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Anterior insular cortex regulates depression-like and ASD-like behaviors via the differential contribution of two subsets of microglia

Molecular Psychiatry (2025)Cite this article

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Abstract

The anterior insular cortex (aIC) is involved in multiple neuropsychiatric disorders. Here, using the Cntnap2-deficient autism spectrum disorder (ASD) mouse model and the chronic social defect stress (CSDS)-induced depression mouse model, we show that two subpopulations of microglia in the mouse aIC played differential roles in ASD-like and depression-like behavioral phenotypes differentially. The Cx3cr1+ microglia had morphological deficits in the Cntnap2-deficient mice and were involved in social deficits and restricted repetitive behaviors, while the Tmem119+ microglia had morphological deficits in the CSDS-induced mice and contributed to impairments in sucrose preference and forced swim performance. Further, we showed that the two subsets of microglia had differential features in morphology, transcriptional profiles, electrophysiological properties, and impacts on synaptic functions. Using proteomic and metabonomic analyses, we identified two secretory factors, Fbl and Hp1bp3, that were crucial for the dysfunctions of the Cx3cr1+ and Tmem119+ microglia, respectively. Finally, we verified that Fbl and Hp1bp3 played essential roles in the behavioral deficits of the Cntnap2-deficient and the CSDS-induced mice, respectively. Our study can help understand the contribution of microglia and the aIC to neuropsychiatric-like behaviors.

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Fig. 1: Microglial deficits in the aIC induce neuropsychiatric-like behaviors.
Fig. 2: Cx3cr1+ and Tmem119+ microglia show differential morphological changes in disease animal models.
Fig. 3: Chemogenetic inhibition of Cx3cr1+ and Tmem119+ microglia in aIC induce differential effects on ASD-like and depression-like behaviors.
Fig. 4: Characterization of Cx3cr1+ and Tmem119+ microglia in the aIC.
Fig. 5: Differential effects of chemogenetic inhibition of Cx3cr1+ and Tmem119+ microglia on neuronal functions.
Fig. 6: Identification of molecules released following microglia inhibition that play crucial roles in behavioral deficits.
Fig. 7: Enhanced expression of Fbl and Hp1bp3 rescues the neuronal and behavioral phenotypes of Cx3cr1/Tmem119-hM4Di mice.
Fig. 8: Fbl and Hp1bp3 rescue the behavioral phenotypes of Cntnap2-deficient and CSDS-induced mice.

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Data availability

All data supporting the findings of this study are included in this paper and the supplementary materials. Metabonomics and scRNA-seq data of microglia are available in the CNSA database (Accession number: CNP0007796). Proteomics data are available in the Integrated Proteome Resources (iProX) database (Accession number: IPX0012891000).

References

  1. Chen YF, Song Q, Colucci P, Maltese F, Siller-Pérez C, Prins K, et al. Basolateral amygdala activation enhances object recognition memory by inhibiting anterior insular cortex activity. Proc Natl Acad Sci USA. 2022;119:e2203680119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Uddin LQ. Salience processing and insular cortical function and dysfunction. Nat Rev Neurosci. 2015;16:55–61.

    Article  CAS  PubMed  Google Scholar 

  3. Menon V, Uddin LQ. Saliency, switching, attention and control: a network model of insula function. Brain Structure Funct. 2010;214:655–67.

    Article  Google Scholar 

  4. Namkung H, Kim SH, Sawa A. The Insula: an underestimated brain area in clinical neuroscience, psychiatry, and neurology. Trends Neurosci. 2017;40:200–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gogolla N, Takesian AE, Feng G, Fagiolini M, Hensch TK. Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron. 2014;83:894–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Caria A, de Falco S. Anterior insular cortex regulation in autism spectrum disorders. Front Behav Neurosci. 2015;9:38.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Moran LV, Tagamets MA, Sampath H, O’Donnell A, Stein EA, Kochunov P, et al. Disruption of anterior insula modulation of large-scale brain networks in schizophrenia. Biol Psychiatry. 2013;74:467–74.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Palaniyappan L, Simmonite M, White Thomas P, Liddle Elizabeth B, Liddle Peter F. Neural primacy of the salience processing system in schizophrenia. Neuron. 2013;79:814–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kühn S, Gallinat J. Common biology of craving across legal and illegal drugs – a quantitative meta-analysis of cue-reactivity brain response. Eur J Neurosci. 2011;33:1318–26.

