Intricate response dynamics enhances stimulus discrimination in the resource-limited C. elegans chemosensory system.

BACKGROUND: Sensory systems evolved intricate designs to accurately encode perplexing environments. However, this encoding task may become particularly challenging for animals harboring a small number of sensory neurons. Here, we studied how the compact resource-limited chemosensory system of Caenorhabditis elegans uniquely encodes a range of chemical stimuli. RESULTS: We find that each stimulus is encoded using a small and unique subset of neurons, where only a portion of the encoding neurons sense the stimulus directly, and the rest are recruited via inter-neuronal communication. Furthermore, while most neurons show stereotypical response dynamics, some neurons exhibit versatile dynamics that are either stimulus specific or network-activity dependent. Notably, it is the collective dynamics of all responding neurons which provides valuable information that ultimately enhances stimulus identification, particularly when required to discriminate between closely related stimuli. CONCLUSIONS: Together, these findings demonstrate how a compact and resource-limited chemosensory system can efficiently encode and discriminate a diverse range of chemical stimuli.

Inheritance of associative memories and acquired cellular changes in C. elegans.

Experiences have been shown to modulate behavior and physiology of future generations in some contexts, but there is limited evidence for inheritance of associative memory in different species. Here, we trained C. elegans nematodes to associate an attractive odorant with stressful starvation conditions and revealed that this associative memory was transmitted to the F1 progeny who showed odor-evoked avoidance behavior. Moreover, the F1 and the F2 descendants of trained animals exhibited odor-evoked cellular stress responses, manifested by the translocation of DAF-16/FOXO to cells' nuclei. Sperm, but not oocytes, transmitted these odor-evoked cellular stress responses which involved H3K9 and H3K36 methylations, the small RNA pathway machinery, and intact neuropeptide secretion. Activation of a single chemosensory neuron sufficed to induce a serotonin-mediated systemic stress response in both the parental trained generation and in its progeny. Moreover, inheritance of the cellular stress responses increased survival chances of the progeny as exposure to the training odorant allowed the animals to prepare in advance for an impending adversity. These findings suggest that in C. elegans associative memories and cellular changes may be transferred across generations.

Principles for coding associative memories in a compact neural network.

A major goal in neuroscience is to elucidate the principles by which memories are stored in a neural network. Here, we have systematically studied how four types of associative memories (short- and long-term memories, each as positive and negative associations) are encoded within the compact neural network of Caenorhabditis elegans worms. Interestingly, sensory neurons were primarily involved in coding short-term, but not long-term, memories, and individual sensory neurons could be assigned to coding either the conditioned stimulus or the experience valence (or both). Moreover, when considering the collective activity of the sensory neurons, the specific training experiences could be decoded. Interneurons integrated the modulated sensory inputs and a simple linear combination model identified the experience-specific modulated communication routes. The widely distributed memory suggests that integrated network plasticity, rather than changes to individual neurons, underlies the fine behavioral plasticity. This comprehensive study reveals basic memory-coding principles and highlights the central roles of sensory neurons in memory formation.

A negative feedback loop in the GPCR pathway underlies efficient coding of external stimuli.

Efficient navigation based on chemical cues is an essential feature shared by all animals. These cues may be encountered in complex spatiotemporal patterns and with orders of magnitude varying intensities. Nevertheless, sensory neurons accurately extract the relevant information from such perplexing signals. Here, we show how a single sensory neuron in Caenorhabditis elegans animals can cell-autonomously encode complex stimulus patterns composed of instantaneous sharp changes and of slowly changing continuous gradients. This encoding relies on a simple negative feedback in the G-protein-coupled receptor (GPCR) signaling pathway in which TAX-6/Calcineurin plays a key role in mediating the feedback inhibition. This negative feedback supports several important coding features that underlie an efficient navigation strategy, including exact adaptation and adaptation to the magnitude of the gradient's first derivative. A simple mathematical model explains the fine neural dynamics of both wild-type and tax-6 mutant animals, further highlighting how the calcium-dependent activity of TAX-6/Calcineurin dictates GPCR inhibition and response dynamics. As GPCRs are ubiquitously expressed in all sensory neurons, this mechanism may be a general solution for efficient cell-autonomous coding of external stimuli.

