Thiazoline-related innate fear stimuli orchestrate hypothermia and anti-hypoxia via sensory TRPA1 activation

Tomohiro Matsuo ,Aiko Yasuda,Lijun Tang,Takeshi Matsuda,Yuichiro Hayashi,Reiko Kobayakawa,Dai Kanagawa,Masahito Ikawa,Satoru Matsunaga ,Koichiro Higasa,Tomoko Isosaka,Chia‐Ying Lee ,Mitsuyoshi Setou,Mikio Hayashi,Natsumaro Kutsuna,Liqin Cao,Akira Doi ,Ikuko Yao,Qinghua Liu,Ko Kobayakawa

doi:10.1038/s41467-021-22205-0

Abstract

Thiazoline-related innate fear-eliciting compounds (tFOs) orchestrate hypothermia, hypometabolism, and anti-hypoxia, which enable survival in lethal hypoxic conditions. Here, we show that most of these effects are severely attenuated in transient receptor potential ankyrin 1 (Trpa1) knockout mice. TFO-induced hypothermia involves the Trpa1-mediated trigeminal/vagal pathways and non-Trpa1 olfactory pathway. TFOs activate Trpa1-positive sensory pathways projecting from trigeminal and vagal ganglia to the spinal trigeminal nucleus (Sp5) and nucleus of the solitary tract (NTS), and their artificial activation induces hypothermia. TFO presentation activates the NTS-Parabrachial nucleus pathway to induce hypothermia and hypometabolism; this activation was suppressed in Trpa1 knockout mice. TRPA1 activation is insufficient to trigger tFO-mediated anti-hypoxic effects; Sp5/NTS activation is also necessary. Accordingly, we find a novel molecule that enables mice to survive in a lethal hypoxic condition ten times longer than known tFOs. Combinations of appropriate tFOs and TRPA1 command intrinsic physiological responses relevant to survival fate.

Highlights

Thiazoline-related innate fear-eliciting compounds orchestrate hypothermia, hypometabolism, and anti-hypoxia, which enable survival in lethal hypoxic conditions
Avoidance and risk assessment behaviors relevant to innate fear induced by 2MT are regulated by transient receptor potential ankyrin 1 (Trpa1). 2MT induces robust physiological responses such as hypothermia and bradycardia[5]
Whereas body temperature in the baseline condition was not significantly altered, 2MT-induced hypothermia was greatly suppressed in Trpa1−/− mice (Fig. 1a, b)

Summary

Introduction

Thiazoline-related innate fear-eliciting compounds (tFOs) orchestrate hypothermia, hypometabolism, and anti-hypoxia, which enable survival in lethal hypoxic conditions. Trpa[1] is considered an alarm sensor detecting multiple signals to transduce pain or danger information to the brain[18,20,21] Extending these findings, we hypothesized that Trpa[1] has a crucial role in tFO-mediated latent physiological responses, which increase survival in lethal conditions. By monitoring the activation of TRPA1 and Sp5/NTS, we identified a novel compound that could prolong survival in hypoxic conditions ten times longer than known tFOs. Taken together, our results indicate that Trpa[1] functions as a danger sensor, and commands the induction of physiological responses relevant to innate fear, and is even involved in the acquisition of viability in lethal hypoxic conditions

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Conclusion