Exploration of Neuroprotective Therapy

Table 1. The beneficial and detrimental effects of microglia under extreme circumstances.

Condition	Microglial role in pathology	Therapeutic potentials	References
Anxiety/Depression	Stress-induced “parainflammation” may contribute to synaptic atrophy in the hippocampus.	Shifting polarization via H3R (histamine 3 receptor) or SSRIs (selective serotonin reuptake inhibitors).	[65, 157]
Schizophrenia	Excessive C4-mediated synaptic pruning and inflammation in white matter are associated with schizophrenia.	Inhibiting excessive synaptic pruning or correcting the maturation of glial cells may be beneficial.	[72, 158]
Autism (ASD)	Early-life immune activation (MIA) disrupts synaptic refinement and neuronal connectivity.	Early intervention to restore synaptic homeostasis.	[159]
Addiction	Activation in reward circuits reinforces behavior.	Targeted neuroimmunomodulation to reduce withdrawal-related anxiety.	[160, 161]

Return to article view

Declarations

Author contributions

TU: Conceptualization, Supervision. CH: Resources, Investigation. AA: Writing—original draft, Resources. AZ: Resources, Writing—review & editing. AN: Supervision, Writing—review & editing. RSN: Methodology, Formal analysis. JF: Investigation, Writing—original draft. RS: Investigation, Methodology. MMM: Writing—review & editing. ST: Supervision. JAR: Supervision, Data curation. NSS: Writing—original draft. All authors read and approved the submitted version.

Conflicts of interest

The authors declare no conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This research received no specific grant from any funding agency.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Hristovska I, Pascual O. Deciphering Resting Microglial Morphology and Process Motility from a Synaptic Prospect. Front Integr Neurosci. 2016;9:73. [DOI] [PubMed] [PMC]

Wang XL, Li L. Microglia Regulate Neuronal Circuits in Homeostatic and High-Fat Diet-Induced Inflammatory Conditions. Front Cell Neurosci. 2021;15:722028. [DOI] [PubMed] [PMC]

Benarroch E. What Is the Role of Cytokines in Synaptic Transmission? Neurology. 2024;103:e209928. [DOI] [PubMed]

Witcher KG, Bray CE, Chunchai T, Zhao F, O'Neil SM, Gordillo AJ, et al. Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia. J Neurosci. 2021;41:1597–616. [DOI] [PubMed] [PMC]

Tremblay MÈ, Lecours C, Samson L, Sánchez-Zafra V, Sierra A. From the Cajal alumni Achúcarro and Río-Hortega to the rediscovery of never-resting microglia. Front Neuroanat. 2015;9:45. [DOI] [PubMed] [PMC]

Kofler J, Wiley CA. Microglia. Toxicol Pathol. 2010;39:103–14. [DOI] [PubMed]

Xavier AL, Menezes JR, Goldman SA, Nedergaard M. Fine-tuning the central nervous system: microglial modelling of cells and synapses. Philos Trans R Soc B: Biol Sci. 2014;369:20130593. [DOI] [PubMed] [PMC]

Gill EL, Raman S, Yost RA, Garrett TJ, Vedam-Mai V. l-Carnitine Inhibits Lipopolysaccharide-Induced Nitric Oxide Production of SIM-A9 Microglia Cells. ACS Chem Neurosci. 2018;9:901–5. [DOI] [PubMed]

Huo A, Wang J, Li Q, Li M, Qi Y, Yin Q, et al. Molecular mechanisms underlying microglial sensing and phagocytosis in synaptic pruning. Neural Regen Res. 2023;19:1284–90. [DOI] [PubMed] [PMC]

10.

Nutma E, Willison H, Martino G, Amor S. Neuroimmunology – the past, present and future. Clin Exp Immunol. 2019;197:278–93. [DOI] [PubMed] [PMC]

11.

Tchessalova D, Posillico CK, Tronson NC. Neuroimmune Activation Drives Multiple Brain States. Front Syst Neurosci. 2018;12:39. [DOI] [PubMed] [PMC]

12.

Comer AL, Carrier M, Tremblay MÈ, Cruz-Martín A. The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation. Front Cell Neurosci. 2020;14:274. [DOI] [PubMed] [PMC]

13.