    Article  PubMed  Google Scholar 

  10. Engelmann JM, Versace F, Robinson JD, Minnix JA, Lam CY, Cui Y, et al. Neural substrates of smoking cue reactivity: a meta-analysis of fMRI studies. Neuroimage. 2012;60:252–62.

    Article  PubMed  Google Scholar 

  11. Bonthius DJ, Solodkin A, Van Hoesen GW. Pathology of the insular cortex in alzheimer disease depends on cortical architecture. J Neuropathol Exp Neurol. 2005;64:910–22.

    Article  PubMed  Google Scholar 

  12. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330:841–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wlodarczyk A, Holtman IR, Krueger M, Yogev N, Bruttger J, Khorooshi R, et al. A novel microglial subset plays a key role in myelinogenesis in developing brain. EMBO J. 2017;36:3292–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Li Y, Du XF, Liu CS, Wen ZL, Du JL. Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo. Dev Cell. 2012;23:1189–202.

    Article  CAS  PubMed  Google Scholar 

  15. Cornell J, Salinas S, Huang HY, Zhou M. Microglia regulation of synaptic plasticity and learning and memory. Neural Regen Res. 2022;17:705–16.

    Article  CAS  PubMed  Google Scholar 

  16. Lukens JR, Eyo UB. Microglia and neurodevelopmental disorders. Annu Rev Neurosci. 2022;45:425–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cserép C, Pósfai B, Lénárt N, Fekete R, László ZI, Lele Z, et al. Microglia monitor and protect neuronal function through specialized somatic purinergic junctions. Science. 2020;367:528–37.

    Article  PubMed  Google Scholar 

  18. Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry. 2015;72:268–75.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Torres-Platas SG, Cruceanu C, Chen GG, Turecki G, Mechawar N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun. 2014;42:50–59.

    Article  CAS  PubMed  Google Scholar 

  20. Böttcher C, Fernández-Zapata C, Snijders GJL, Schlickeiser S, Sneeboer MAM, Kunkel D, et al. Single-cell mass cytometry of microglia in major depressive disorder reveals a non-inflammatory phenotype with increased homeostatic marker expression. Transl Psychiatry. 2020;10:310.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Steiner J, Bielau H, Brisch R, Danos P, Ullrich O, Mawrin C, et al. Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J Psychiatr Res. 2008;42:151–7.

    Article  PubMed  Google Scholar 

  22. Suzuki K, Sugihara G, Ouchi Y, Nakamura K, Futatsubashi M, Takebayashi K, et al. Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry. 2013;70:49–58.

    Article  PubMed  Google Scholar 

  23. Öngür D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci. 1998;95:13290–5.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Réus GZ, Fries GR, Stertz L, Badawy M, Passos IC, Barichello T, et al. The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders. Neuroscience. 2015;300:141–54.

    Article  PubMed  Google Scholar 

  25. Bennett ML, Bennett FC, Liddelow SA, Ajami B, Zamanian JL, Fernhoff NB, et al. New tools for studying microglia in the mouse and human CNS. Proc Natl Acad Sci. 2016;113:E1738–E1746.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Favuzzi E, Huang S, Saldi GA, Binan L, Ibrahim LA, Fernandez-Otero M, et al. GABA-receptive microglia selectively sculpt developing inhibitory circuits. Cell. 2021;184:5686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zrzavy T, Hametner S, Wimmer I, Butovsky O, Weiner HL, Lassmann H. Loss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis. Brain. 2017;140:1900–13.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Cao P, Chen C, Liu A, Shan Q, Zhu X, Jia C, et al. Early-life inflammation promotes depressive symptoms in adolescence via microglial engulfment of dendritic spines. Neuron. 2021;109:2573–2589 e2579.

