Type 2 diabetes is a metabolic disease affecting millions of people around the world. Cognitive and mood impairments are among its many debilitating complications, but disease mechanism(s) remain elusive. Here, we present a series of behavioral tasks that demonstrate impairment of cognitive flexibility in db/db mice, a commonly used type 2 diabetes model. Using immunohistochemistry, we demonstrate disruption of axon initial segments (AIS) and nodes of Ranvier, excitable axonal domains regulating neuronal output, in brain regions associated with cognitive and mood impairments. Finally, we present results of exercise treatment that ameliorates AIS disruption in these animals. Establishing cognitive flexibility deficits in db/db mice that parallel disease complications in patients with type 2 diabetes allows future research to test novel treatment strategies, while discovering disruption of excitable axonal domains fills the missing gap in our understanding of disease pathophysiology
