Investigating Mechanisms of Obesity-Induced Cognitive Decline

Abstract

Obesity is a global health epidemic associated with numerous comorbidities. Less well recognized is the link between obesity and cognitive decline. The mechanisms underlying obesity-associated cognitive decline in humans remain unclear. To investigate the cellular mechanisms of obesity-associated deficits in cognition, we induced obesity in male mice with high fat diet and found impairments on object memory tasks dependent on the hippocampus and perirhinal cortex. In these brain regions, we found reduced synaptic density and increased reactivity of microglia, the brain’s resident immune cell. Blockade of microglial activation through pharmacologic treatment with minocycline rescued obese mice from cognitive deficits and synaptic loss. Partial knockdown of the fractalkine receptor also prevented microglial reactivity and cognitive deficits in obese mice. We found that partial knockout of the fractalkine receptor delayed but did not prevent weight gain in high fat diet-fed mice, indicating that microglial activation facilitates increased caloric intake and weight gain during early exposure to high fat diet. We propose that microglial phagocytosis of synapses causes dendritic spine loss and cognitive decline in obesity.