Abstract
Impaired learning and cognitive function often occurs during systemic infection or inflammation. Although activation of the innate immune system has been linked to the behavioral and cognitive effects that are associated with infection, the underlying mechanisms remain poorly understood. Here we mimicked viral immune activation with poly(I:C), a synthetic analog of double-stranded RNA, and longitudinally imaged postsynaptic dendritic spines of layer V pyramidal neurons in the mouse primary motor cortex using two-photon microscopy. We found that peripheral immune activation caused dendritic spine loss, impairments in learning-dependent dendritic spine formation and deficits in multiple learning tasks in mice. These observed synaptic alterations in the cortex were mediated by peripheral-monocyte-derived cells and did not require microglial function in the central nervous system. Furthermore, activation of CX3CR1highLy6Clow monocytes impaired motor learning and learning-related dendritic spine plasticity through tumor necrosis factor (TNF)-α-dependent mechanisms. Taken together, our results highlight CX3CR1high monocytes and TNF-α as potential therapeutic targets for preventing infection-induced cognitive dysfunction.
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Acknowledgements
We thank W.B. Gan (New York University) for the Cx3cr1–CreER mice and D.R. Littman (New York University) for the Cx3cr1–GFP mice. We also thank W.B. Gan and M.V. Bennett for critical reading of the manuscript. This work was supported by a Whitehall Foundation Research Grant (G.Y.), the US National Institutes of Health grants R01GM107469 (G.Y.) and R21AG048410 (G.Y.) and a National Council for Scientific and Technological Development (CNPq) (Brazil) fellowship (H.M.S.).
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J.M.G., H.M.S., J.J.L. and G.Y. designed the experiments; J.M.G. performed the in vivo imaging experiments, animal behavior assays and biochemical experiments; J.M.G. and H.M.S. performed the flow cytometry experiments; all authors contributed to the data analysis and interpretation; and J.M.G. and G.Y. wrote the manuscript.
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Garré, J., Silva, H., Lafaille, J. et al. CX3CR1+ monocytes modulate learning and learning-dependent dendritic spine remodeling via TNF-α. Nat Med 23, 714–722 (2017). https://doi.org/10.1038/nm.4340
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DOI: https://doi.org/10.1038/nm.4340
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