Dopamine-dependent biphasic behaviour under 'deep diving' conditions in Caenorhabditis elegans.

Underwater divers are susceptible to neurological risks due to their exposure to increased pressure. Absorption of elevated partial pressure of inert gases such as helium and nitrogen may lead to nitrogen narcosis. Although the symptoms of nitrogen narcosis are known, the molecular mechanisms underlying these symptoms have not been elucidated. Here, we examined the behaviour of the soil nematode Caenorhabditis elegans under scuba diving conditions. We analysed wild-type animals and mutants in the dopamine pathway under hyperbaric conditions, using several gas compositions and under varying pressure levels. We found that the animals changed their speed on a flat bacterial surface in response to pressure in a biphasic mode that depended on dopamine. Dopamine-deficient cat-2 mutant animals did not exhibit a biphasic response in high pressure, while the extracellular accumulation of dopamine in dat-1 mutant animals mildly influenced this response. Our data demonstrate that in C. elegans, similarly to mammalian systems, dopamine signalling is involved in the response to high pressure. This study establishes C. elegans as a powerful system to elucidate the molecular mechanisms that underly nitrogen toxicity in response to high pressure.

Systematic analysis of long intergenic non-coding RNAs in C. elegans germline uncovers roles in somatic growth.

Long intergenic non-coding RNAs (lincRNAs) are transcripts longer than 200 nucleotides that are transcribed from non-coding loci yet undergo biosynthesis similar to coding mRNAs. The disproportional number of lincRNAs expressed in testes suggests that lincRNAs are important during gametogenesis, but experimental evidence has implicated very few lincRNAs in this process. We took advantage of the relatively limited number of lincRNAs in the genome of the nematode Caenorhabditis elegans to systematically analyse the functions of lincRNAs during meiosis. We deleted six lincRNA genes that are highly and dynamically expressed in the C. elegans gonad and tested the effects on central meiotic processes. Surprisingly, whereas the lincRNA deletions did not strongly impact fertility, germline apoptosis, crossovers, or synapsis, linc-4 was required for somatic growth. Slower growth was observed in linc-4-deletion mutants and in worms depleted of linc-4 using RNAi, indicating that linc-4 transcripts are required for this post-embryonic process. Unexpectedly, analysis of worms depleted of linc-4 in soma versus germline showed that the somatic role stems from linc-4 expression in germline cells. This unique feature suggests that some lincRNAs, like some small non-coding RNAs, are required for germ-soma interactions.

Author Correction: Concerted pulsatile and graded neural dynamics enables efficient chemotaxis in C. elegans.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Addendum: Irrational behavior in C. elegans arises from asymmetric modulatory effects within single sensory neurons.

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.

Irrational behavior in C. elegans arises from asymmetric modulatory effects within single sensory neurons.

C. elegans worms exhibit a natural chemotaxis towards food cues. This provides a potential platform to study the interactions between stimulus valence and innate behavioral preferences. Here we perform a comprehensive set of choice assays to measure worms' relative preference towards various attractants. Surprisingly, we find that when facing a combination of choices, worms' preferences do not always follow value-based hierarchy. In fact, the innate chemotaxis behavior in worms robustly violates key rationality paradigms of transitivity, independence of irrelevant alternatives and regularity. These violations arise due to asymmetric modulatory effects between the presented options. Functional analysis of the entire chemosensory system at a single-neuron resolution, coupled with analyses of mutants, defective in individual neurons, reveals that these asymmetric effects originate in specific sensory neurons.

Concerted pulsatile and graded neural dynamics enables efficient chemotaxis in C. elegans.