Andoh M, Koyama R. Microglia regulate synaptic development and plasticity. Dev Neurobiol. 2021;81:568–90. [DOI] [PubMed] [PMC]

14.

Rodriguez JI, Kern JK. Evidence of microglial activation in autism and its possible role in brain underconnectivity. Neuron Glia Biol. 2012;7:205–13. [DOI] [PubMed] [PMC]

15.

Bisht K, Sharma KP, Lecours C, Sánchez MG, El Hajj H, Milior G, et al. Dark microglia: A new phenotype predominantly associated with pathological states. Glia. 2016;64:826–39. [DOI] [PubMed] [PMC]

16.

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

17.

Milligan Armstrong A, Porter T, Quek H, White A, Haynes J, Jackaman C, et al. Chronic stress and Alzheimer’s disease: the interplay between the hypothalamic–pituitary–adrenal axis, genetics and microglia. Biol Rev. 2021;96:2209–28. [DOI] [PubMed]

18.

Jung H, Kim B, Jang G, Kim H, Lee AR, Yoon SH, et al. The NLRP3 inflammasome in microglia regulates repetitive behavior by modulating NMDA glutamate receptor functions. Cell Rep. 2025;44:115656. [DOI] [PubMed]

19.

Hinwood M, Tynan RJ, Charnley JL, Beynon SB, Day TA, Walker FR. Chronic Stress Induced Remodeling of the Prefrontal Cortex: Structural Re-Organization of Microglia and the Inhibitory Effect of Minocycline. Cereb Cortex. 2012;23:1784–97. [DOI] [PubMed]

20.

Bivona G, Iemmolo M, Agnello L, Lo Sasso B, Gambino CM, Giglio RV, et al. Microglial Activation and Priming in Alzheimer’s Disease: State of the Art and Future Perspectives. Int J Mol Sci. 2023;24:884. [DOI] [PubMed] [PMC]

21.

Cao Y, Zhang JF. Research progress in the effects of stress on microglial immune checkpoints. Chin J Cell Mol Immunol. 2023;39:181–5.

22.

Bauer ME, Teixeira AL. Neuroinflammation in Mood Disorders: Role of Regulatory Immune Cells. Neuroimmunomodulation. 2021;28:99–107. [DOI] [PubMed]

23.

Mallya AP, Wang HD, Lee HNR, Deutch AY. Microglial Pruning of Synapses in the Prefrontal Cortex During Adolescence. Cereb Cortex. 2018;29:1634–43. [DOI] [PubMed] [PMC]

24.

Beckhauser TF, Francis-Oliveira J, De Pasquale R. Reactive Oxygen Species: Physiological and Physiopathological Effects on Synaptic Plasticity. J Exp Neurosci. 2016;10:23–48. [DOI] [PubMed] [PMC]

25.

O'Connor TG, Moynihan JA, Caserta MT. Annual Research Review: The neuroinflammation hypothesis for stress and psychopathology in children – developmental psychoneuroimmunology. J Child Psychol Psychiatry. 2013;55:615–31. [DOI] [PubMed] [PMC]

26.

Kumar M, Yip L, Wang F, Marty SE, Fathman CG. Autoimmune disease: genetic susceptibility, environmental triggers, and immune dysregulation. Where can we develop therapies? Front Immunol. 2025;16:1626082. [DOI] [PubMed] [PMC]

27.

Bloomfield PS, Selvaraj S, Veronese M, Rizzo G, Bertoldo A, Owen DR, et al. Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [¹¹C]PBR28 PET Brain Imaging Study. Am J Psychiatry. 2016;173:44–52. [DOI] [PubMed] [PMC]

28.

Hellwig S, Domschke K. Update on PET imaging biomarkers in the diagnosis of neuropsychiatric disorders. Curr Opin Neurol. 2019;32:539–47. [DOI] [PubMed]

29.

Berríos-Cárcamo P, Quezada M, Quintanilla ME, Morales P, Ezquer M, Herrera-Marschitz M, et al. Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules. Antioxidants. 2020;9:830. [DOI] [PubMed] [PMC]

30.

