Differential mechanisms of cold sensitivity in mouse trigeminal and vagal ganglion neurons

Abstract

Thermal signals are critical elements in the operation of interoceptive and exteroceptive neural circuits, essential for triggering thermally-driven reflexes and conscious behaviors. A fraction of cutaneous and visceral sensory endings are activated by cold temperatures. Compared to somatic (DRG and TG) neurons, little is known about the mechanisms underlying cold sensitivity of visceral vagal neurons. We used molecular, pharmacological and genetic tools for a side-by-side characterization of cold-sensitive (CS) neurons in adult mouse trigeminal (TG) and vagal ganglia (VG). We found that CS neurons are larger in size and more abundant in VG than in TG. In VG, the majority of CS neurons co-express TRPA1 markers and cold-evoked responses are severely blunted in Trpa1 KO mice. Cold sensitivity was evident in neurons with the highest TRPA1 expression. In contrast, TRPM8 deletion or pharmacological TRPM8 blockade had little impact on VG cold sensitivity. Consistent with these findings, in Trpm8eYFP reporter mice we found limited expression of TRPM8 in VG and restricted to the rostral jugular ganglion. In vivo retrograde labelling of airway-innervating vagal neurons demonstrated their enhanced cold sensitivity and a higher expression of TRPA1 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 reduction of TRPA1 showed that these channels contribute significantly 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 yet to be characterized. Finally, in both ganglia, sensitivity to cold varied widely and was enhanced by the potassium channel blocker 4-AP. This effect was independent of the cold sensor expressed by the neuron, suggestive of a common excitability brake mechanism. Significance statementTemperature sensing and its regulation is a critical homeostatic function. Little is known about the molecular mechanism of cold sensing by visceral sensory endings and their relative weight in different visceral organs. This study highlights important differences in thermotransduction mechanisms between somatic (trigeminal) and visceral (vagal) primary sensory neurons, establishing a critical role of TRPA1 channels in visceral cold transduction. The study describes quantitative differences in cold sensitivity of visceral neurons innervating the stomach and the lower airways, suggesting that cold transduction mechanisms may be fine-tuned to the specific needs of different organs. This study significantly advances our understanding of cold sensing in trigeminal and vagal neurons and reveals distinct drug targets for the pharmacological modulation of these thermoreceptors.