The ability of animals to effectively locate and navigate toward food sources is central for survival. Here, using C. elegans nematodes, we reveal the neural mechanism underlying efficient navigation in chemical gradients. This mechanism relies on the activity of two types of chemosensory neurons: one (AWA) coding gradients via stochastic pulsatile dynamics, and the second (AWCON) coding the gradients deterministically in a graded manner. The pulsatile dynamics of the AWA neuron adapts to the magnitude of the gradient derivative, allowing animals to take trajectories better oriented toward the target. The robust response of AWCON to negative derivatives promotes immediate turns, thus alleviating the costs incurred by erroneous turns dictated by the AWA neuron. This mechanism empowers an efficient navigation strategy that outperforms the classical biased-random walk strategy. This general mechanism thus may be applicable to other sensory modalities for efficient gradient-based navigation.

Salient experiences are represented by unique transcriptional signatures in the mouse brain.

It is well established that inducible transcription is essential for the consolidation of salient experiences into long-term memory. However, whether inducible transcription relays information about the identity and affective attributes of the experience being encoded, has not been explored. To this end, we analyzed transcription induced by a variety of rewarding and aversive experiences, across multiple brain regions. Our results describe the existence of robust transcriptional signatures uniquely representing distinct experiences, enabling near-perfect decoding of recent experiences. Furthermore, experiences with shared attributes display commonalities in their transcriptional signatures, exemplified in the representation of valence, habituation and reinforcement. This study introduces the concept of a neural transcriptional code, which represents the encoding of experiences in the mouse brain. This code is comprised of distinct transcriptional signatures that correlate to attributes of the experiences that are being committed to long-term memory.

A multi-animal tracker for studying complex behaviors.

BACKGROUND: Animals exhibit astonishingly complex behaviors. Studying the subtle features of these behaviors requires quantitative, high-throughput, and accurate systems that can cope with the often rich perplexing data. RESULTS: Here, we present a Multi-Animal Tracker (MAT) that provides a user-friendly, end-to-end solution for imaging, tracking, and analyzing complex behaviors of multiple animals simultaneously. At the core of the tracker is a machine learning algorithm that provides immense flexibility to image various animals (e.g., worms, flies, zebrafish, etc.) under different experimental setups and conditions. Focusing on C. elegans worms, we demonstrate the vast advantages of using this MAT in studying complex behaviors. Beginning with chemotaxis, we show that approximately 100 animals can be tracked simultaneously, providing rich behavioral data. Interestingly, we reveal that worms' directional changes are biased, rather than random - a strategy that significantly enhances chemotaxis performance. Next, we show that worms can integrate environmental information and that directional changes mediate the enhanced chemotaxis towards richer environments. Finally, offering high-throughput and accurate tracking, we show that the system is highly suitable for longitudinal studies of aging- and proteotoxicity-associated locomotion deficits, enabling large-scale drug and genetic screens. CONCLUSIONS: Together, our tracker provides a powerful and simple system to study complex behaviors in a quantitative, high-throughput, and accurate manner.

The C. elegans Connectome Consists of Homogenous Circuits with Defined Functional Roles.

A major goal of systems neuroscience is to decipher the structure-function relationship in neural networks. Here we study network functionality in light of the common-neighbor-rule (CNR) in which a pair of neurons is more likely to be connected the more common neighbors it shares. Focusing on the fully-mapped neural network of C. elegans worms, we establish that the CNR is an emerging property in this connectome. Moreover, sets of common neighbors form homogenous structures that appear in defined layers of the network. Simulations of signal propagation reveal their potential functional roles: signal amplification and short-term memory at the sensory/inter-neuron layer, and synchronized activity at the motoneuron layer supporting coordinated movement. A coarse-grained view of the neural network based on homogenous connected sets alone reveals a simple modular network architecture that is intuitive to understand. These findings provide a novel framework for analyzing larger, more complex, connectomes once these become available.