Flavor is implicated to guide ingestive decisions that impact nutritional status and can lead to health problems in humans, such as obesity and diabetes. Flavor involves the actions of multiple sensory pathways, including neural circuits that invoke taste sensations, such as sweet and bitter, and those that give rise to oral somatosensation. Somatosensory cues elicited by foods can include temperature and pain (e.g., chili pepper burn). Neural messages about oral somatosensation are partly signaled by electrical activity in the fifth cranial nerve and brain nuclei known as the trigeminal system. The involvement of brain trigeminal pathways in flavor is poorly understood and many questions remain, including how central trigeminal neurons signal information about noxious and innocuous oral temperature. The proposed research will address this and other questions with the long-term goal of elucidating how orosensory trigeminal neurons contribute to and perform unimodal and multisensory processing relevant to flavor. Specific Aim #1 will use neurophysiological recordings from single trigeminal neurons in the mouse medulla to test the hypothesis that heterogeneous subpopulations of cells distinguish noxious from innocuous oral temperatures, focusing on the neural representation of oral cooling. Cellular function will be gauged by using antidromic electrical activation to verify projections of recorded neurons to the parabrachial nucleus, which is involved with integrative and affective processing. To define afferent inputs that reach different types of cooling-responsive orosensory cells, units will be tested with chemical agonists of transient receptor potential (TRP) ion channels that mediate thermosensation and nociception, and also recorded from mice genetically deficient for a select TRP channel implicated for cooling sensation. Specific Aim #2 will test the hypothesis that the parabrachial nucleus is a brain site of logical trigeminal and taste integration. Interaction between taste and trigeminal pathways has been discussed to contribute to flavor perception, albeit brain neurons that support merger of gustatory and trigeminal sensory signals remain undefined. There are scant anatomical and physiological data to suggest convergence of taste and trigeminal pathways arises in the parabrachial nucleus, which has been studied for separate roles in taste or pain processing. Here, we will use neurophysiological recording, stimulation, and optogenetic techniques that afford rapid and reversible inhibition of neural activity to dissect whether and how neuronal projections from medullary trigeminal nuclei reach gustatory-responsive neurons in the parabrachial nucleus. Genetically TRP-deficient mice will also be tested in recording studies to index receptors mediating somatosensory activity in parabrachial gustatory cells. Finally, we will apply optogenetics to assess how primary trigeminal afferents that reach the parabrachial nucleus interact with gustatory-sensitive neurons in this structure. Overall, these studies aim to use physiological and molecular analyses of neural circuits in mice to understand how trigeminal neurons encode oral sensory information relevant to flavor and interact with neural circuits for taste.