Recovery of Functional Visual Pathways in the Adult Mammalian Brain Using an Alpha7 nAChR Agonist After Blast Exposure
Abstract
Vision loss resulting from blast exposure in combat significantly affects a Soldier s quality of life and results in a substantial burden on national health care systems. Although regeneration of neural tissue is not typical in adult humans once neuronal damage occurs, the ability to generate new retinal neurons in adults could reverse the effects of vision loss. In previous studies from this lab, eye drop application of a specific acetylcholine agonist, PNU-282987, in adult rats and mice triggered robust growth of new neurons in all retinal cell layers in control untreated adult rodents (3-12 months) as well as in rodents with neurodegenerative diseases such as glaucoma and retinitis pigmentosa. With prolonged topical treatment of the acetylcholine agonist, as many as 32% new neurons appear in all retinal layers. Studies to examine the mechanism of this response has demonstrated that when the agonist is applied topically, it acts on specific receptors in the retinal pigment epithelium (RPE) that lie outside the neural retina. Stimulation of these RPE receptors release signaling molecules to induce neurogenesis from Muller glia in the retina. From previous DoD-sponsored studies, blast exposure of 35 psi from a modified paintball gun was shown to decrease the numbers of retinal neurons in all retinal layers in a rodent model and decreased the amplitude of all ERG waveforms. ERG recordings were used as a functional assay of retinal activity. After PNU-282987 eye drop treatment, however, the decrease of retinal neurons was significantly reversed and all ERG waveforms recovered to near control conditions. However, this previous study only addressed morphological and functional changes that occur in the retina with blast and with blast and PNU-282987 treatment. For vision to improve, new retinal ganglion cells from the retina must send axons through the optic nerve to synapse on appropriate targets in the brain. If synapses are made in appropriate nuclei in the brain, then changes should be seen in the occipital lobe where final visual perception occurs. As a result, this study is designed to determine if newly generated retinal ganglion cells that are induced by PNU-282987 send axons to appropriate targets in the brain and if these induced pathways affect visually evoked potentials (VEP) that are recorded from the occipital lobe using the Celeris Diagnosys ERG and VEP system. Two main objectives are outlined for this study to test the hypothesis that neurogenesis of retinal neurons resulting from PNU-282987 treatment make appropriate connections in the brain to improve vision after blast exposure: (1) To determine if PNU-282987-induced RGC axons that extend into the optic nerve terminate in the superior colliculus of the brain. (2) To demonstrate that newly generated retinal neurons resulting from PNU-282987 eye drop treatment after blast exposure affects visually evoked potentials recorded from the occipital lobe. Taken together, these experiments will be the first to determine if eye drop application of PNU-282987 can induce newly generated neurons to make appropriate connections in the brain and functionally improve visual perception. The results of these studies could lead to relatively straightforward eye drop treatments that significantly improve visual function in Soldiers that experience blast exposure in combat to improve their quality of life. In addition, the results of these studies could challenge current ideas that maintain the adult mammalian central nervous system is incapable of regeneration.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310835
Entities
People
- Cindy Linn
Organizations
- United States Army
- Western Michigan University