    Article  CAS  PubMed  Google Scholar 

  29. Lawson LJ, Perry VH, Dri P, Gordon S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience. 1990;39:151–70.

    Article  CAS  PubMed  Google Scholar 

  30. De Biase LM, Schuebel KE, Fusfeld ZH, Jair K, Hawes IA, Cimbro R, et al. Local Cues establish and maintain region-specific phenotypes of Basal Ganglia Microglia. Neuron. 2017;95:341–356.e346.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Schmid CD, Sautkulis LN, Danielson PE, Cooper J, Hasel KW, Hilbush BS, et al. Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J Neurochem. 2002;83:1309–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wu S, Nguyen LTM, Pan H, Hassan S, Dai Y, Xu J, et al. Two phenotypically and functionally distinct microglial populations in adult zebrafish. Sci Adv. 2020;6:eabd1160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Stratoulias V, Ruiz R, Kanatani S, Osman AM, Keane L, Armengol JA, et al. ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain. Nat Neurosci. 2023;26:1008–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Stephan DA. Unraveling autism. Am J Hum Genet. 2008;82:7–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Alarcon M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV, Bomar JM, et al. Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet. 2008;82:150–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Penagarikano O, Abrahams BS, Herman EI, Winden KD, Gdalyahu A, Dong H, et al. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell. 2011;147:235–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Satoh J, Kino Y, Asahina N, Takitani M, Miyoshi J, Ishida T, et al. TMEM119 marks a subset of microglia in the human brain. Neuropathology. 2016;36:39–49.

    Article  CAS  PubMed  Google Scholar 

  38. Armbruster BN, Li X, Pausch MH, Herlitze S, Roth BL. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc Natl Acad Sci USA. 2007;104:5163–8.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Yasumoto Y, Stoiljkovic M, Kim JD, Sestan-Pesa M, Gao X-B, Diano S, et al. Ucp2-dependent microglia-neuronal coupling controls ventral hippocampal circuit function and anxiety-like behavior. Mol Psychiatry. 2021;26:2740–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Woodburn SC, Bollinger JL, Wohleb ES. The semantics of microglia activation: neuroinflammation, homeostasis, and stress. J Neuroinflammation. 2021;18:258.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Ueshima S, Nagata K, Okuwaki M. Upstream binding factor-dependent and pre-rRNA transcription-independent association of pre-rRNA processing factors with rRNA gene. Biochem Biophys Res Commun. 2014;443:22–27.

    Article  CAS  PubMed  Google Scholar 

  42. Shang M, Weng L, Wu S, Liu B, Yin X, Wang Z, et al. HP1BP3 promotes tumor growth and metastasis by upregulating miR-23a to target TRAF5 in esophageal squamous cell carcinoma. Am J Cancer Res. 2021;11:2928–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Reiss K, Cornelsen I, Husmann M, Gimpl G, Bhakdi S. Unsaturated fatty acids drive disintegrin and metalloproteinase (ADAM)-dependent cell adhesion, proliferation, and migration by modulating membrane fluidity. J Biol Chem. 2011;286:26931–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Li D, Tong Y, Li Y. Associations between dietary oleic acid and linoleic acid and depressive symptoms in perimenopausal women: the study of women’s health across the nation. Nutrition. 2020;71:110602.

    Article  CAS  PubMed  Google Scholar 

  45. Hermans EJ, Henckens MJAG, Joëls M, Fernández G. Dynamic adaptation of large-scale brain networks in response to acute stressors. Trends Neurosci. 2014;37:304–14.

    Article  CAS  PubMed  Google Scholar 

  46. Downar J, Blumberger DM, Daskalakis ZJ. The neural crossroads of psychiatric illness: an emerging target for brain stimulation. Trends Cognit Sci. 2016;20:107–20.

    Article  Google Scholar 

  47. Goodkind M, Eickhoff SB, Oathes DJ, Jiang Y, Chang A, Jones-Hagata LB, et al. Identification of a Common Neurobiological Substrate for Mental Illness. JAMA Psychiatry. 2015;72:305–15.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Stratmann M, Konrad C, Kugel H, Krug A, Schöning S, Ohrmann P, et al. Insular and hippocampal gray matter volume reductions in patients with major depressive disorder. PLoS ONE. 2014;9:e102692.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Huang Y, Xu Z, Xiong S, Sun F, Qin G, Hu G, et al. Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion. Nat Neurosci. 2018;21:530–40.

