Worms get the munchies: the endocannabinoid AEA induces hedonic amplification in C. elegans by modulating the activity of the AWC chemosensory neuron.

The mammalian endocannabinoid system, comprised of the endocannabinoids AEA (N-arachidonoyl-ethanolamine) and 2-AG (2-Arachidonoylglycerol), their receptors, CB1 and CB2, and their metabolic enzymes, is believed to integrate internal energy state and external food cues to modulate feeding. For example, cannabinoids can increase preference for more palatable, calorically dense food: a response called hedonic amplification, colloquially known as "the munchies." In mammals, cannabinoids can increase sensitivity to odors and sweet tastes, which may underlie amplification. We use C. elegans, an omnivorous bacterivore, as a model in which to investigate the neurophysiology of hedonic amplification. We found that exposure to AEA increases the worms' preference for strongly preferred (more palatable) bacteria over weakly preferred (less palatable) bacteria, mimicking hedonic amplification in mammals. Furthermore, AEA acts bidirectionally, increasing consumption of strongly preferred bacteria while decreasing consumption of weakly preferred bacteria. We also found that deletion of the putative CB1 homolog, npr-19, eliminates hedonic amplification, which can be rescued by expression of wild type npr-19 or human CB1, establishing a humanized worm for cannabinoid signaling studies. Deletion of the olfactory neuron AWC, which directs chemotaxis to food, abolishes hedonic amplification. Consistent with this finding, calcium imaging revealed that AEA bidirectionally modulates AWC activity, increasing its responses to strongly preferred food and decreasing its response for weakly preferred food. In a GFP expression analysis, we found that npr-19 is expressed in approximately 21 neuron classes but, surprisingly, not in AWC. Although AEA's effect could be mediated by NPR-19-expressing neurons presynaptic to AWC, nearly complete elimination of fast synaptic transmission, via the mutation unc-13(e51), had no effect on modulation. Instead, it appears that AEA modulates AWC by activating one or more npr-19-expressing neurons that release a diffusible neuromodulator to which AWC is sensitive.

Computing Temporal Sequences Associated With Dynamic Patterns on the C. elegans Connectome

Understanding how the structural connectivity and spatial geometry of a network constrains the dynamics it is able to support is an active and open area of research. We simulated the plausible dynamics resulting from the known C. elegans connectome using a recent model and theoretical analysis that computes the dynamics of neurobiological networks by focusing on how local interactions among connected neurons give rise to the global dynamics in an emergent way. We studied the dynamics which resulted from stimulating a chemosensory neuron (ASEL) in a known feeding circuit, both in isolation and embedded in the full connectome. We show that contralateral motorneuron activations in ventral (VB) and dorsal (DB) classes of motorneurons emerged from the simulations, which are qualitatively similar to rhythmic motorneuron firing pattern associated with locomotion of the worm. One interpretation of these results is that there is an inherent—and we propose—purposeful structural wiring to the C. elegans connectome that has evolved to serve specific behavioral functions. To study network signaling pathways responsible for the dynamics we developed an analytic framework that constructs Temporal Sequences (TSeq), time-ordered walks of signals on graphs. We found that only 5% of TSeq are preserved between the isolated feeding network relative to its embedded counterpart. The remaining 95% of signaling pathways computed in the isolated network are not present in the embedded network. This suggests a cautionary note for computational studies of isolated neurobiological circuits and networks.

Inheritance of associative memories in C. elegans nematodes

SummaryThe notion that associative memories may be transmitted across generations is intriguing, yet controversial. Here, we trained C. elegans nematodes to associate an odorant with stressful starvation conditions, and surprisingly, this associative memory was evident two generations down of the trained animals. The inherited memory endowed the progeny with a fitness advantage, as memory reactivation induced rapid protective stress responses that allowed the animals to prepare in advance for an impending adversity. Sperm, but not oocytes, transmitted the associative memory, and the inheritance required H3K9 and H3K36 methylations, the small RNA-binding Argonaute NRDE-3, and intact neuropeptide secretion. Remarkably, 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. These findings challenge long-held concepts by establishing that associative memories may indeed be transferred across generations.

