A dedicated skin-to-brain circuit for cool sensation in mice.

Perception of external temperature is essential for maintaining homeostasis and avoiding thermal injury. Although molecular thermosensors such as transient receptor potential melastatin type 8 (TRPM8) have been identified, the neural circuits responsible for transmitting cool signals remain unclear. Here we show that a spinal circuit in mice conveys cool signals from the skin to the brain. Excitatory interneurons in the spinal dorsal horn expressing thyrotropin-releasing hormone receptor (Trhr) act as a central hub for cool sensation. These Trhr neurons receive monosynaptic input from TRPM8 sensory afferents and are selectively activated by innocuous cool stimuli. Ablating Trhr interneurons abolishes behavioral responses to cool, but not to warm or cold stimuli. We also identify a population of calcitonin receptor-like receptor-positive (Calcrl) spinal projection neurons that receive convergent input from both TRPM8 afferents and Trhr interneurons, and transmit cool-specific signals to the lateral parabrachial nucleus (lPBN). Our findings define a feedforward amplification circuit for cool sensation and reveal a modality-specific spinal pathway for thermal processing.