Date of Award

Summer 6-10-2024

Embargo Period

6-19-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Stephen Tomlinson

Second Advisor

Barbel Rohrer

Third Advisor

Heather Boger

Fourth Advisor

Shahid Husain

Fifth Advisor

Kumar Sambamurti

Abstract

Background: Traumatic brain injury is associated with the development of visual system disorders, including deficits in visual acuity. Visual deficits can present with delay and worsen over time, suggesting that ongoing neuroinflammatory changes contribute to their development and progression. Complement activation is strongly associated with the neuroinflammatory response after TBI and has been shown to contribute to neuronal and synaptic loss. However, the contributions of complement activation after TBI to vision loss remains unclear.

Methods: We employed an open skull controlled cortical impact model of traumatic brain injury in adult male mice to study how TBI affects vision. Animals were treated with a single i.v. dose of complement inhibitor CR2-Crry or saline. Acute neuroinflammatory changes were assessed in the dorsal LGN at 3 days after injury. Behavioral and visual function tests were performed in another cohort of animals, and neuroinflammatory and histopathological changes were assessed at 49 days after injury.

Results: C3 was deposited on retinogeniculate synapses in both the ipsilateral and contralateral dorsal lateral geniculate nuclei (dLGN) within 3 days after TBI, and was reduced in CR2-Crry treated animals. Microglia exhibited quantifiable morphological changes in both the ipsilateral and contralateral dLGN, with a more amoeboid phenotype after TBI in vehicle vs. CR2-Crry treated animals. Microglia in vehicle treated animals also had a greater internalized VGLUT2+ synaptic volume after TBI compared to CR2-Crry treated animals, reminiscent of aberrant phagocytosis seen in perilesional areas of the brain after TBI and stroke. There were no changes in the thickness of the retina. These pathologies were accompanied by reduced visual acuity in both the ipsilateral and contralateral eyes at 10 and 35 days after TBI; vision was absent in the majority of contralateral eyes in both groups of animals, but complement inhibition preserved visual acuity in the ipsilateral eye.

Conclusion: Traumatic brain injury induces complement activation within the dorsal lateral geniculate nucleus and promotes synaptic internalization and microglial activation. Inhibition of the complement system with an injury site-targeted complement inhibitor is sufficient to preserve visual acuity in the ipsilateral eye, reduce complement activation and microglial morphological changes, and preserve synaptic count within the dorsal LGN. Altogether, these data suggest that complement plays a role in the development of visual deficits after TBI, and that inhibition of complement acutely after TBI has therapeutic potential for ameliorating visual and other deficits.

Rights

Copyright is held by the author. All rights reserved.

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