Journal
JOURNAL OF NEUROSCIENCE
Volume 38, Issue 41, Pages 8889-8904Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0789-18.2018
Keywords
cognition; dendritic spine; microglia; obesity; synapse
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Funding
- National Institutes of Health, National Institute of Neurological Disorders and Stroke Grant [1R21NS087460-01]
- National Institutes of Health Training Fellowship [T32MH065214]
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Obesity affects >600 million people worldwide, a staggering number that appears to be on the rise. One of the lesser known consequences of obesity is its deleterious effects on cognition, which have been well documented across many cognitive domains and age groups. To investigate the cellular mechanisms that underlie obesity-associated cognitive decline, we used diet-induced obesity in male mice and found memory impairments along with reductions in dendritic spines, sites of excitatory synapses, increases in the activation of microglia, the brain's resident immune cells, and increases in synaptic profiles within microglia, in the hippocampus, a brain region linked to cognition. We found that partial knockdown of the receptor for fractalkine, a chemokine that can serve as a find me cue for microglia, prevented microglial activation and cognitive decline induced by obesity. Furthermore, we found that pharmacological inhibition of microglial activation in obese mice was associated with prevention of both dendritic spine loss and cognitive degradation. Finally, we observed that pharmacological blockade of microglial phagocytosis lessened obesity-associated cognitive decline. These findings suggest that microglia play an active role in obesity-associated cognitive decline by phagocytosis of synapses that are important for optimal function.
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