Impact of TrkB Receptor Modulation on Tongue Exercise-Induced Plasticity in an Inducible Rodent Model of Hypoglossal (XII) Motor Neuron Death

Patients with motor neuron diseases (MNDs) often develop upper airway dysfunction due to degeneration of XII lower motor neurons (MNs) that innervate the genioglossus muscle causing extensive tongue weakness, suggesting a role for therapeutic exercise. Available treatments for patients with MNDs are largely palliative, resulting in a critical need for therapies targeting the preservation of upper airway function. Using our established model of targeted XII MN loss induced by intralingual injection of cholera toxin B conjugated to saporin (CTB-SAP), we have shown that tongue exercise mitigates XII axis deficits by increasing airflow and lick rate/force. However, the underlying mechanism of exercise-induced plasticity remains unknown. Preliminary immunohistochemistry and western blot data suggest that XII brain-derived neurotrophic factor (BDNF) expression is increased in exercise-treated vs. sham exercise-treated CTB-SAP rats. We hypothesize that the source of tongue exercise-induced plasticity in CTB-SAP rats arises from a BDNF-dependent pathway to preserve upper airway function. Here, we targeted tropomyosin receptor kinase B (TrkB; high affinity receptor for BDNF) by delivery of either a TrkB receptor antagonist (ANA-12) or vehicle (veh; 50:50 DMSO + aCSF) into the XII nucleus of the brainstem via a surgically implanted cannula and attached osmotic minipump in adult male rats for the following groups: 1) control + sham exercise + veh, n=2; 2) CTB-SAP + exercise + veh, n=3; and 3) CTB-SAP + exercise + ANA-12, n=3. We assessed the effect of TrkB receptor inhibition on tongue exercise-induced plasticity by conducting the following behavioral assays: 1) lickometer and videofluoroscopic swallow studies to determine swallowing behavior ( i.e., lick force/rate); and 2) plethysmography to study airflow. Values for veh treated rats in this study were consistent with past studies in control and CTB-SAP rats ( i.e., rats not implanted), thus values were combined to enable group comparisons in addition to comparing to past values for control + exercise rats and CTB-SAP + sham exercise rats to determine the impact of TrkB receptor inhibition. Our preliminary findings suggest that CTB-SAP + exercise + ANA-12 rats have decreased lick force/rate vs. CTB-SAP +/- exercise +/- veh rats (n=12-15) as well as control +/- exercise +/- veh rats (n=10-13). To conclude, these preliminary results suggest that tongue exercise-induced therapeutic effects may be abolished in CTB-SAP + exercise + ANA-12 rats, and that tongue exercise-induced plasticity in CTB-SAP rats appears to potentially arise from a BDNF-dependent pathway to preserve upper airway function. If successful, these studies may help guide future translational studies in patients with MNDs by offering a modality to preserve upper airway function by harnessing a BDNF-dependent pathway to enhance neuroplasticity. R01 HL153612, NIH T32 OD011126 and MU Phi Zeta Grants This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.