Long-Term Vision and Non-Vision Dominant Behavioral Deficits in the 2-VO Rats Are Accompanied by Time and Regional Glial Activation in the White Matter

The permanent occlusion of common carotid arteries (2-VO) in rats has been shown to induce progressive and long-lasting deficits in cognitive performance, however, whether these aberrant behaviors are attributed to visual dysfunction or cognitive impairment and what are the underlying mechanisms, remain controversial. In the present study, vision dominant (Morris water maze) and non-vision dominant (voice-cued fear conditioning) behavioral tests were assigned to comprehensively evaluate the influence of 2-VO lesion on cognitive behaviors. In the Morris water maze test, escape latencies of 2-VO rats were markedly increased in both hidden and unfixed visible platform tasks, which were accompanied by severe retinal damage. In the voice-cued fear conditioning test, significant reduction in the percentage of freezing behavior was observed at 60 days after 2-VO lesion. Chronic lesion by 2-VO failed to cause noticeable changes in the grey matter, as indicated by intact hippocampal and prefrontal cortical structures, sustained synaptic protein levels and glial cell numbers. In contrast, aberrant arrangement of myelinated axons was observed in the optic tract, but not in the corpus callosum and inner capsule of 2-VO rats. Concurrently, marked astrocyte proliferation and microglia activation in the optic tract occurred at 3 days after 2-VO lesion, and continued for up to 60 days. Differently, robust glial activation was observed in the corpus callosum at 3 days after 2-VO surgery, and then gradually returned to the baseline level at 14 and 60 days. Our study reported for the first time about the effect of 2-VO on the long-term cognitive impairment in the non-vision dominant fear conditioning test, which may be more applicable than the Morris water maze test for assessing 2-VO associated cognitive function. The time and region specific glial activation in the white matter may relate to retinal impairment, even behavioral deficits, in the setting of chronic cerebral hypoperfusion.