Assessment of Diet and Stress Effects on Ocular Vulnerability in Rodent Models of Traumatic Brain Insults using a Multi-Omics Approach

Ocular injuries and visual deterioration occur in a large percentage of Warfighters sustaining physical and psychological trauma. From 2000 through the end of 2017, more than 275,000 Service-members have suffered from eye injuries, as shown by Surveillance data from the Department of Defense (DOD). Exposure to blast overpressure (BOP) also directly affects the brain visual signal processing centers (e.g., optic tracts). Likewise, traumatic brain injury (TBI)-induced impairments of vision are commonly seen among Military Veterans even when there is no direct injury to the eye, e.g., retina. Hence, these traumatic insults can influence the regulation of the visual and nonvisual retinal signaling pathways. The ocular system could be directly injured or could degenerate secondary to injury induced by psychological stress. Despite the lifelong disservice that vision losses exhibit, there are only few studies demonstrating the effect of these insults on retinal transcriptomics and the signaling mechanisms underlying the eye damage. Studies have shown that docosahexaenoic acid (DHA) is the most abundant ω-3 PUFA (polyunsaturated fatty acid) in the central nervous system and especially the retina and plays an important role in neuronal membrane structure integrity and neural dendritic connectivity. Hence, inclusion of ω-3s as dietary supplements could possibly be a vital therapeutic approach in alleviating stress-related ocular impairments. The objective of this study is to study the role of essential nutrients i.e., dietary ω-3 fatty acids on the ocular vulnerability to TBI and psychological stress. The retina was collected at 14 days post-insult, and gene expression changes were assessed by analyzing extracted total RNA on whole rat genome microarrays. Our findings in rats showed that TBI exposure significantly impaired the expression of retinal genes in all the diet groups, with highest change observed in the ω-3 rich house chow (HC) group. Psychological stress had a greater effect on retinal gene expression, particularly in rats fed with ω-3 deficient 1% LA diet (2249 genes downregulated and 1256 genes upregulated). The network clusters like neurovascular coupling and synaptic signaling were affected by TBI in ω-3 rich HC diet group while chemokine and actin cytoskeleton signaling were shown to be disrupted in ω-3 deficient 8% LA diet. Together, the results showed that these two diets (i.e., house chow and 8% LA) had opposing effects on some of the signaling pathways including endocannabinoid pathway and neuronal plasticity. For the UWT (underwater trauma) study, exposure to psychological stress significantly altered CREB (cAMP response element-binding protein) and opioid signaling in rodents fed with ω-3 deficient diets (i.e., 8% LA and 1% LA). Additionally, ephrin receptor and calcium signaling were differentially regulated by psychological stress in 1% LA versus 8% LA diet. Overall, the findings of our study suggest that poor dietary conditions can greatly influence the resilience to TBI and psychological stress. This work was intramurally funded by the USAMRDC/MOMRP. The objective of this study is to study the role of essential nutrients i.e., dietary ω-3 fatty acids on the ocular vulnerability to TBI and psychological stress. The retina was collected at 14 days post-insult, and gene expression changes were assessed by analyzing extracted total RNA on whole rat genome microarrays.