Abstract TP123: Inhibition of Tropomyosin-related Kinase B (trkb) Reduces the Benefit of Cortical Stimulation Combined With Motor Rehabilitation in Experimental Stroke

Abstract

Motor impairments are one of the more debilitating and persistent functional deficits following stroke. Several clinical and experimental studies suggest that combining impaired limb rehabilitation (RT) with low-frequency inhibitory contra-lesion or high-frequency excitatory ipsi-lesion motor cortical stimulation (CS) can improve motor recovery and increase neural remodeling. However, results have been mixed and there is no consensus on which CS approach is more beneficial. Further, the mechanism by which excitatory CS (ECS) and inhibitory CS (ICS) alter motor recovery after stroke are unknown. One theory is that CS may alter the expression of neurotrophic factors. Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) are important for motor learning and neural plasticity in healthy brains may be involved in motor recovery after stroke. In this study, we compared the efficacy of motor RT alone to ECS or ICS combined with RT following experimental motor cortical stroke in adult male rats. Additionally, we investigated whether inhibiting the TrkB receptor during treatment would block behavioral recovery and alter neural remodeling in the motor cortex. Methods: Adult male rats received an endothelin-1 induced unilateral focal stroke to the caudal forelimb area of the motor cortex. Bipolar electrodes were then implanted either over remaining peri-lesion motor cortex or over the contra-lesion motor cortex. Four days after stroke, rats received daily RT on a reaching task without CS or concurrent with 100 Hz ECS or 1 Hz ICS 6 days per week for 3 weeks. Three hours prior to RT, animals were injected with ANA-12 (.5mg/kg, i.p.), a small molecule TrkB antagonist, or vehicle. Preliminary results indicate that ANA-12 injections resulted in decreased functional improvements in rats receiving ECS+RT and RT compared to rats receiving these treatments with vehicle injections. Alternatively, ANA-12 had no effect on motor performance in the ICS+RT group. These data suggest that ECS and RT may be, at least in part, dependent upon TrkB receptor signaling. However, contra-lesion ICS induced functional recovery is likely not dependent upon TrkB signaling.