Neural modulation of systemic stress response requires the insulin like-peptide INS-3

Abstract

Throughout the animal kingdom, the perpetuation of the flight response leads to reduced ability to cope with environmental challenges, a drastic lifespan reduction, and an increase in disease susceptibility. We showed that, in C. elegans, the tyraminergic neuron RIM supplies a state- dependent neural switch between acute flight and long-term environmental stress responses. During the flight-stress response RIM neurons release TA, which stimulates the intestinal adrenergic-like receptor TYRA-3. This leads to DAF-2/Insulin/IGF- 1 pathway activation and inhibition of cytoprotective mechanisms in the intestine and other tissues. We hypothesized that TYRA-3 stimulates the release of Insulin-Like Peptides (ILPs) from the intestine that can systemically activate the DAF-2 insulin/ IGF1 receptors. We focused on strong agonist ILPs that are expressed in the intestine (INS-3, -4, -6, -32, and DAF-28). We found that ins-3 mutants are resistant to both heat and oxidative stress, much like tyra-3 mutants. Moreover, ins-3 mutants are resistant to the impairment of stress resistance upon exposure to exogenous tyramine. In addition, ins-3;tyra-3 double mutants are as resistant to environmental stress as single mutants, suggesting that both genes act in the same pathway. Since ins-3 is expressed in neurons and the intestine, we performed tissue-specific rescue experiments. We found that expression of ins-3 in the intestine restores stress resistance to wild-type levels. Taken together, our results suggest that intestinal activation of TYRA-3 by the escape neurohormone TA leads to INS-3 release which acts as an endocrine, autocrine, and/or paracrine signal to activate DAF-2 in different tissues.