ABSTRACT Dry mouth affects nearly 30% of Americans, yet there are no treatments that effectively regulate saliva production and composition long-term. Autonomic neurons innervating the major salivary glands have been well-characterized and represent a main therapeutic target to trigger saliva production. However, this approach only offers acute alleviation and results in unwanted side effects. Somatosensory neurons found in the trigeminal ganglion initiate the detection of touch, pain, temperature, and chemicals in various craniofacial tissues. Previous findings suggest that trigeminal sensory neurons innervating the periodontal ligament and other oral structures initiate salivary-reflexes and indirectly contribute to saliva regulation. Now, our preliminary data suggest that direct sensory innervation is also present. We hypothesize the direct trigeminal sensory innervation of submandibular glands by Trp-positive trigeminal neurons provides feedback to modulate the salivary system. The objective of this proposal is to determine the targets of Trp-positive trigeminal sensory neurons innervating the submandibular salivary gland and the role they play in altering the secretion of saliva volume and composition based on chemical cues. In Aim 1, we will combine viral vector, genetic, and immunohistochemistry strategies to determine the central and peripheral targets of Trp-positive trigeminal sensory neurons innervating the submandibular glands. In Aim 2, we will use in vivo calcium imaging and chemogenetics to determine how this trigeminal innervation to the glands respond to chemical stimulation and modulate saliva outputs. The submandibular gland maintains the continuous basal flow rate of saliva, thus defining the function of Trp-positive sensory neurons present in this gland might reveal a long-term therapeutic target to modulate basal saliva secretion. Overall, our results will for the first time provide a mechanistic, cellular basis for novel sensory feedback and its role in saliva modulation. Furthermore, this research will provide a foundation for determining how trigeminal innervation of the submandibular gland can be used to address salivary gland dysfunction and provide additional therapeutic targets to counteract the loss of saliva.