Marques TR, Ashok AH, Pillinger T, Veronese M, Turkheimer FE, Dazzan P, et al. Neuroinflammation in schizophrenia: meta-analysis of in vivo microglial imaging studies. Psychol Med. 2018;49:2186–96. [DOI] [PubMed] [PMC]

31.

Maezawa I, Zimin PI, Wulff H, Jin LW. Amyloid-β Protein Oligomer at Low Nanomolar Concentrations Activates Microglia and Induces Microglial Neurotoxicity. J Biol Chem. 2011;286:3693–706. [DOI] [PubMed] [PMC]

32.

Prinz M, Masuda T, Wheeler MA, Quintana FJ. Microglia and Central Nervous System–Associated Macrophages—From Origin to Disease Modulation. Annu Rev Immunol. 2021;39:251–77. [DOI] [PubMed] [PMC]

33.

Shi Q, Gutierrez RA, Bhat MA. Microglia, Trem2, and Neurodegeneration. Neuroscientist. 2024;31:159–76. [DOI] [PubMed] [PMC]

34.

Venegas C, Heneka MT. Danger-associated molecular patterns in Alzheimer’s disease. J Leukoc Biol. 2016;101:87–98. [DOI] [PubMed]

35.

Xu Z, Chen ZM, Wu X, Zhang L, Cao Y, Zhou P. Distinct Molecular Mechanisms Underlying Potassium Efflux for NLRP3 Inflammasome Activation. Front Immunol. 2020;11:609441. [DOI] [PubMed] [PMC]

36.

Xia J, Jiang S, Dong S, Liao Y, Zhou Y. The Role of Post-Translational Modifications in Regulation of NLRP3 Inflammasome Activation. Int J Mol Sci. 2023;24:6126. [DOI] [PubMed] [PMC]

37.

Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri ES. Non-transcriptional Priming and Deubiquitination Regulate NLRP3 Inflammasome Activation. J Biol Chem. 2012;287:36617–22. [DOI] [PubMed] [PMC]

38.

Ahmed S, Panda SR, Kwatra M, Sahu BD, Naidu V. Perillyl Alcohol Attenuates NLRP3 Inflammasome Activation and Rescues Dopaminergic Neurons in Experimental In Vitro and In Vivo Models of Parkinson’s Disease. ACS Chem Neurosci. 2021;13:53–68. [DOI] [PubMed]

39.

Zhang X, Wang Y, Dong H, Xu Y, Zhang S. Induction of Microglial Activation by Mediators Released from Mast Cells. Cell Physiol Biochem. 2016;38:1520–31. [DOI] [PubMed]

40.

Zhu J, Qu C, Lu X, Zhang S. Activation of Microglia by Histamine and Substance P. Cell Physiol Biochem. 2014;34:768–80. [DOI] [PubMed]

41.

Stratoulias V, Venero JL, Tremblay MÈ, Joseph B. Microglial subtypes: diversity within the microglial community. EMBO J. 2019;38:e101997. [DOI] [PubMed] [PMC]

42.

Hu X. Microglia/macrophage polarization: Fantasy or evidence of functional diversity? J Cereb Blood Flow Metab. 2020;40:S134–S136. [DOI] [PubMed] [PMC]

43.

Francos-Quijorna I, Amo-Aparicio J, Martinez-Muriana A, López-Vales R. IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair and functional recovery after spinal cord injury. Glia. 2016;64:2079–92. [DOI] [PubMed]

44.

Galleguillos D, Wang Q, Steinberg N, Zaidi A, Shrivastava G, Dhami K, et al. Anti-inflammatory role of GM1 and other gangliosides on microglia. J Neuroinflammation. 2022;19:9. [DOI] [PubMed] [PMC]

45.

Ohsawa K, Irino Y, Sanagi T, Nakamura Y, Suzuki E, Inoue K, et al. P2Y₁₂receptor‐mediated integrin‐β1 activation regulates microglial process extension induced by ATP. Glia. 2010;58:790–801. [DOI] [PubMed]

46.

