Gillespie, K. M., Kemps, E., White, M. J. & Bartlett, S. E. The impact of free sugar on human health—a narrative review. Nutrients 15, 889 (2023).
Aucoin, M. et al. Diet and anxiety: a scoping review. Nutrients 13, 4418 (2021).
Jacques, A. et al. The impact of sugar consumption on stress driven, emotional and addictive behaviors. Neurosci. Biobehav. Rev. 103, 178–199 (2019).
Prinz, M., Jung, S. & Priller, J. Microglia biology: one century of evolving concepts. Cell 179, 292–311 (2019).
Jung, S., Bae, H., Song, W. S. & Jang, C. Dietary fructose and fructose-induced pathologies. Annu. Rev. Nutr. 42, 45–66 (2022).
Oppelt, S. A., Zhang, W. & Tolan, D. R. Specific regions of the brain are capable of fructose metabolism. Brain Res. 1657, 312–322 (2017).
Funari, V. A., Crandall, J. E. & Tolan, D. R. Fructose metabolism in the cerebellum. Cerebellum 6, 130–140 (2007).
Jain, S. & Zipursky, S. L. Temporal control of neuronal wiring. Semin. Cell Dev. Biol. 142, 81–90 (2023).
Reemst, K., Noctor, S. C., Lucassen, P. J. & Hol, E. M. The indispensable roles of microglia and astrocytes during brain development. Front. Hum. Neurosci. 10, 566 (2016).
Márquez-Ropero, M., Benito, E., Plaza-Zabala, A. & Sierra, A. Microglial corpse clearance: lessons from macrophages. Front. Immunol. https://doi.org/10.3389/fimmu.2020.00506 (2020).
Pereira-Iglesias, M. et al. Microglia as hunters or gatherers of brain synapses. Nat. Neurosci. 28, 15–23 (2025).
Lammert, C. R. et al. AIM2 inflammasome surveillance of DNA damage shapes neurodevelopment. Nature 580, 647–652 (2020).
Zhan, Y. et al. Deficient neuron–microglia signaling results in impaired functional brain connectivity and social behavior. Nat. Neurosci. 17, 400–406 (2014).
Kolb, B. et al. Experience and the developing prefrontal cortex. Proc. Natl Acad. Sci. USA 109, 17186–17193 (2012).
Carlén, M. What constitutes the prefrontal cortex? Science 358, 478–482 (2017).
VanElzakker, M. B., Dahlgren, M. K., Davis, F. C., Dubois, S. & Shin, L. M. From Pavlov to PTSD: the extinction of conditioned fear in rodents, humans, and anxiety disorders. Neurobiol. Learn. Mem. 113, 3–18 (2014).
Chu, C. et al. The microbiota regulate neuronal function and fear extinction learning. Nature 574, 543–548 (2019).
Berger, P. K. et al. Associations of maternal fructose and sugar-sweetened beverage and juice intake during lactation with infant neurodevelopmental outcomes at 24 months. Am. J. Clin. Nutr. 112, 1516–1522 (2020).
Berger, P. K., Fields, D. A., Demerath, E. W., Fujiwara, H. & Goran, M. I. High-fructose corn-syrup-sweetened beverage intake increases 5-hour breast milk fructose concentrations in lactating women. Nutrients 10, 669 (2018).
Montrose, D. C. et al. Dietary fructose alters the composition, localization, and metabolism of gut microbiota in association with worsening colitis. Cell. Mol. Gastroenterol. Hepatol. 11, 525–550 (2021).
Blank, T. & Prinz, M. Microglia as modulators of cognition and neuropsychiatric disorders. Glia 61, 62–70 (2013).
Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).
Douard, V. & Ferraris, R. P. Regulation of the fructose transporter GLUT5 in health and disease. Am. J. Physiol. 295, E227–E237 (2008).
Douard, V. & Ferraris, R. P. The role of fructose transporters in diseases linked to excessive fructose intake. J. Physiol. 591, 401–414 (2013).
