIA inhibition) was experienced when the worm's head was bent ventrally rather than dorsally. The inverse was seen for animals steering dorsally toward IAA. This asymmetric inhibition is lost in acc-2 mutants, strongly suggesting that it results from inhibitory input from AIY to RIA. Does the asymmetry of the compartmentalized RIA activity lead to steering? To address this, Liu et al., 2018Liu H. Yang W. Wu T. Duan F. Soucy E. Jin X. Zhang Y. Cholinergic sensorimotor integration regulates olfactory steering.Neuron. 2018; 97 (this issue): 390-405Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar used mini-SOG fused to the vesicle-associated membrane protein synaptobrevin 2/VAMP-2; mini-SOG is a useful interrogation tool that generates reactive oxygen species upon illumination with blue light, disrupting the function of proteins in the vicinity. Remarkably, this enabled a reduction in synaptic output localized specifically to nrD or to nrV: focused illumination of nrD led to large dorsal head-bend biases, whereas illumination of nrV led to large ventral biases. Therefore, RIA synaptic output from nrD reduces dorsal head bending, and synaptic output from nrV reduces ventral head bending. This provides a clear mechanism for how RIA asymmetry leads to steering: when the odor source is located on the animal's dorsal side, nrD shows weaker signals than nrV, and therefore, RIA inhibits dorsal motor neurons to a lesser degree than ventral motor neurons, resulting in dorsal steering (Figure 1B); the inverse occurs when IAA is located on the animal's ventral side. Taken together with previous work (Chalasani et al., 2007Chalasani S.H. Chronis N. Tsunozaki M. Gray J.M. Ramot D. Goodman M.B. Bargmann C.I. Dissecting a circuit for olfactory behaviour in Caenorhabditis elegans.Nature. 2007; 450: 63-70Crossref PubMed Scopus (425) Google Scholar), this steering circuit sets another benchmark example in which sensory input can be traced down to the motor response through multiple layers of neurons. Notably, information flow seems to occur largely through inhibition. It remains to be shown how general this circuit motif is and what its computational advantages are. Hendricks et al., 2012Hendricks M. Ha H. Maffey N. Zhang Y. Compartmentalized calcium dynamics in a C. elegans interneuron encode head movement.Nature. 2012; 487: 99-103Crossref PubMed Scopus (102) Google Scholar and Liu et al., 2018Liu H. Yang W. Wu T. Duan F. Soucy E. Jin X. Zhang Y. Cholinergic sensorimotor integration regulates olfactory steering.Neuron. 2018; 97 (this issue): 390-405Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar discovered, in the simple nervous system of C. elegans, the implementation of what is termed corollary discharge (Crapse and Sommer, 2008Crapse T.B. Sommer M.A. Corollary discharge across the animal kingdom.Nat. Rev. Neurosci. 2008; 9: 587-600Crossref PubMed Scopus (419) Google Scholar). Corollary discharge is a motor command copy that is fed back to other brain areas so that animals can integrate their own movements when processing sensory information. The finding that worms employ a dedicated interneuron layer for this purpose, with additional sub-cellular specialization, points toward a high level of sophistication by which these animals navigate their environments. The work by the Zhang lab thus opens up an array of interesting future research opportunities aimed at uncovering fundamental computations performed by these neural circuits. A first step in this direction was the demonstration that RIA expresses a form of memory in worms: the learning of malaise derived from pathogenic bacteria turns an initially attractive chemotactic behavior into an aversive one. As Liu et al., 2018Liu H. Yang W. Wu T. Duan F. Soucy E. Jin X. Zhang Y. Cholinergic sensorimotor integration regulates olfactory steering.Neuron. 2018; 97 (this issue): 390-405Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar discuss, this memory is likely established in circuits upstream of RIA. Earlier studies by Yun Zhang and Cori Bargmann suggest AIY as a likely neuron where this memory could be formed (Zhang et al., 2005Zhang Y. Lu H. Bargmann C.I. Pathogenic bacteria induce aversive olfactory learning in Caenorhabditis elegans.Nature. 