Gaikwad S, Larionov S, Wang Y, Dannenberg H, Matozaki T, Monsonego A, et al. Signal Regulatory Protein-β1. Am J Pathol. 2009;175:2528–39. [DOI] [PubMed] [PMC]

47.

Stefano GB, Esch T, Ptacek R, Kream RM. Dysregulation of Nitric Oxide Signaling in Microglia: Multiple Points of Functional Convergence in the Complex Pathophysiology of Alzheimer Disease. Med Sci Monit. 2020;26:e927739. [DOI] [PubMed] [PMC]

48.

Pozzi D, Menna E, Canzi A, Desiato G, Mantovani C, Matteoli M. The Communication Between the Immune and Nervous Systems: The Role of IL-1β in Synaptopathies. Front Mol Neurosci. 2018;11:111. [DOI] [PubMed] [PMC]

49.

Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Investig. 2012;122:787–95. [DOI] [PubMed] [PMC]

50.

Deng W, Mandeville E, Terasaki Y, Li W, Holder J, Chuang AT, et al. Transcriptomic characterization of microglia activation in a rat model of ischemic stroke. J Cereb Blood Flow Metab. 2020;40:S34–S48. [DOI] [PubMed] [PMC]

51.

Smith AM, Davey K, Tsartsalis S, Khozoie C, Fancy N, Tang SS, et al. Diverse human astrocyte and microglial transcriptional responses to Alzheimer’s pathology. Acta Neuropathol. 2022;143:75–91. [DOI] [PubMed] [PMC]

52.

Xie M, Wang T, Feng J, Ma D, Feng L, Hao Y. Roles of Microglia in Synaptogenesis, Synaptic Pruning, and Synaptic Plasticity in Physiological Conditions and Central Nervous System Disorders. Curr Neuropharmacol. 2025;24:2–35. [DOI] [PubMed] [PMC]

53.

Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of Two Distinct Macrophage Subsets with Divergent Effects Causing either Neurotoxicity or Regeneration in the Injured Mouse Spinal Cord. J Neurosci. 2009;29:13435–44. [DOI] [PubMed] [PMC]

54.

Colonna M, Butovsky O. Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annu Rev Immunol. 2017;35:441–68. [DOI] [PubMed] [PMC]

55.

Sierra A, Miron VE, Paolicelli RC, Ransohoff RM. Microglia in Health and Diseases: Integrative Hubs of the Central Nervous System (CNS). Cold Spring Harb Perspect Biol. 2024;16:a041366. [DOI] [PubMed] [PMC]

56.

Matuleviciute R, Akinluyi ET, Muntslag TAO, Dewing JM, Long KR, Vernon AC, et al. Microglial contribution to the pathology of neurodevelopmental disorders in humans. Acta Neuropathol. 2023;146:663–83. [DOI] [PubMed] [PMC]

57.

Sturchio A, Rocha EM, Kauffman MA, Marsili L, Mahajan A, Saraf AA, et al. Recalibrating the Why and Whom of Animal Models in Parkinson Disease: A Clinician’s Perspective. Brain Sci. 2024;14:151. [DOI] [PubMed] [PMC]

58.

Bruno A, Dolcetti E, Rizzo FR, Fresegna D, Musella A, Gentile A, et al. Inflammation-Associated Synaptic Alterations as Shared Threads in Depression and Multiple Sclerosis. Front Cell Neurosci. 2020;14:169. [DOI] [PubMed] [PMC]

59.

Yrondi A, Aouizerate B, El-Hage W, Moliere F, Thalamas C, Delcourt N, et al. Assessment of Translocator Protein Density, as Marker of Neuroinflammation, in Major Depressive Disorder: A Pilot, Multicenter, Comparative, Controlled, Brain PET Study (INFLADEP Study). Front Psychiatry. 2018;9:326. [DOI] [PubMed] [PMC]

60.

Herman JP, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, et al. Regulation of the Hypothalamic‐Pituitary‐Adrenocortical Stress Response. Compr Physiol. 2016;6:603–21. [DOI]

61.

Spiers JG, Chen HJ, Sernia C, Lavidis NA. Activation of the hypothalamic-pituitary-adrenal stress axis induces cellular oxidative stress. Front Neurosci. 2015;8:456. [DOI] [PubMed] [PMC]

62.