Kellett, G. L., Brot-Laroche, E., Mace, O. J. & Leturque, A. Sugar absorption in the intestine: the role of GLUT2. Annu. Rev. Nutr. 28, 35–54 (2008).
Rand, E. B., Depaoli, A. M., Davidson, N. O., Bell, G. I. & Burant, C. F. Sequence, tissue distribution, and functional characterization of the rat fructose transporter GLUT5. Am. J. Physiol. 264, G1169–G1176 (1993).
Butovsky, O. & Weiner, H. L. Microglial signatures and their role in health and disease. Nat. Rev. Neurosci. 19, 622–635 (2018).
Wu, X. et al. Glucose transporter 5 is undetectable in outer hair cells and does not contribute to cochlear amplification. Brain Res. 1210, 20–28 (2008).
Carreau, A., El Hafny-Rahbi, B., Matejuk, A., Grillon, C. & Kieda, C. Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. J. Cell. Mol. Med. 15, 1239–1253 (2011).
Bohlen, C. J. et al. Diverse requirements for microglial survival, specification, and function revealed by defined-medium cultures. Neuron 94, 759–773.e758 (2017).
VanRyzin, J. W. et al. Microglial phagocytosis of newborn cells is induced by endocannabinoids and sculpts sex differences in juvenile rat social play. Neuron 102, 435–449.e436 (2019).
Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).
Jeong, S. et al. High fructose drives the serine synthesis pathway in acute myeloid leukemic cells. Cell Metab. 33, 145–159.e6 (2021).
Tee, S. S. et al. Ketohexokinase-mediated fructose metabolism is lost in hepatocellular carcinoma and can be leveraged for metabolic imaging. Sci. Adv. 8, eabm7985 (2022).
Jang, C. et al. The small intestine converts dietary fructose into glucose and organic acids. Cell Metab. 27, 351–361.e353 (2018).
Begoyan, V. V. et al. Multicolor GLUT5-permeable fluorescent probes for fructose transport analysis. Chem. Commun. 54, 3855–3858 (2018).
Leng, L. et al. Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance. Nat. Metab. 4, 1287–1305 (2022).
Fairley, L. H. et al. Mitochondrial control of microglial phagocytosis by the translocator protein and hexokinase 2 in Alzheimer’s disease. Proc. Natl Acad. Sci. USA 120, e2209177120 (2023).
Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013).
Wang, C. et al. Microglia mediate forgetting via complement-dependent synaptic elimination. Science 367, 688–694 (2020).
Dundee, J. M., Puigdellívol, M., Butler, R., Cockram, T. O. J. & Brown, G. C. P2Y6 receptor-dependent microglial phagocytosis of synapses mediates synaptic and memory loss in aging. Aging Cell 22, e13761 (2023).
Pattwell, S. S. et al. Altered fear learning across development in both mouse and human. Proc. Natl Acad. Sci. USA 109, 16318–16323 (2012).
Hu, Y. et al. Dual roles of hexokinase 2 in shaping microglial function by gating glycolytic flux and mitochondrial activity. Nat. Metab. 4, 1756–1774 (2022).
He, D. et al. Disruption of the IL-33–ST2–AKT signaling axis impairs neurodevelopment by inhibiting microglial metabolic adaptation and phagocytic function. Immunity 55, 159–173.e159 (2022).
Bernier, L.-P. et al. Microglial metabolic flexibility supports immune surveillance of the brain parenchyma. Nat. Commun. 11, 1559 (2020).
Wang, Y.-T. et al. Metabolic adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments. Cell Metab. 35, 316–331.e316 (2023).
Tsai, T. L. et al. Multiomics reveal the central role of pentose phosphate pathway in resident thymic macrophages to cope with efferocytosis-associated stress. Cell Rep. 40, 111065 (2022).
Wishart, D. S. et al. The human cerebrospinal fluid metabolome. J. Chromatogr. B 871, 164–173 (2008).
Van Hove, H. et al. A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat. Neurosci. 22, 1021–1035 (2019).
