Transduction Mechanisms for Cold Temperature in Mouse Trigeminal and Vagal Ganglion Neurons Innervating Different Peripheral Organs

Abstract

Aim

To elucidate the molecular mechanism of cold sensing by visceral sensory endings, a side-by-side characterization of cold-sensitive (CS) neurons in adult mouse trigeminal (TG) and vagal ganglia (VG) was performed.

Methods

A combination of physiological, pharmacological, molecular, and genetic tools was employed on trigeminal and vagal neurons.

Results

CS neurons are more abundant in VG, and the majority co-express TRPA1. Cold-evoked responses are severely blunted in Trpa1 KO mice. In contrast, TRPM8 deletion or pharmacological TRPM8 blockade had little impact on VG cold sensitivity. In Trpm8^eYFP reporter mice, VG TRPM8 expression was restricted to the rostral jugular ganglion. In vivo labeling of airway-innervating VG neurons demonstrated their enhanced cold sensitivity and higher TRPA1 expression compared to neurons innervating the stomach wall. In contrast, the majority of CS TG neurons co-express TRPM8 markers, and their cold sensitivity is reduced after TRPM8 deletion or blockade. However, pharmacological or genetic ablation of TRPA1 confirmed its contribution to high-threshold cold sensitivity in TG, suggestive of a role in noxious cold sensing. In both ganglia, a fraction of CS neurons responded to cooling by a mechanism independent of TRPA1 or TRPM8. Blocking potassium channels enhanced cold sensitivity independently of the specific transducer mechanism, suggestive of a common excitability brake mechanism.

Conclusions

The study highlights the differential contribution of TRPM8 and TRPA1 channels to cold sensitivity in somatic and visceral ganglia, establishing a critical role of TRPA1 channels in visceral cold transduction. Finally, cold sensitivity seems fine-tuned to the specific physiological needs of different organs.