Coupled dopamine and insulin signaling mediated transgenerational and multigenerational inheritance of adaptive traits in <i>Caenorhabditis elegans</i> upon parental training with <i>Salmonella enterica</i> Serovar Typhi

The nervous system's ability to perceive and learn about the environment can help organisms evolve and acquire traits, potentially generating adaptive responses. However, its potential to produce heritable modulations is a scientific lacuna, which is under-explored. Here, with the help of <i>Caenorhabditis elegans</i>, which has a well-established neuronal networking, we found that on training the worms on a candidate pathogenic bacterium <i>Salmonella enterica</i> Serovar Typhi, the worms could exhibit a characteristic transgenerational pathogenic avoidance up to three subsequent generations to the otherwise attractive pathogen. Our further analyses suggested that dopamine signaling is essential for the learning and transmission of the learned traits across generations and that inhibiting or mutating the expression of DAT-1 involved in dopamine transportation eliminated the inheritance patterns. Also, the offspring generations showed enhanced survival resistance against <i>S</i>. Typhi, which was coupled with the higher levels of C-type lectins suggesting priming of the offspring's immune system to generate resistance against <i>S</i>. Typhi upon re-exposure. Enhanced DAF-2/DAF-16-mediated insulin signaling pathway was observed, suggesting that the inherited immune response could be mediated through insulin/IGF-1 signaling (IIS). Furthermore, mutigenerational training on <i>S</i>. Typhi for three continuous generations induced preferential adaptation and better survivability toward <i>S</i>. Typhi. Taken together, the present study indicates that <i>S</i>. Typhi infection could generate transgenerational heritable dopaminergic modulations, which could possibly be the key signaling player in determining the decision-making ability of the host and also generate adaptive survival response, which could be mediated by the insulin-signaling pathway.IMPORTANCEAdaptation is a phenomenon by which an organism learns and develops a mechanism to respond to dynamic and challenging conditions. It provides animals with an advantage to exhibit phenotypic as well as genotypic plasticity, enabling better survivability. The current study helps in understanding how animals respond to environmental stresses such as bacterial infections and the possible mechanism by which the information of the experience is being transmitted across future generations. Neuronal signaling promotes the brain's ability to learn and generate memory, thereby reorganizing the response of the organism. The study also tries to understand how neuronal signaling could be essential for transmitting the information of parental experiences transgenerationally. Collectively, the study helps us understand the evolutionary adaptations exhibited across generations, which will also help us understand the long-term effects of pathogenesis.