Acute hypercapnic stress modulates innate and learned defensive behavior

Survival depends on avoiding threats, a process shaped by experience and internal states. Notably, acute stress can induce analgesia, yet the neural mechanisms by which stress alters aversive value coding remain unclear. Using Drosophila, we show that prior noxious experience induces intensity-dependent analgesia and triggers the release of CO2, a known stress signal. Surprisingly, this effect is mediated by tracheal dendrite (td) neurons in the respiratory system rather than classic olfactory pathways. We then demonstrated that activation of td neurons induces analgesia, whereas their inhibition suppresses it and restores normal nocifensive and learned behavior. Finally, high CO2 exposure decreases dopaminergic neuron responses to electric shocks, thereby impairing aversive memory formation. Together, we propose that under hypercapnic (high CO2) stress, td neurons modulate nociceptive computation and aversive value coding in the brain to facilitate appropriate innate and learned behavioral responses.