    Article  CAS  PubMed  Google Scholar 

  50. Najafi AR, Crapser J, Jiang S, Ng W, Mortazavi A, West BL, et al. A limited capacity for microglial repopulation in the adult brain. Glia. 2018;66:2385–96.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Rogers JT, Morganti JM, Bachstetter AD, Hudson CE, Peters MM, Grimmig BA, et al. CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J Neurosci. 2011;31:16241–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani F, et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci. 2014;17:400–6.

    Article  CAS  PubMed  Google Scholar 

  53. Slouzkey I, Rosenblum K, Maroun M. Memory of conditioned taste aversion is erased by inhibition of PI3K in the insular cortex. Neuropsychopharmacology. 2013;38:1143–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hellwig S, Brioschi S, Dieni S, Frings L, Masuch A, Blank T, et al. Altered microglia morphology and higher resilience to stress-induced depression-like behavior in CX3CR1-deficient mice. Brain Behav Immun. 2016;55:126–37.

    Article  PubMed  Google Scholar 

  55. Liu X, Yu Z, Li Y, Huang J. CX3CL1 and its receptor CX3CR1 interact with RhoA signaling to induce paclitaxel resistance in gastric cancer. Heliyon. 2024;10:e29100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Cangalaya C, Sun W, Stoyanov S, Dunay IR, Dityatev A. Integrity of neural extracellular matrix is required for microglia-mediated synaptic remodeling. Glia. 2024;72:1874–92.

    Article  CAS  PubMed  Google Scholar 

  57. Li L, Xu N, He Y, Tang M, Yang B, Du J, et al. Dehydroervatamine as a promising novel TREM2 agonist, attenuates neuroinflammation. Neurotherapeutics. 2025;22:e00479.

    Article  PubMed  Google Scholar 

  58. Umpierre AD, Wu LJ. How microglia sense and regulate neuronal activity. Glia. 2021;69:1637–53.

    Article  CAS  PubMed  Google Scholar 

  59. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci. 2005;8:752–8.

    Article  CAS  PubMed  Google Scholar 

  60. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308:1314–8.

    Article  CAS  PubMed  Google Scholar 

  61. Walker DG, Lue L-F. Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains. Alzheimer’s Res Ther. 2015;7:56.

    Article  Google Scholar 

  62. Raj DDA, Jaarsma D, Holtman IR, Olah M, Ferreira FM, Schaafsma W, et al. Priming of microglia in a DNA-repair deficient model of accelerated aging. Neurobiol Aging. 2014;35:2147–60.

    Article  CAS  PubMed  Google Scholar 

  63. Barreto C, Curtin A, Topoglu Y, Day-Watkins J, Garvin B, Foster G, et al. Prefrontal cortex responses to social video stimuli in young children with and without autism spectrum disorder. Brain Sci. 2024;14:503.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Bove M, Palmieri MA, Santoro M, Agosti LP, Gaetani S, Romano A, et al. Amygdalar neurotransmission alterations in the BTBR mice model of idiopathic autism. Transl Psychiatry. 2024;14:193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yao Y, Li Q. The role of parvalbumin interneurons in autism spectrum disorder. J Neurosci Res. 2024;102:e25391.

    Article  CAS  PubMed  Google Scholar 

  66. Zheng J, Zhang XM, Tang W, Li Y, Wang P, Jin J, et al. An insular cortical circuit required for itch sensation and aversion. Curr Biol. 2024;34:1453–1468 e1456.

    Article  CAS  PubMed  Google Scholar 

  67. Taxier LR, Neira S, Flanigan ME, Haun HL, Eberle MR, Kooyman LS, et al. Retrieval of an ethanol-conditioned taste aversion promotes GABAergic plasticity in the anterior insular cortex. J Neurosci. 2025;45:e0525242024.

