Aversive Behavior in the Nematode C. elegans Is Modulated by cGMP and a Neuronal Gap Junction Network

Electrical synapses are established between specific neurons and within distinct subcellular compartments, but the mechanisms that direct gap junction assembly in the nervous system are largely unknown. Here we show that a transcriptional program tunes cAMP signaling to direct the neuron-specific assembly and placement of electrical synapses in the C. elegans motor circuit. For these studies, we use live cell imaging to visualize electrical synapses in vivo and a novel optogenetic assay to confirm that they are functional. In VA motor neurons, the UNC-4 transcription factor blocks expression of cAMP antagonists that promote gap junction miswiring. In unc-4 mutants, VA electrical synapses are established with an alternative synaptic partner and are repositioned from the VA axon to soma. We show that cAMP counters these effects by driving gap junction trafficking into the VA axon for electrical synapse assembly. Thus, our experiments in an intact nervous system establish that cAMP regulates gap junction trafficking for the biogenesis of electrical synapses.

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INX-18 and INX-19 play distinct roles in electrical synapses that modulate aversive behavior in Caenorhabditis elegans

10.1101/725903 ◽

2019 ◽

Author(s):

Lisa Voelker ◽

Bishal Upadhyaya ◽

Denise M. Ferkey ◽

Sarah Woldemariam ◽

Noelle D. L’Etoile ◽

...

Keyword(s):

Sensory Neurons ◽

Internal State ◽

Nerve Ring ◽

Electrical Synapse ◽

Electrical Synapses ◽

C Elegans ◽

Internal States ◽

Sensory Responses ◽

Aversive Behavior ◽

Sites Of Action

AbstractIn order to respond to changing environments and fluctuations in internal states, animals adjust their behavior through diverse neuromodulatory mechanisms. In this study we show that electrical synapses between the ASH primary quinine-detecting sensory neurons and the neighboring ASK neurons are required for modulating the aversive response to the bitter tastant quinine in C. elegans. Mutant worms that lack the electrical synapse proteins INX-18 and INX-19 become hypersensitive to dilute quinine. Cell-specific rescue experiments indicate that inx-18 operates in ASK while inx-19 is required in both ASK and ASH for proper quinine sensitivity. Imaging analyses find that INX-19 in ASK and ASH localizes to the same regions in the nerve ring, suggesting that both sides of ASK-ASH electrical synapses contain INX-19. While inx-18 and inx-19 mutant animals have a similar behavioral phenotype, several lines of evidence suggest the proteins encoded by these genes play different roles in modulating the aversive quinine response. First, INX-18 and INX-19 localize to different regions of the nerve ring, indicating that they are not present in the same synapses. Second, removing inx-18 disrupts the distribution of INX-19, while removing inx-19 does not alter INX-18 localization. Finally, by using a fluorescent cGMP reporter, we find that INX-18 and INX-19 have distinct roles in establishing cGMP levels in ASK and ASH. Together, these results demonstrate that electrical synapses containing INX-18 and INX-19 facilitate modulation of ASH nociceptive signaling. Our findings support the idea that a network of electrical synapses mediates cGMP exchange between neurons, enabling modulation of sensory responses and behavior.Author SummaryAnimals are constantly adjusting their behavior to respond to changes in the environment or to their internal state. This behavior modulation is achieved by altering the activity of neurons and circuits through a variety of neuroplasticity mechanisms. Chemical synapses are known to impact neuroplasticity in several different ways, but the diversity of mechanisms by which electrical synapses contribute is still being investigated. Electrical synapses are specialized sites of connection between neurons where ions and small signaling molecules can pass directly from one cell to the next. By passing small molecules through electrical synapses, neurons may be able to modify the activity of their neighbors. In this study we identify two genes that contribute to electrical synapses between two sensory neurons in C. elegans. We show that these electrical synapses are crucial for proper modulation of sensory responses, as without them animals are overly responsive to an aversive stimulus. In addition to pinpointing their sites of action, we present evidence that they may be contributing to neuromodulation by facilitating passage of the small molecule cGMP between neurons. Our work provides evidence for a role of electrical synapses in regulating animal behavior.

