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

Abstract

Background Recognition of stress and mobilization of adequate “fight-or-flight” responses is key for survival and health. Previous studies have shown that exposure of Caenorhabditis elegans to pathogens or toxins simultaneously stimulates cellular stress and detoxification responses and aversive behavior. However, whether a coordinated regulation exists between cytoprotective stress responses and behavioral defenses remains unclear. Results Here, we show that exposure of C. elegans to high concentrations of naturally attractive food-derived odors, benzaldehyde and diacetyl, induces toxicity and food avoidance behavior. Benzaldehyde preconditioning activates systemic cytoprotective stress responses involving DAF-16/FOXO, SKN-1/Nrf2, and Hsp90 in non-neuronal cells, which confer both physiological (increased survival) and behavioral tolerance (reduced food avoidance) to benzaldehyde exposure. Benzaldehyde preconditioning also elicits behavioral cross-tolerance to the structurally similar methyl-salicylate, but not to the structurally unrelated diacetyl. In contrast, diacetyl preconditioning augments diacetyl avoidance, weakens physiological diacetyl tolerance, and does not induce apparent molecular defenses. The inter-tissue connection between cellular and behavioral defenses is mediated by JNK-like stress-activated protein kinases and the neuropeptide Y receptor NPR-1. Reinforcement of the stressful experiences using spaced training forms stable stress-specific memories. Memory retrieval by the 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. Conclusions Our study reveals a regulatory link between conserved cytoprotective stress responses and behavioral avoidance, which underlies “fight-or-flight” responses and facilitates self-protection in real and anticipated stresses. These findings imply that variations in the efficiency of physiological protection during past episodes of stress might shape current behavioral decisions. Graphical abstract

The Intestine as a Lifespan- and Proteostasis-Promoting Signaling Tissue

“…Interestingly, the C. elegans intestine may even dictate behavioral decisions based on the level of damage sustained from a particular sensory cue ( Hajdú et al, 2021 ). Upon exposure to toxic concentrations of benzaldehyde or diacetyl there was a cytoprotective response initiated in the intestine.…”

“…This response effectively restored proteostasis in the intestine damaged by benzaldehyde but not diacetyl. The intestinal damage was suggested to be signaled from the intestine to the nervous system to confer either flexible or robust avoidance responses upon re-exposure to each chemical ( Hajdú et al, 2021 ). Although this mechanism needs further characterization, it presents a potential role of the intestine in controlling memory formation in the nervous system to dictate future behaviors based on damage levels as a form of decision making between defensive avoidance and food searching.…”

Activation of intestinal immunity by pathogen effector-triggered aggregation of lysosomal TIR-1/SARM1

“…Loss of lysosome-related organelles inhibited transcriptional activation of some putative immune genes. 53 Here, we showed that lysosome-related organelles are scaffolds for an innate immune signaling regulator that change dynamically during infection to enable sensing of a pathogen-derived toxin. These data suggest that the evolutionarily ancient function of lysosome-related organelles may be in stress sensing, offering a clue to their function in higher order hosts.…”

Hsp90: From Cellular to Organismal Proteostasis

“…As DAF-16 is also an important regulator of proteostasis, further studies might reveal how Hsp90 affects its function in proteotoxic conditions. One connection might be that in a volatile toxicity model, both DAF-16 and Hsp90 were required for physiological and behavioral tolerance against benzaldehyde, a protein adduct forming oxidative agent [ 67 ]. The SIRT1 deacetylase binds to Hsp90, and proteasomal degradation of SIRT1 occurs in response to Hsp90 inhibition or knockdown in both nematodes and mammalian cells [ 68 ].…”