Genetic characterization of MesV sensory cells in normal development and in the neurodegenerative disease spinal muscular atrophy

Proper feeding behavior during early postnatal development is essential for survival, relying on a seamless transition from suckling to mastication as cranial sensory-motor circuits mature. In mammals, orofacial movements required for nutrient intake depend on the coordinated development of specific motor and sensory pathways, yet the mechanisms governing this maturation process remain poorly understood. Moreover, these circuits are selectively vulnerable in several neurodegenerative conditions such as spinal muscular atrophy (SMA), underscoring the importance of elucidating their normal developmental activation and modulation. The masseter muscle, the primary jaw-closing muscle, is central to effective nutrient intake. Its proprioceptive afferents, along with a population of periodontal pressoreceptors (PP), reside in the Mesencephalic trigeminal nucleus (MesV). This anatomical configuration suggests a potential modulatory role of PP on masseter muscle activity, possibly mediated by electrical coupling via gap junctions. I hypothesize that the transition from suckling to mastication is driven by the developmental emergence of electrical connections mediated by select connexins, and that their disruption contributes to the orofacial motor deficits observed in disease states. This project aims to inform, in a developmental time-course, the mechanisms governing sensory-motor circuit modulation in the masseter system, both under normal conditions and in the context of SMA. SMA is a severe neurodegenerative disease characterized by motor neuron loss, muscle atrophy, and impaired feeding. SMA, caused by homozygous deletion of the Survival Motor Neuron 1 gene, is the leading genetic cause of infant mortality. Clinical and preclinical evidence indicate profound impairments in nutrient intake in SMA, yet the contribution of orofacial circuit dysfunction remains unexplored. To address this, I will employ a multidisciplinary approach using the well- established SMNΔ7 mouse model of SMA. Techniques will include developmental stage specific immunohistochemistry for select connexins, dual whole-cell electrophysiological recordings to assess electrical coupling, laser capture microdissection, and mRNA-sequencing to define molecular signatures of affected neuronal populations. This research will provide novel insights into the developmental logic and disease vulnerability of orofacial sensory-motor circuits. By defining how these pathways form and function, and how they dysfunction in SMA, this work may uncover new therapeutic targets for improving motor function and feeding in affected infants. Project Number: 1R03DE036052-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Danny Florez Paz | Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES, NEW YORK, NY | Award Amount: $329,000 | Activity Code: R03 | Study Section: Sensory-Motor Neuroscience Study Section[SMN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11356582