Date of Award

5-2010

Document Type

Honors Thesis

Degree Name

Bachelor of Arts

Abstract

A major side-effect of intensive insulin replacement therapy, is recurrent hypoglycemia (RH). Clinical and experimental evidence suggest that RH may be associated with deficits in higher cognitive processes; specifically, in judgment and mental flexibility, processes believed to be mediated in large part by the medial prefrontal cortex. The present study investigates the effects of short-term RH on mental flexibility in rats. Animals underwent food restriction and were extensively handled and habituated. Prior to testing animals were randomly assigned to one of four groups with varying levels of RH. Animals were then tested for two consecutive days on a set-shift maze task designed to be analogous to the Wisconsin-Card Sorting Task used in humans as a task of frontal cortex-based rule-learning and flexibility processes. The Set-Shift maze is a rotating plus maze with a food well at the end of each arm, where each arm varies with respect to two stimulus dimensions: brightness (smooth or dark) and texture (rough or smooth). Day 1 of testing required each animal to learn a contingency rule: food reward is associated with one value of a single dimension. On day two, the reward contingency switched dimensions such that for example on day 1, if brightness was rewarded, on day 2, an aspect of texture would be rewarded. Performance on day 2 requires the animal to both (i) inhibit the previously learnt behavior, and (ii) employ a novel mental strategy to acquire the new rule, testing mental flexibility. We investigated the effects of RH on brain metabolite and neurotransmitter levels during behavioral testing using in vivo microdialysis. Post-testing, brain tissue was harvested, sectioned, and stained for proper probe placement verification and future analysis. Results indicate that on day two of testing, animals tested while euglycemic but with prior RH required significantly more trials to reach criterion as compared to controls (f=3.673; p=.029). Acute hypoglycemic status had no effect on maze performance, possibly because of the increased Effect of Recurrent Hypoglycemia on Cognition 4 motivation for receiving a food reward while hypoglycemic. These findings suggest that a history of prior hypoglycemia may lead to impaired mental flexibility and decision-making, a result which is consistent with anecdotal clinical findings and which has important implications for diabetics undergoing insulin replacement therapy. Further research may be necessary to develop more effective treatment regimens that reduce the risk of RH.

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