Blast-induced traumatic brain injury is the signature injury of modern military conflicts. To more fully understand the effects of blast exposure, we placed rats in different holder configurations, exposed them to blast overpressure, and assessed the degree of eye and brain injury. Anesthetized Long-Evans rats received blast exposures directed at the head (63 kPa, 195 dB-SPL) in either an “open holder” (head and neck exposed; n = 7), or an “enclosed holder” (window for blast exposure to eye; n = 15) and were compared to non-blast exposed (control) rats (n = 22). Outcomes included optomotor response (OMR), electroretinography (ERG), and spectral domain optical coherence tomography (SD-OCT) at 2, 4, and 6 months post-blast, and cognitive function (Y-maze) at 3 months. Spatial frequency and contrast sensitivity were reduced in ipsilateral blast-exposed eyes in both holders (p < 0.01), while contralateral eyes showed greater deficits with the enclosed holder (p < 0.05). Thinner retinas (p < 0.001) and reduced ERG a- and b- wave amplitudes (p < 0.05) were observed for both ipsilateral and contralateral eyes with the enclosed, but not the open, holder. Rats in the open holder showed cognitive deficits compared to rats in the enclosed holder (p < 0.05). Overall, the animal holder configuration used in blast exposure studies can significantly affect outcomes. Enclosed holders may cause secondary damage to the contralateral eye by concussive injury or blast wave reflection off the holder wall. Open holders may damage the brain via rapid head movement (contrecoup injury). These results highlight additional factors to be considered when evaluating patients with blast exposure or developing models of blast injury.

Diseases that affect the eye, including photoreceptor degeneration, diabetic retinopathy, and glaucoma, affect 11.8 million people in the US, resulting in vision loss and blindness. Loss of sight affects patient quality of life and puts an economic burden both on individuals and the greater healthcare system. Despite the urgent need for treatments, few effective options currently exist in the clinic. Here, we review research on promising neuroprotective strategies that promote neuronal survival with the potential to protect against vision loss and retinal cell death. Due to the large number of neuroprotective strategies, we restricted our review to approaches that we had direct experience with in the laboratory. We focus on drugs that target survival pathways, including bile acids like UDCA and TUDCA, steroid hormones like progesterone, therapies that target retinal dopamine, and neurotrophic factors. In addition, we review rehabilitative methods that increase endogenous repair mechanisms, including exercise and electrical stimulation therapies. For each approach, we provide background on the neuroprotective strategy, including history of use in other diseases; describe potential mechanisms of action; review the body of research performed in the retina thus far, both in animals and in humans; and discuss considerations when translating each treatment to the clinic and to the retina, including which therapies show the most promise for each retinal disease. Despite the high incidence of retinal diseases and the complexity of mechanisms involved, several promising neuroprotective treatments provide hope to prevent blindness. We discuss attractive candidates here with the goal of furthering retinal research in critical areas to rapidly translate neuroprotective strategies into the clinic.

The optomotor response and the Y-maze are behavioral tests useful for assessing visual and cognitive function, respectively. The optomotor response is a valuable tool to track changes in spatial frequency (SF) and contrast sensitivity (CS) thresholds over time in a number of retinal disease models, including diabetic retinopathy. Similarly, the Y-maze can be used to monitor spatial cognition (as measured by spontaneous alternation) and exploratory behavior (as measured by a number of entries) in a number of disease models that affect the central nervous system. Advantages of the optomotor response and the Y-maze include sensitivity, speed of testing, the use of innate responses (training is not needed), and the ability to be performed on awake (non-anesthetized) animals. Here, protocols are described for both the optomotor response and the Y-maze and examples of their use shown in models of Type I and Type II diabetes. Methods include preparation of rodents and equipment, performance of the optomotor response and the Y-maze, and post-test data analysis.

Spectral-domain optical coherence tomography (SD-OCT) is useful for visualizing retinal and ocular structures in vivo. In research, SD-OCT is a valuable tool to evaluate and characterize changes in a variety of retinal and ocular disease and injury models. In light induced retinal degeneration models, SD-OCT can be used to track thinning of the photoreceptor layer over time. In glaucoma models, SD-OCT can be used to monitor decreased retinal nerve fiber layer and total retinal thickness and to observe optic nerve cupping after inducing ocular hypertension. In diabetic rodents, SD-OCT has helped researchers observe decreased total retinal thickness as well as decreased thickness of specific retinal layers, particularly the retinal nerve fiber layer with disease progression. In mouse models of myopia, SD-OCT can be used to evaluate axial parameters, such as axial length changes. Advantages of SD-OCT include in vivo imaging of ocular structures, the ability to quantitatively track changes in ocular dimensions over time, and its rapid scanning speed and high resolution. Here, we detail the methods of SD-OCT and show examples of its use in our laboratory in models of retinal degeneration, glaucoma, diabetic retinopathy, and myopia. Methods include anesthesia, SD-OCT imaging, and processing of the images for thickness measurements.

Glaucoma is the leading cause of irreversible blindness worldwide, and women represent roughly 60% of the affected population. Early menopause and estrogen signaling defects are risk factors for glaucoma. Recently, we found that surgical menopause exacerbated visual dysfunction in an ocular hypertension model of glaucoma. Here, we investigated if surgical menopause exacerbated visual dysfunction in a model of direct retinal ganglion cell (RGC) damage via optic nerve crush (ONC). Female Long Evans rats (n = 12) underwent ovariectomy (OVX) to induce surgical menopause or Sham surgery. Eight weeks post-surgery, baseline visual function was assessed via optomotor response. Afterwards, rats underwent monocular ONC. Visual function was assessed at 4, 8, and 12 weeks post-ONC. At 12 weeks, retinal function via electroretinography and retinal nerve fiber layer (RNFL) thickness via optical coherence tomography were measured. Visual acuity was reduced after ONC (p < 0.001), with surgical menopausal animals having 31.7% lower visual acuity than Sham animals at 12 weeks (p = 0.01). RNFL thinning (p < 0.0001) and decreased RGC function (p = 0.0016) occurred at 12 weeks in ONC groups. Surgical menopause worsens visual acuity after direct RGC damage using an ONC model. This demonstrates that surgical menopause plays a role in visual function after injury.

