Neuroscientists have confirmed the viability of an animal model for researching how insulin resistance, a precursor to Type II diabetes, compromises learning and memory. Their findings appear in the October issue of APA's Behavioral Neuroscience (Vol. 119, No. 5). The research, led by Gordon Winocur, PhD, of Trent University in Peterborough, Ontario, and Toronto's Rotman Research Institute, compared the cognitive performance of genetically obese and lean rats. The scientists trained rats on a food-reward, lever-pressing task in which 12 reinforced trials alternated with 12 nonreinforced trials. Experimenters randomly varied the intertrial intervals, which were zero, five, 10, 20, 40 or 80 seconds long.

After five days of testing and one week off, the experimenters tested the rats' fasting blood-glucose levels. Although the specially bred strain of obese Zucker rats-which have markedly higher fasting blood glucose-learned the rules of the game as well as the lean rats, the obese rats had trouble remembering what to do after longer delays between trials. Relative to the lean controls, the obese rats hit the lever much faster on nonreinforced trials when long delays followed the preceding trial.

Although the obese rats appeared to have fine strategic and working memory, both linked to the prefrontal cortex, the longer-interval problem reflected hippocampal dysfunction. That made it hard for the rats to recall cause-and-effect from a previous trial, especially after a long delay.

Biology explained the behavior, say Winocur and his colleagues at the University of Toronto, Rockefeller University in New York and the University of South Carolina School of Medicine. When the researchers studied the rats' hippocampi-a brain area that is important to memory-the obese rats' hippocampi had significantly less evidence of the gene that instructs the body to make the GLUT4 glucose-transporter protein. GLUT4 boosts the ability of muscle and fat cells to burn glucose as a metabolic fuel; impaired GLUT4 function may be why diabetes harms peripheral tissues such as the feet. Yet until now, scientists didn't know what GLUT4 did in the brain. They suspected that insulin stimulates GLUT4 transfer from outside a cell to the plasma membrane, where it works. Insulin resistance would lessen the amount of activated GLUT4.

And indeed, Winocur says, "The current studies demonstrate that insulin-mediated trafficking is disrupted in the hippocampus of Type II animals. These events may contribute to the observed deficits." In sum, if enough GLUT4 doesn't make it into the hippocampus, brain cells waiting there can't burn enough glucose for energy, making it harder to do heavy cognitive lifting.

The authors conclude that the hippocampus is particularly susceptible to insulin resistance. Confirming this relationship in rats sheds light on why human adults with insulin resistance or Type II diabetes have subtle but noticeable problems with learning and memory.

-R.K. Adelson