Moderate Recurrent Hypoglycemia Markedly Impairs Set-Shifting Ability in a Rodent Model: Cognitive and Neurochemical Effects

Abstract

Recurrent hypoglycemia (RH) is the major complication of intensive insulin treatment for diabetes mellitus. Of particular concern is the perceived potential for long-term impact of RH on cognition. Because diabetic patients have been reported to have deficits in mental flexibility and judgment, both generally considered to be mediated predominantly by the prefrontal cortex, the purpose of the present study was to determine whether RH would affect prefrontal cortex function. Medial prefrontal cortex (mPFC)-mediated set-shifting ability was tested in male Sprague-Dawley rats using a maze-based, food-reward Set-Shift task analogous to the Wisconsin card-sorting task. The performance measure was the number of trials to criterion on both day 1 (initial rule-learning) and day 2 (set-shifting in response to a changed contingency). In vivo microdialysis was used to measure mPFC extracellular glucose, lactate, pyruvate, glutamate, and dopamine. Post-mortem measures within the mPFC included glucose transporter 3 (GluT3) and c-Fos. RH animals had enhanced performance on day 1, consistent with previous work that showed RH to improve subsequent hippocampal function when euglycemic. The key finding of the present work is that RH led to impaired set-shifting performance on day 2, suggesting impairment in e.g. mental flexibility. Consistent with this finding, RH animals show decreased mPFC glycolysis on day 2 compared to controls. Our data show that RH can lead to subsequent impaired judgment, accompanied by reduced prefrontal cortex function. The findings suggest a potential underlying mechanism for the impaired judgment seen in diabetic patients.

Recurrent Hypoglycemia Increases Anxiety and Amygdala Norepinephrine Release During Subsequent Hypoglycemia

“…Taken together with our previous studies, the findings here indicate that RH affects multiple neural systems and brain structures, with the impact of RH varying by region and system. For instance, during subsequent euglycemia, RH enhances hippocampal memory ( 22 , 23 ), impairs mental flexibility processes in the prefrontal cortex ( 24 ), but does not affect performance in an elevated plus-maze test of anxiety (present data). The ability of a rodent model of RH to accurately mimic many of the cognitive effects seen in human patients after RH suggests that this is an appropriate system for further studies aimed at identifying the molecular mechanisms transducing the cognitive, neural, and metabolic impact of RH, with a goal of identifying appropriate therapeutic approaches to prevention and intervention.…”

“…In studies to date, RH in our model has not impaired or reduced motor activity, visual acuity, or, e.g., motivation: for example, RH animals make the same number of maze-arm choices ( 22 , 23 ), have the same latency to seek reward ( 24 ), and perceive both visual and textural stimuli as well as or better than control animals ( 24 ). We confirmed that RH had no measureable effects on motor performance, motivation, or sensory acuity using small separate cohorts of animals, treated identically to those reported here and tested on a simple Y-maze alternation task.…”

“…Our previous work ( 22 – 24 , 50 ) suggested that neural adaptations seen following RH might be maladaptive during subsequent hypoglycemia. This is consistent with the clinical experience of patients, where RH is associated with, e.g., increased risk of death while driving.…”

“…Our recent review ( 19 ) concluded that there is strong evidence that RH can alter cognitive and neural function, but studies of RH in human beings have often had difficulty in controlling for confounding disease states and/or variable prior history of hypoglycemia ( 6 , 15 , 17 , 20 , 21 ). In three previous reports that examined RH in rats, we have characterized the impact of RH on subsequent hippocampal function including spatial memory ( 22 , 23 ) and on mental flexibility, mediated by the prefrontal cortex ( 24 ). The rat model of RH used in those studies accurately simulates the effects of RH and HAAF in human beings ( 22 – 28 ), and we have continued to use this model in the present work.…”

Recurrent Moderate Hypoglycemia Suppresses Brain-Derived Neurotrophic Factor Expression in the Prefrontal Cortex and Impairs Sensorimotor Gating in the Posthypoglycemic Period in Young Rats

“…However, this possibility remains speculative in the absence of confirmatory protein assay or histochemical analysis. It is noteworthy that recurrent moderate hypoglycemia leads to dampening of PFC activation in the post-hypoglycemia period in adult rats [49,50]. …”