A disynaptic trigeminal circuit for the transformation and integration of oral chemesthesis in male mice

Chemesthesis, encompassing oral sensations such as spiciness and coolness, is an important yet incompletely understood component of mammalian chemical sensing. Unlike taste or olfaction, these sensations are conveyed primarily through trigeminal pathways; however, how modality-specific peripheral signals are processed and transformed along central ascending pathways remains poorly understood. Herein, we delineate the structural and functional organization of an ascending trigeminal-brainstem-parabrachial circuit that mediates oral chemesthetic processing in male mice. Using viral tracing, in vivo calcium imaging, and chemogenetic and optogenetic manipulations, we identify a genetically defined disynaptic glutamatergic pathway (trigeminal ganglion → spinal trigeminal nucleus caudalis → lateral parabrachial nucleus) that is both necessary and sufficient for capsaicin- and menthol-evoked defensive behaviors. Although peripheral TRPV1 ⁺ and TRPM8 ⁺ neurons retain a degree of modality bias, we observe substantial convergence of spicy and cooling signals within the spinal trigeminal nucleus, followed by sustained and synchronized population activity in vglut2 ⁺ neurons of the external lateral parabrachial nucleus. This hierarchical transformation from peripheral segregation to central integration reveals the organizational principle by which distinct chemesthetic modalities are progressively integrated along a trigeminal-mediated ascending pathway, providing a circuit-level framework for understanding how chemical stimuli are processed and coordinated to drive defensive behaviors.