Fixsen, B. R. et al. SALL1 enforces microglia-specific DNA binding and function of SMADs to establish microglia identity. Nat. Immunol. 24, 1188–1199 (2023).
Hwang, J. J. et al. Fructose levels are markedly elevated in cerebrospinal fluid compared to plasma in pregnant women. PLoS ONE 10, e0128582 (2015).
Chiba, Y. et al. Glucose, fructose, and urate transporters in the choroid plexus epithelium. Int. J. Mol. Sci. 21, 7230 (2020).
Petanjek, Z. et al. Extraordinary neoteny of synaptic spines in the human prefrontal cortex. Proc. Natl Acad. Sci. USA 108, 13281–13286 (2011).
Salter, M. W. & Stevens, B. Microglia emerge as central players in brain disease. Nat. Med. 23, 1018–1027 (2017).
Maynard, T. M., Sikich, L., Lieberman, J. A. & LaMantia, A. S. Neural development, cell-cell signaling, and the “two-hit” hypothesis of schizophrenia. Schizophr. Bull. 27, 457–476 (2001).
Ostlund, B. & Pérez-Edgar, K. Two-hit model of behavioral inhibition and anxiety. Annu. Rev. Dev. Psychol. 5, 239–261 (2023).
Picci, G. & Scherf, K. S. A two-hit model of autism: adolescence as the second hit. Clin. Psychol. Sci. 3, 349–371 (2015).
Goran, M. I., Martin, A. A., Alderete, T. L., Fujiwara, H. & Fields, D. A. Fructose in breast milk is positively associated with infant body composition at 6 months of age. Nutrients 9, 146 (2017).
Goncalves, M. D. et al. High-fructose corn syrup enhances intestinal tumor growth in mice. Science 363, 1345–1349 (2019).
Monsorno, K. et al. Loss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice. Nat. Commun. 14, 5749 (2023).
Schafer, D. P., Lehrman, E. K., Heller, C. T. & Stevens, B. An engulfment assay: a protocol to assess interactions between CNS phagocytes and neurons. J. Vis. Exp. https://doi.org/10.3791/51482-v (2014).
Davis, B. M., Salinas-Navarro, M., Cordeiro, M. F., Moons, L. & De Groef, L. Characterizing microglia activation: a spatial statistics approach to maximize information extraction. Sci. Rep. 7, 1576 (2017).
Young, K. & Morrison, H. Quantifying microglia morphology from photomicrographs of immunohistochemistry prepared tissue using ImageJ. J. Vis. Exp. https://doi.org/10.3791/57648-v (2018).
Yang, W. et al. in StemBook (Harvard Stem Cell Institute, 2008).
Lachmann, N. et al. Large-scale hematopoietic differentiation of human induced pluripotent stem cells provides granulocytes or macrophages for cell replacement therapies. Stem Cell Rep. 4, 282–296 (2015).
Bolte, S. & Cordelières, F. P. A guided tour into subcellular colocalization analysis in light microscopy. J. Microsc. 224, 213–232 (2006).
Faraco, G. et al. Dietary salt promotes cognitive impairment through tau phosphorylation. Nature 574, 686–690 (2019).
Faraco, G. et al. Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response. Nat. Neurosci. 21, 240–249 (2018).
Aguilar, S. V. et al. ImmGen at 15. Nat. Immunol. 21, 700–703 (2020).
Consortium, T. M. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 583, 590–595 (2020).
Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947 (2014).
Zhang, Y. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37–53 (2016).
Li, Q. et al. Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing. Neuron 101, 207–223.e210 (2019).
Srinivasan, K. et al. Alzheimer’s patient microglia exhibit enhanced aging and unique transcriptional activation. Cell Rep. 31, 107843 (2020).
Matcovitch-Natan, O. et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353, aad8670 (2016).
Bennett, M. L., Bennett, F. C., Liddelow, S. A. & Barres, B. A. New tools for studying microglia in the mouse and human CNS. Proc. Natl Acad. Sci. USA 113, E1738–E1746 (2016).