High fat diets (HFD) have been utilized in rodent models of visual disease for over 50 years to model the effects of lipids, metabolic dysfunction, and diet-induced obesity on vision and ocular health. HFD treatment can recapitulate the pathologies of some of the leading causes of blindness, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR) in rodent models of visual disease. However, there are many important factors to consider when using and interpreting these models. To synthesize our current understanding of the importance of lipid signaling, metabolism, and inflammation in HFD-driven visual disease processes, we systematically review the use of HFD in mouse and rat models of visual disease. The resulting literature is grouped into three clusters: models that solely focus on HFD treatment, models of diabetes that utilize both HFD and streptozotocin (STZ), and models of AMD that utilize both HFD and genetic models and/or other exposures. Our findings show that HFD profoundly affects vision, retinal function, many different ocular tissues, and multiple cell types through a variety of mechanisms. We delineate how HFD affects the cornea, lens, uvea, vitreous humor, retina, retinal pigmented epithelium (RPE), and Bruch's membrane (BM). Furthermore, we highlight how HFD impairs several retinal cell types, including glia (microglia), retinal ganglion cells, bipolar cells, photoreceptors, and vascular support cells (endothelial cells and pericytes). However, there are a number of gaps, limitations, and biases in the current literature. We highlight these gaps and discuss experimental design to help guide future studies. Very little is known about how HFD impacts the lens, ciliary bodies, and specific neuronal populations, such as rods, cones, bipolar cells, amacrine cells, and retinal ganglion cells. Additionally, sex bias is an important limitation in the current literature, with few HFD studies utilizing female rodents. Future studies should use ingredient-matched control diets (IMCD), include both sexes in experiments to evaluate sex-specific outcomes, conduct longitudinal metabolic and visual measurements, and capture acute outcomes. In conclusion, HFD is a systemic exposure with profound systemic effects, and rodent models are invaluable in understanding the impacts on visual and ocular disease.

Diabetes has been demonstrated to be one of the strongest predictors of risk for postoperative delirium and functional decline in older patients undergoing surgery. Exercise is often prescribed as a treatment for diabetic patients and regular physical activity is hypothesized to decrease the risk of postoperative cognitive impairments. Prior studies suggest that anesthetic emergence trajectories and recovery are predictive of risk for later postoperative cognitive impairments. Therapeutic strategies aimed at improving emergence and recovery from anesthesia may therefore be beneficial for diabetic patients. Wistar (n = 32) and Goto-Kakizaki (GK) type 2 diabetic (n = 32) rats between 3–4 months old underwent treadmill exercise for 30 min/day for ten days or remained inactive. Pre-anesthesia spontaneous alternation behavior was recorded with a Y-maze. Rats then received a 2-h exposure to 1.5–2 % isoflurane or oxygen only. The time to reach anesthetic emergence and post-anesthesia recovery behaviors was recorded for each rat. Postsynaptic density protein-95 (PSD-95), an important scaffolding protein required for synaptic plasticity, protein levels were quantified from hippocampus using western blot. Spontaneous alternation behavior (p = 0.044) and arm entries (p < 0.001) were decreased in GK rats. There was no difference between groups in emergence times from isoflurane, but exercise hastened the recovery time (p = 0.008) for both Wistar and GK rats. Following 10 days of exercise, both Wistar and GK rats show increased levels of PSD-95 in the hippocampus. Prehabilitation with moderate intensity exercise, even on a short timescale, is beneficial for recovery from isoflurane in rats, regardless of metabolic disease status.

Purpose: L-DOPA treatment initiated at the start of hyperglycemia preserves retinal and visual function in diabetic rats. Here, we investigated a more clinically relevant treatment strategy in which retinal and visual dysfunction designated the beginning of the therapeutic window for L-DOPA treatment. Methods: Spatial frequency thresholds using optomotor response and oscillatory potential (OP) delays using electroretinograms were compared at baseline, 3, 6, and 10 weeks after streptozotocin (STZ) between diabetic and control rats. L-DOPA/carbidopa treatment (DOPA) or vehicle was delivered orally 5 days per week beginning at 3 weeks after STZ, when significant retinal and visual deficits were measured. At 10 weeks after STZ, retinas were collected to measure L-DOPA, dopamine, and 3,4-dihydroxyphenylacetic acid (DOPAC) levels using high-performance liquid chromatography. Results: Spatial frequency thresholds decreased at 6 weeks in diabetic vehicle rats (28%), whereas diabetic DOPA rats had stable thresholds (<1%) that maintained to 10 weeks, creating significantly higher thresholds compared with diabetic vehicle rats (P < 0.0001). OP2 implicit times in response to dim, rod-driven stimuli were decreased in diabetic compared with control rats (3 weeks, P < 0.0001; 10 weeks, P < 0.01). With L-DOPA treatment, OP2 implicit times recovered in diabetic rats to be indistinguishable from control rats by 10 weeks after STZ. Rats treated with L-DOPA showed significantly increased retinal L-DOPA (P < 0.001) and dopamine levels (P < 0.05). Conclusions: L-DOPA treatment started after the detection of retinal and visual dysfunction showed protective effects in diabetic rats. Translational Relevance: Early retinal functional deficits induced by diabetes can be used to identify an earlier therapeutic window for L-DOPA treatment which protects from further vision loss and restores retinal function.