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J Neurosci. 2018 Oct 10;38(41):8889-8904. doi: 10.1523/JNEUROSCI.0789-18.2018. Epub 2018 Sep 10.

Microglia Play an Active Role in Obesity-Associated Cognitive Decline.

Author information

1
Princeton Neuroscience Institute and Department of Psychology, Princeton University, Princeton, New Jersey 08544.
2
Princeton Neuroscience Institute and Department of Psychology, Princeton University, Princeton, New Jersey 08544 goulde@princeton.edu.

Abstract

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.SIGNIFICANCE STATEMENT Obesity in humans correlates with reduced cognitive function. To investigate the cellular mechanisms underlying this, we used diet-induced obesity in mice and found impaired performance on cognitive tests of hippocampal function. These deficits were accompanied by reduced numbers of dendritic spines, increased microglial activation, and increased synaptic profiles within microglia. Inhibition of microglial activation by transgenic and pharmacological methods prevented cognitive decline and dendritic spine loss in obese mice. Moreover, pharmacological inhibition of the phagocytic activity of microglia was also sufficient to prevent cognitive degradation. This work suggests that microglia may be responsible for obesity-associated cognitive decline and dendritic spine loss.

KEYWORDS:

cognition; dendritic spine; microglia; obesity; synapse

PMID:
30201764
PMCID:
PMC6181311
[Available on 2019-04-10]
DOI:
10.1523/JNEUROSCI.0789-18.2018

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