2005; 438: 179-184Crossref PubMed Scopus (527) Google Scholar). Such an interneuron-level segregation of long-term learning tasks from the sensorimotor integration task potentially enhances the functional repertoire of the neural circuit. Worm behavior likely did not evolve to simply navigate idealized linear gradients, like the ones conveniently used in laboratory settings. In their natural soil habitats, C. elegans worms must face rather complex temporally and spatially fluctuating multisensory environments. Notably, RIA is one of the most integrating interneurons in the worm brain, receiving input from many other sensory modalities, like other smells, nociception, carbon dioxide, and oxygen. It will be interesting to see how RIA processes such multisensory cues, all of which exclusively converge onto its loop domain. We find both how different sensory inputs are temporally separated by the animal's head swings and how this temporal pattern is preserved throughout all processing layers in the circuit particularly intriguing. It has been a long-standing hypothesis that nervous systems reduce their computational load by packaging streams of inflowing information into discrete temporal bouts (Luczak et al., 2015Luczak A. McNaughton B.L. Harris K.D. Packet-based communication in the cortex.Nat. Rev. Neurosci. 2015; 16: 745-755Crossref PubMed Scopus (112) Google Scholar). An intuitive example of how this could be achieved is the sniffing cycle in rodents. Here, periodic breathing, whisking, and consummatory behaviors like licking are phase locked to an overarching periodic pattern generator mechanism (Moore et al., 2013Moore J.D. Deschênes M. Furuta T. Huber D. Smear M.C. Demers M. Kleinfeld D. Hierarchy of orofacial rhythms revealed through whisking and breathing.Nature. 2013; 497: 205-210Crossref PubMed Scopus (191) Google Scholar), potentially binding cross-modal information into discrete "snapshots" for the purpose of their integration. Liu et al., 2018Liu H. Yang W. Wu T. Duan F. Soucy E. Jin X. Zhang Y. Cholinergic sensorimotor integration regulates olfactory steering.Neuron. 2018; 97 (this issue): 390-405Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar show that a lot is still to be learnt by studying the sub-cellular dynamics of individual neurons in C. elegans. It will also be of interest to see how these fast timescale oscillations feed into the longer timescale brain-wide network oscillations that generate entire action sequences (Kato et al., 2015Kato S. Kaplan H.S. Schrödel T. Skora S. Lindsay T.H. Yemini E. Lockery S. Zimmer M. Global brain dynamics embed the motor command sequence of Caenorhabditis elegans.Cell. 2015; 163: 656-669Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar). The coupling of rhythmic behaviors to perception, as in worms and rodents, could be an ancient mechanism from which other, more complex cognitive functions in higher animals could have evolved (Yuste et al., 2005Yuste R. MacLean J.N. Smith J. Lansner A. The cortex as a central pattern generator.Nat. Rev. Neurosci. 2005; 6: 477-483Crossref PubMed Scopus (231) Google Scholar, Luczak et al., 2015Luczak A. McNaughton B.L. Harris K.D. Packet-based communication in the cortex.Nat. Rev. Neurosci. 2015; 16: 745-755Crossref PubMed Scopus (112) Google Scholar), many of which also rely on neuronal oscillations. Liu et al., 2018Liu H. Yang W. Wu T. Duan F. Soucy E. Jin X. Zhang Y. Cholinergic sensorimotor integration regulates olfactory steering.Neuron. 2018; 97 (this issue): 390-405Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar thus highlight with their findings how a tractable small model organism can contribute to our understanding of general brain principles. Cholinergic Sensorimotor Integration Regulates Olfactory SteeringLiu et al.NeuronDecember 28, 2017In BriefLiu et al. show that during olfactory steering, two different cholinergic signals representing the motor state and the sensory response integrate in a C. elegans interneuron to decode the spatial information of the odorant and steer the locomotory trajectory. Full-Text PDF Open Archive