Antecedent recurrent hypoglycemia mitigated cognitive dysfunction induced by severe hypoglycemia. Morris water maze testing
was performed 6–8 weeks following severe hypoglycemic or euglycemic clamps. A: During the cue trial, CON-SH90 rats (open circles) (n = 11) performed worse as evidenced by longer escape-path lengths than those of CON-EUG rats (open triangles) (n = 7) (aP = 0.002). Notably, rats exposed to recurrent moderate hypoglycemia before severe hypoglycemia (RH-SH90, n = 9 (closed circles) had shorter escape-path lengths than CON-SH90 rats (bP = 0.0025) and performed similarly to CON-EUG and RH-EUG rats (closed triangles) (n = 9). B: A similar pattern was observed during the place trials, where CON-SH90 rats had significantly higher escape-path lengths
than CON-EUG (cP = 0.0001) and RH-SH90 (dP = 0.0006) rats. C: During the probe trial, CON-SH90 rats (diagonal hatch) had significantly fewer platform crossings than CON-EUG rats (white
bar) (eP = 0.014). No significant differences were observed between CON-SH90 and RH-SH90 rats (gray horizontal hatch) or between CON-EUG
and RH-EUG rats (black bar). D: RH-SH90, CON-EUG, and RH-EUG rats had a spatial bias toward the target quadrant while CON-SH90 rats did not (*P < 0.0025). E: During the probe trial, CON-SH90 rats showed an average proximity to the platform location that was significantly farther
away than that of the CON-EUG rats (fP = 0.014). RH-SH90 rats swam significantly closer to the platform location than CON-SH90 rats (gP = 0.014)—similar to euglycemic controls. F: The number of episodes of seizure-like behaviors observed during severe hypoglycemia 6–8 weeks prior positively correlated
with average path length during the place trials (R = 0.685; P < 0.001; n = 20).