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Intercellular calcium signaling in a gap junction-coupled cell network establishes asymmetric neuronal fates in C. elegans

Development ◽

10.1242/dev.083428 ◽

2012 ◽

Vol 139 (22) ◽

pp. 4191-4201 ◽

Cited By ~ 27

Author(s):

J. A. Schumacher ◽

Y.-W. Hsieh ◽

S. Chen ◽

J. K. Pirri ◽

M. J. Alkema ◽

...

Keyword(s):

Calcium Signaling ◽

Gap Junction ◽

C Elegans ◽

Cell Network

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Complexity and Vulnerability Analysis of the C. Elegans Gap Junction Connectome

Entropy ◽

10.3390/e19030104 ◽

2017 ◽

Vol 19 (3) ◽

pp. 104 ◽

Cited By ~ 3

Author(s):

James Kunert-Graf ◽

Nikita Sakhanenko ◽

David Galas

Keyword(s):

Gap Junction ◽

Vulnerability Analysis ◽

C Elegans

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1P007 Structural analysis of C. elegans innexin-6 gap junction channels by electron microscopy(01A. Protein:Structure,Poster)

Seibutsu Butsuri ◽

10.2142/biophys.53.s107_1 ◽

2013 ◽

Vol 53 (supplement1-2) ◽

pp. S107

Author(s):

Tomohiro Matsuzawa ◽

Kazuyoshi Murata ◽

Kouki Nishikawa ◽

Yoshinori Fujiyoshi ◽

Atsunori Oshima

Keyword(s):

Electron Microscopy ◽

Structural Analysis ◽

Gap Junction ◽

Gap Junction Channels ◽

C Elegans

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Toxic stress-specific cytoprotective responses regulate learned behavioral decisions in C. elegans

10.1101/2020.02.24.962381 ◽

2020 ◽

Author(s):

Gábor Hajdú ◽

Eszter Gecse ◽

István Taisz ◽

István Móra ◽

Csaba Sőti

Keyword(s):

Stress Responses ◽

Physiological Stress ◽

Cross Tolerance ◽

Coordinate Regulation ◽

C Elegans ◽

Behavioral Decision ◽

Regulatory Link ◽

High Concentrations ◽

Aversive Behavior ◽

Self Protection

AbstractBackgroundProtection of organismal integrity involve physiological stress responses and behavioral defenses. Recent studies in the roundworm Caenorhabditis elegans have shown that pathogen and toxin exposure simultaneously stimulate cellular stress and detoxification responses and aversive behavior. However, whether a coordinate regulation exists between cellular and neurobehavioral defenses remains unclear.ResultsHere we show that exposure of C. elegans to high concentrations of naturally attractive food-derived odors, benzaldehyde and diacetyl, induces toxicity and aversive behavior. Benzaldehyde preconditioning activates systemic cytoprotective stress responses involving DAF-16/FOXO, SKN-1/Nrf and Hsp90 in somatic cells, which confer behavioral tolerance to benzaldehyde and cross-tolerance to the structurally similar methyl-salicylate, but not to the structurally unrelated diacetyl. In contrast, diacetyl preconditioning augments diacetyl avoidance and does not induce apparent molecular defenses. Reinforcement of the experiences using massed training forms relevant associative memories. Memory retrieval by the odor olfactory cues leads to avoidance of food contaminated by diacetyl and context-dependent behavioral decision to avoid benzaldehyde only if there is an alternative, food-indicative odor.ConclusionsOur findings reveal a regulatory link between physiological stress responses and learned behavior which facilitates self-protection in real and anticipated stresses. The potential conservation of this somato-neuronal connection might have relevance in maladaptive avoidant human behaviors.

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