Microglia Play an Active Role in Obesity-Associated Cognitive Decline

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. 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.

Microglial regulation of satiety and cognition

“…Notably, the detrimental effects of microglial ablation on motor learning are linked to a reduction in synapse formation in the motor cortex in the learning phases of this task . Likewise, the detrimental effects of high‐fat diet on novel object recognition performance can be restored by preventing excessive microglia‐mediated pruning of dendritic spines . These data again suggest that both the absence of microglia and their excessive activity can encourage excess synaptic pruning with a negative outcome for cognition.…”

“…There is some evidence to suggest microglial activation is detrimental to cognition and that removing microglia altogether may be beneficial. Cope et al have recently shown that 10 weeks of high‐fat diet in the mouse leads to microglial activation in the hippocampus, as well as cognitive deficits, and preventing this activation with knockdown of the fractalkine receptor or with minocycline restores cognition. Although microglial activation outside of the hypothalamus is rarely seen with short‐term high‐fat feeding, there is evidence to suggest that it can occur with longer exposures and that this may be linked with cognitive dysfunction .…”

“…Although microglial activation outside of the hypothalamus is rarely seen with short‐term high‐fat feeding, there is evidence to suggest that it can occur with longer exposures and that this may be linked with cognitive dysfunction . In this case, microglia may be encouraged in excessive pruning of dendritic spines by an over‐activation of the complement signalling pathway initiated at the level of the neurone because annexin‐V, a compound that blocks microglial phagocytosis by binding to “eat me” phosphatidylserine residues on dying cells, also completely restores cognition . In ageing rats, microgliosis and microglial priming are also associated with cognitive decline and microglial priming in the amygdala, in particular, is linked to poor cognitive outcomes .…”

“…However, it is still unclear whether microglial activation is a cause or an attempt‐at‐a‐protective consequence of obesity. Preventing microglial activation with minocycline fails to restore body weight in high‐fat diet‐fed mice of the same strain as that used for the Ara‐C experiments . Likewise, microglial priming associated with ageing does not automatically lead to obesity in this population and circadian rhythm disruption with dim light at night leads to weight gain in the absence of changes in microglial morphology .…”

“…Similarly, studies employing other pharmacological agents to block microglial proliferation, activity or interactions with neurones (eg AraC, mice, 15 μg μL ‐1 i.c.v. at 0.11 μL L ‐1 for 4 weeks; minocycline: mice, 40 mg kg ‐1 in drinking water for 2 weeks; annexin‐V: mice, 200 μg kg ‐1 i.v. for 3 days) also often show no effect on weight in control animals .…”