THE IMPACT OF PROLONGED HYPERGLYCEMIA ON COGNITIVE FUNCTION AND MOLECULAR PATHWAYS IN Danio rerio

The present study used Danio rerio (zebrafish) and induced prolonged hyperglycemia (a hallmark symptom of Type II diabetes) for eight or twelve weeks. The goal was threefold: (1) assess cognitive and visual decline in hyperglycemic zebrafish, as diabetes and dementia seem to be correlated, (2) determine if there are any vascular complications in the blood brain or retinal barrier that might contribute to these deficits, and (3) examine if the fish were able to recover from hyperglycemic insult following removal from treatment (i.e., returning to normglycemia). Overall behavioral data did not support our hypothesis that glucose-treated fish would perform worse than water-treated fish. Responses in hyperglycemic fish were similar to mannitol (osmotic)- controls, suggesting glucose induced an increase in osmotic load to the cells, rather than triggering a specific intracellular pathway. These results were not changed when assessed after the recovery period, however vision-based optomotor responses revealed no glucose-induced osmotic effects. In contrast, the molecular analysis showed increased inflammation and decreased tight junction proteins in hyperglycemic fish, with recovery noted. Taken together, these data suggest that prolonged hyperglycemia triggers an inflammatory response and effects tight junction proteins associated with blood brain and blood retinal barriers. Correlated changes in cognitive-behaviors, however, reflect osmotic changes, suggesting differential effects of glucose exposure. Further, osmotically-driven changes tend to be prolonged, as behavioral deficits remained even after return to normglycemic conditions.