Computing temporal sequences associated with dynamic patterns on the C. elegans connectome

Understanding how the structural connectivity of a network constrains the dynamics it is able to support is a very active and open area of research. We simulated the plausible dynamics resulting from the known C. elegans connectome using a recent model and theoretical analysis that computes the dynamics of neurobiological networks by focusing on how local interactions among connected neurons give rise to the global dynamics in an emergent way, independent of the biophysical or molecular details of the cells themselves. We studied the dynamics which resulted from stimulating a chemosensory neuron (ASEL) in a known feeding circuit, both in isolation and embedded in the full connectome. We show that contralateral motor neuron activations in ventral (VB) and dorsal (DB) classes of motor neurons emerged from the simulations, which are qualitatively similar to rhythmic motor neuron firing pattern associated with locomotion of the worm. One interpretation of these results is that there is an inherent - and we propose - purposeful structural wiring to the C. elegans connectome that has evolved to serve specific behavioral functions. To study network signaling pathways responsible for the dynamics we developed an analytic framework that constructs Temporal Sequences (TSeq), time-ordered walks of signals on graphs. We found that only 5% of TSeq are preserved between the isolated feeding network relative to its embedded counterpart. The remaining 95% of signaling pathways computed in the isolated network are not present in the embedded network. This suggests a cautionary note for computational studies of isolated neurobiological circuits and networks.

Social behavioral deficits in NF1 emerge from peripheral chemosensory neuron dysfunction

Neurofibromatosis type 1 (NF1) is a neurodevelopmental disorder commonly associated with social and communicative disabilities. The cellular and circuit mechanisms by which loss of neurofibromin 1 (Nf1) function results in social deficits are unknown. Here, we identify social behavioral dysregulation with loss of Nf1 in Drosophila. These deficits map to primary dysfunction of a small group of peripheral sensory neurons, rather than central brain circuits. Specifically, Nf1 regulation of Ras signaling in adult, Ppk23+ chemosensory cells is required for normal social behaviors in flies. Loss of Nf1 results in attenuated ppk23+ neuronal activity in response to pheromonal cues, and circuit-specific manipulation of Nf1 expression or neuronal activity in ppk23+ neurons rescues social deficits. Unexpectedly, this disrupted sensory processing gives rise to persistent changes in behavior lasting beyond the social interaction, indicating a sustained effect of an acute sensory misperception. Together our data identify a specific circuit mechanism through which Nf1 acts to regulate social behaviors, and suggest social deficits in NF1 arise from propagation of sensory misinformation.

Repression of an activity-dependent autocrine insulin signal is required for sensory neuron development in C. elegans

Nervous system development is instructed both by genetic programs and activity-dependent refinement of gene expression and connectivity. How these mechanisms are integrated remains poorly understood. Here, we report that the regulated release of insulin-like peptides (ILPs) during development of the C. elegans nervous system accomplishes such an integration. We find that the p38 MAP kinase PMK-3, which is required for the differentiation of chemosensory BAG neurons, functions by limiting expression of an autocrine ILP signal that represses a chemosensory-neuron fate. ILPs are released from BAGs in an activity-dependent manner during embryonic development, and regulate neurodifferentiation through a non-canonical insulin receptor signaling pathway. The differentiation of a specialized neuron-type is, therefore, coordinately regulated by a genetic program that controls ILP expression and by neural activity, which regulates ILP release. Autocrine signals of this kind may have general and conserved functions as integrators of deterministic genetic programs with activity-dependent mechanisms during neurodevelopment.

Thioredoxin shapes the C. elegans sensory response to Pseudomonas produced nitric oxide

Nitric oxide (NO) is released into the air by NO-producing organisms; however, it is unclear if animals utilize NO as a sensory cue. We show that C. elegans avoids Pseudomonas aeruginosa (PA14) in part by detecting PA14-produced NO. PA14 mutants deficient for NO production fail to elicit avoidance and NO donors repel worms. PA14 and NO avoidance are mediated by a chemosensory neuron (ASJ) and these responses require receptor guanylate cyclases and cyclic nucleotide gated ion channels. ASJ exhibits calcium increases at both the onset and removal of NO. These NO-evoked ON and OFF calcium transients are affected by a redox sensing protein, TRX-1/thioredoxin. TRX-1’s trans-nitrosylation activity inhibits the ON transient whereas TRX-1’s de-nitrosylation activity promotes the OFF transient. Thus, C. elegans exploits bacterially produced NO as a cue to mediate avoidance and TRX-1 endows ASJ with a bi-phasic response to NO exposure.