    Article  CAS  PubMed  Google Scholar 

  68. Taylor A, Adank DN, Young PA, Quan Y, Nabit BP, Winder DG. Forced abstinence from volitional ethanol intake drives a vulnerable period of hyperexcitability in BNST-projecting insular cortex neurons. J Neurosci. 2024;44:e1121232023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Del Vecchio M, Avanzini P, Gerbella M, Costa S, Zauli FM, d’Orio P, et al. Anatomo-functional basis of emotional and motor resonance elicited by facial expressions. Brain. 2024;147:3018–31.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Park S, Huh Y, Kim JJ, Cho J. Bidirectional fear modulation by discrete anterior insular circuits in male mice. eLife. 2024;13:RP95821.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Sullivan O, Ciernia AV. Work hard, play hard: how sexually differentiated microglia work to shape social play and reproductive behavior. Front Behav Neurosci. 2022;16:989011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gabele L, Bochow I, Rieke N, Sieben C, Michaelsen-Preusse K, Hosseini S, et al. H7N7 viral infection elicits pronounced, sex-specific neuroinflammatory responses in vitro. Front Cell Neurosci. 2024;18:1444876.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lazzarini G, Gatta A, Miragliotta V, Vaglini F, Viaggi C, Pirone A. Glial cells are affected more than interneurons by the loss of Engrailed 2 gene in the mouse cerebellum. J Anat. 2024;244:667–75.

    Article  CAS  PubMed  Google Scholar 

  74. Ugursu B, Sah A, Sartori S, Popp O, Mertins P, Dunay IR, et al. Microglial sex differences in innate high anxiety and modulatory effects of minocycline. Brain Behav Immun. 2024;119:465–81.

    Article  CAS  PubMed  Google Scholar 

  75. Guneykaya D, Ugursu B, Logiacco F, Popp O, Feiks MA, Meyer N, et al. Sex-specific microglia state in the Neuroligin-4 knock-out mouse model of autism spectrum disorder. Brain Behav Immun. 2023;111:61–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Shi W, Fu Y, Shi T, Zhou W. Different synaptic plasticity after physiological and psychological stress in the anterior insular cortex in an observational fear mouse model. Front Synaptic Neurosci. 2022;14:851015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yang EJ, Frolinger T, Iqbal U, Estill M, Shen L, Trageser KJ, et al. The role of the Toll like receptor 4 signaling in sex-specific persistency of depression-like behavior in response to chronic stress. Brain Behav Immun. 2024;115:169–78.

    Article  CAS  PubMed  Google Scholar 

  78. Golden SA, Covington HE 3rd, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011;6:1183–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Mertens J, Wang QW, Kim Y, Yu DX, Pham S, Yang B, et al. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature. 2015;527:95–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Zheng Y, Shen W, Zhang J, Yang B, Liu YN, Qi H, et al. CRISPR interference-based specific and efficient gene inactivation in the brain. Nat Neurosci. 2018;21:447–54.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Xiaxia Duan, Xin-Yu She, and Songhai Shi (Tsinghua University) for technical and material help. We thank all members of the laboratory for helpful discussion. This work was supported by the Beijing Natural Science Foundation (Grant No. Z210011), the National Natural Science Foundation of China (NSFC) (Grant No. 32371008, 31830038), the Open Project of Collaborative Innovation Center for Language Ability of Jiangsu Province, China, and funding from Tsingha-Peking Center for Life Sciences.

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  1. These authors contributed equally: Qiao-Ming Zhang, Yan-Fen Chen.

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  1. State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University, Beijing, 100084, China

    Qiao-Ming Zhang, Yan-Fen Chen, Yun-Yun Xing, Mengliu Yang, Na Li, Xi Jiang, Hongyan Gao & Jun Yao

  2. Jiangsu Key Laboratory of Language and Cognitive Neuroscience, School of Linguistic Sciences and Arts, Jiangsu Normal University, Xuzhou, 221116, China

    Si-Yao Lu

  3. Jiangsu Collaborative Innovation Center for Language Ability, Xuzhou, 221009, China

    Si-Yao Lu

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Contributions

Q.M.Z. and Y.F.C. performed the behavioral, biochemical, proteomic, and metabonomic experiments. Y.Y.X., M.Y., and S.Y.L performed the electrophysiology experiments. Q.M.Z., Y.F.C. and N.L. performed the imaging experiments. X.J. performed the molecular biology experiments. H.G. performed the scRNA-seq analysis. J.Y. wrote the manuscript with inputs from all authors. All authors read and approved the final manuscript.

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Zhang, QM., Chen, YF., Xing, YY. et al. Anterior insular cortex regulates depression-like and ASD-like behaviors via the differential contribution of two subsets of microglia. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03139-1

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