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

VEUTHEY TANIA V; GIUNTI SEBASTIAN; DE ROSA, MARÍA JOSÉ; ALKEMA MARK; RAYES, DIEGO

Viena

Congreso; C. elegans Topic Meeting: neuronal development, synaptic function and behavior; 2022

Throughout the animal kingdom, it has been observed that 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 have recently shown that, in C. elegans, the tyraminergic neuron RIM supplies a state-dependent neural switch between acute flight and long-term environmental stress responses (De Rosa MJ, et al 2019). We found that 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 not only in the intestinebut also in other tissues. We hypothesized that TYRA-3 stimulates the release of InsulinLike Peptides (ILPs) from the intestine that can systemically activate the DAF-2 insulin/IGF1 receptors. Since tyramine signaling leads to the activation of the DAF-2/IIS pathway we focused on strong agonists 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, ins3;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 neuronsand the intestine, we performed tissue-specific rescue experiments. We found thatexpression 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. Our data uncover brain-gut communication pathway in which flight stress neurohormones activate the Insulin/IGF-1 pathway and inhibit the induction of cytoprotective mechanisms.