Separation of oral cooling and warming requires TRPM8.

Cooling sensations arise inside the mouth during ingestive and homeostasis behaviors. Oral presence of cooling temperature engages the cold and menthol receptor TRPM8 (transient receptor potential melastatin 8) on trigeminal afferents. Yet, how TRPM8 influences brain and behavioral responses to oral temperature is undefined. Here we used in vivo neurophysiology to record action potentials stimulated by cooling and warming of oral tissues from trigeminal nucleus caudalis neurons in female and male wild-type and TRPM8 gene deficient mice. Using these lines, we also measured orobehavioral licking responses to cool and warm water in a novel, temperature-controlled fluid choice test. Capture of antidromic electrophysiological responses to thalamic stimulation identified that wild-type central trigeminal neurons showed diverse responses to oral cooling. Some neurons displayed relatively strong excitation to cold <10°C (COLD neurons) while others responded to only a segment of mild cool temperatures below 30°C (COOL neurons). Notably, TRPM8 deficient mice retained COLD-type but lacked COOL cells. This deficit impaired population responses to mild cooling temperatures below 30°C and allowed warmth-like (≥35°C) neural activity to pervade the normally innocuous cool temperature range, predicting TRPM8 deficient mice would show anomalously similar orobehavioral responses to warm and cool temperatures. Accordingly, TRPM8 deficient mice avoided both warm (35°C) and mild cool (≤30°C) water and sought colder temperatures in fluid licking tests, whereas control mice avoided warm but were indifferent to mild cool and colder water. Results imply TRPM8 input separates cool from warm temperature sensing and suggest other thermoreceptors also participate in oral cooling sensation. Significance Statement TRPM8 contributes to the detection of cutaneous cooling. Yet how TRPM8 influences neural representations for temperatures in somatosensory circuits in the brain is not fully understood. Here we show that in central trigeminal neurons, TRPM8 input drives a neural information breakpoint between cool and warm temperature sensing inside the mouth. Mice gene deficient for TRPM8 showed reduced, but not abolished, neural responses to oral cooling that were impaired to distinguish mild cool temperatures from warmth. This neural deficit predicted a behavioral generalization between mild cooling and warmth that appeared in licking responses to temperature-controlled fluids in TRPM8 deficient mice. These data reveal a novel role for TRPM8 in thermosensory coding and have implications for the multiplicity of oral cooling receptors.