Voluntary Exercise is Neuroprotective in an Inherited Retinal Degeneration Mouse Model

Abstract

Purpose: Our previous investigations demonstrated that forced exercise provides BDNF-mediated neuroprotection in a light damage model of retinal injury (Lawson et al., J Neurosci 2014). In this study, we hypothesized that voluntary running wheel exercise would preserve retinal structure and function through this same BDNF pathway in the rd10 model of retinitis pigmentosa (RP).

Methods: Breeding pairs were given either free-spinning (Active, n=20) or locked (Inactive, n=22) wheels. Pups were weaned into separate cages with their respective wheel types and tested for visual acuity via a virtual optokinetic system at 4, 5, and 6 weeks of age. Mice were sacrificed at 6 weeks of age, and retinal cross sections were prepared for photoreceptor counting. Additionally, separate cohorts of Active and Inactive groups were injected daily with either a BDNF TrkB receptor antagonist (ANA-12), or vehicle solution (Active + ANA-12, n=10; Active + Vehicle, n=6; Inactive + ANA-12, n=4; Inactive + Vehicle, n=5), and assessed as described above.

Results: Active mice exhibited significantly greater preservation of visual acuity thresholds at every time point (At 6 wks; Active: 0.168 ± 0.010 c/d, Inactive: 0.084 ± 0.013 c/d; p<0.001). Additionally, mean photoreceptor counts of Active mice were significantly higher than those of Inactive mice (Active: 161.1 ± 15.6; Inactive: 81.4 ± 15.5; p<0.001). ANA-12 injections of Active mice precluded the higher visual acuity and resulted in thresholds similar to Inactive mice (At 6 wks; Active + ANA-12: 0.148 ± 0.062 c/d, Active + Vehicle: 0.248 ± 0.051 c/d, Inactive + ANA-12: 0.104 ± 0.011 c/d; Inactive + Vehicle: 0.100 ± 0.030 c/d; p<0.001). Visual acuity thresholds of Inactive mice injected daily with either ANA-12 or vehicle were statistically indistinguishable. Similarly, ANA-12 blocked exercise's protection of photoreceptor counts (Active + ANA-12: 112.39 ± 8.08, Active + Vehicle: 136.44 ± 9.95, Inactive + ANA-12: 104.08 ± 17.54; Inactive + Vehicle: 100.89 ± 9.35; p=0.01).

Conclusions: Our findings suggest that voluntary exercise preserves visual acuity and retinal structure in inherited retinal degeneration, advancing our findings from forced exercise in an acute model. Activated TrkB signal transduction is requisite for this protective effect. Exercise may serve as an effective, clinically translational intervention against retinal degeneration.