The influence of obesity on structure, biochemistry and function of brain regions involved in cognition

Abstract

Obesity is a major public health problem, affecting more than one-third of the U.S. population. Several studies suggest deficits in cognition in obese people and several neuroimaging studies indicate reduced volume of certain brain regions, including the hippocampus and prefrontal cortex. These brain regions are important for cognition and anxiety regulation, and thus structural change in them may contribute to alterations in cognition and mood reported in overweight people. No studies have investigated the effects of weight gain on brain structure and function at a level of analysis that would permit identification of cellular mechanisms, which could lead to future treatment options. This dissertation uses a rat model of diet-induced obesity (DIO) to explore behavioral, structural and biochemical changes in three brain regions important in cognition: the medial prefrontal cortex (mPFC), perirhinal cortex (PRC), and hippocampus (HIP).

Obese rats performed poorly on cognitive tasks specific to the mPFC and PRC, but not the HIP, compared to normal weight controls. In order to begin to characterize the behavioral differences observed, the influence of obesity on brain volume, dendritic architecture and spine density, as well as on associated pre- and post-synaptic markers in the mPFC, PRC and HIP were determined. Deficits in mPFC and PRC-related tasks were accompanied by decreased dendritic spine density and decreased pre- and post-synaptic markers in the mPFC and PRC. Finally, to identify potential mechanisms that might be driving these results, hormones that have previously been linked to changes in brain structure, and/or metabolism and obesity, were surveyed. While there was no difference in testosterone, glucose or insulin levels between groups, leptin was increased in the DIO model, providing a potential mechanism leading to changes in neurological structure and function. Further, obese rats had decreased peripheral corticosterone levels, a condition previously linked to decreased dendritic architecture, suggesting another potential involved mechanism.

The DIO animal model of obesity has allowed us to look into the cellular changes that underlie alterations in brain structure and function, and provided us with foundational research needed to identify mechanisms for future intervention.