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. [DOI] [PubMed] [PMC]

63.

Eggerstorfer B, Kim JH, Cumming P, Lanzenberger R, Gryglewski G. Meta-analysis of molecular imaging of translocator protein in major depression. Front Mol Neurosci. 2022;15:981442. [DOI] [PubMed] [PMC]

64.

Cakmak JD, Liu L, Poirier SE, Schaefer B, Poolacherla R, Burhan AM, et al. The functional and structural associations of aberrant microglial activity in major depressive disorder. J Psychiatry Neurosci. 2022;47:E197–E208. [DOI] [PubMed] [PMC]

65.

Yirmiya R, Rimmerman N, Reshef R. Depression as a Microglial Disease. Trends Neurosci. 2015;38:637–58. [DOI] [PubMed]

66.

Zhang J, He H, Qiao Y, Zhou T, He H, Yi S, et al. Priming of microglia with IFN‐γ impairs adult hippocampal neurogenesis and leads to depression‐like behaviors and cognitive defects. Glia. 2020;68:2674–92. [DOI] [PubMed]

67.

Mao ZF, Ouyang SH, Zhang QY, Wu YP, Wang GE, Tu LF, et al. New insights into the effects of caffeine on adult hippocampal neurogenesis in stressed mice: Inhibition of CORT‐induced microglia activation. FASEB J. 2020;34:10998–1014. [DOI] [PubMed]

68.

Dai J, Ding Z, Zhang J, Xu W, Guo Q, Zou W, et al. Minocycline Relieves Depressive-Like Behaviors in Rats With Bone Cancer Pain by Inhibiting Microglia Activation in Hippocampus. Anesth Analg. 2019;129:1733–41. [DOI] [PubMed]

69.

Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, et al. Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation. 2008;5:15. [DOI] [PubMed] [PMC]

70.

Tay TL, Béchade C, D'Andrea I, St-Pierre MK, Henry MS, Roumier A, et al. Microglia Gone Rogue: Impacts on Psychiatric Disorders across the Lifespan. Front Mol Neurosci. 2018;10:421. [DOI] [PubMed] [PMC]

71.

Hartmann SM, Heider J, Wüst R, Fallgatter AJ, Volkmer H. Microglia-neuron interactions in schizophrenia. Front Cell Neurosci. 2024;18:1345349. [DOI] [PubMed] [PMC]

72.

Sellgren CM, Gracias J, Watmuff B, Biag JD, Thanos JM, Whittredge PB, et al. Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nat Neurosci. 2019;22:374–85. [DOI] [PubMed] [PMC]

73.

Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, et al. Synaptic Pruning by Microglia Is Necessary for Normal Brain Development. Science. 2011;333:1456–8. [DOI] [PubMed]

74.

Cannon TD. Microglial Activation and the Onset of Psychosis. Am J Psychiatry. 2016;173:3–4. [DOI] [PubMed]

75.

Neniskyte U, Gross CT. Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders. Nat Rev Neurosci. 2017;18:658–70. [DOI] [PubMed]

76.

Orhan F, Malwade S, Khanlarkhani N, Gkogka A, Langeder A, Jungholm O, et al. Kynurenic Acid and Promotion of Activity-Dependent Synapse Elimination in Schizophrenia. Am J Psychiatry. 2025;182:389–400. [DOI] [PubMed]

77.

Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2004;57:67–81. [DOI] [PubMed]

78.

Takano T. Role of Microglia in Autism: Recent Advances. Dev Neurosci. 2015;37:195–202. [DOI] [PubMed]

79.

Meng J, Zhang L, Zhang YW. Microglial Dysfunction in Autism Spectrum Disorder. Neuroscientist. 2024;30:744–58. [DOI] [PubMed]

80.

Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM, et al. Elevated immune response in the brain of autistic patients. J Neuroimmunol. 2009;207:111–6. [DOI] [PubMed] [PMC]

81.

Kern JK, Geier DA, Audhya T, King PG, Sykes LK, Geier MR. Evidence of parallels between mercury intoxication and the brain pathology in autism. Acta Neurobiol Exp. 2012;72:113–53. [DOI] [PubMed]

82.

Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 2011;474:380–4. [DOI] [PubMed] [PMC]

83.

Tan T, Wang W, Xu H, Huang Z, Wang YT, Dong Z. Low-Frequency rTMS Ameliorates Autistic-Like Behaviors in Rats Induced by Neonatal Isolation Through Regulating the Synaptic GABA Transmission. Front Cell Neurosci. 2018;12:46. [DOI] [PubMed] [PMC]

84.

Meng J, Han L, Zheng N, Wang T, Xu H, Jiang Y, et al. Microglial Tmem59 Deficiency Impairs Phagocytosis of Synapse and Leads to Autism-Like Behaviors in Mice. J Neurosci. 2022;42:4958–79. [DOI] [PubMed] [PMC]

85.

Soteros BM, Sia GM. Complement and microglia dependent synapse elimination in brain development. WIREs Mech Dis. 2021;14:e1545. [DOI] [PubMed] [PMC]

86.

Loewen SM, Chavesa AM, Murray CJ, Traetta ME, Burns SE, Pekarik KH, et al. The Outcomes of Maternal Immune Activation Induced with the Viral Mimetic Poly I:C on Microglia in Exposed Rodent Offspring. Dev Neurosci. 2023;45:191–209. [DOI] [PubMed]

87.

Carbone E, Buzzelli V, Manduca A, Leone S, Rava A, Trezza V. Maternal Immune Activation Induced by Prenatal Lipopolysaccharide Exposure Leads to Long-Lasting Autistic-like Social, Cognitive and Immune Alterations in Male Wistar Rats. Int J Mol Sci. 2023;24:3920. [DOI] [PubMed] [PMC]

88.

Cipriani C, Tartaglione AM, Giudice M, D'Avorio E, Petrone V, Toschi N, et al. Differential Expression of Endogenous Retroviruses and Inflammatory Mediators in Female and Male Offspring in a Mouse Model of Maternal Immune Activation. Int J Mol Sci. 2022;23:13930. [DOI] [PubMed] [PMC]

89.

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. [DOI] [PubMed]

90.

Enache D, Pariante CM, Mondelli V. Markers of central inflammation in major depressive disorder: A systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue. Brain Behav Immun. 2019;81:24–40. [DOI] [PubMed]

91.

Michopoulos V, Powers A, Gillespie CF, Ressler KJ, Jovanovic T. Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond. Neuropsychopharmacology. 2016;42:254–70. [DOI] [PubMed] [PMC]

92.

Nahum K, Todder D, Zohar J, Cohen H. The Role of Microglia in the (Mal)adaptive Response to Traumatic Experience in an Animal Model of PTSD. Int J Mol Sci. 2022;23:7185. [DOI] [PubMed] [PMC]

93.

Mifsud KR, Gutièrrez-Mecinas M, Trollope AF, Collins A, Saunderson EA, Reul JM. Epigenetic mechanisms in stress and adaptation. Brain Behav Immun. 2011;25:1305–15. [DOI] [PubMed]

94.

Kokkosis AG, Madeira MM, Hage Z, Valais K, Koliatsis D, Resutov E, et al. Chronic psychosocial stress triggers microglial‐/macrophage‐induced inflammatory responses leading to neuronal dysfunction and depressive‐related behavior. Glia. 2023;72:111–32. [DOI] [PubMed] [PMC]

95.

Schubert I, Ahlbrand R, Winter A, Vollmer L, Lewkowich I, Sah R. Enhanced fear and altered neuronal activation in forebrain limbic regions of CX3CR1-deficient mice. Brain Behav Immun. 2018;68:34–43. [DOI] [PubMed] [PMC]

96.

Shimizu K, Sawamura T, Nibuya M, Nakai K, Takahashi Y, Nomura S. An animal model of posttraumatic stress disorder and its validity: effect of paroxetine on a PTSD model in rats. Jpn J Psychopharmacol. 2004;24:283–90.

97.

Sun Y, Gooch H, Sah P. Fear conditioning and the basolateral amygdala. F1000Research. 2020;9:53. [DOI] [PubMed] [PMC]

98.

Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56. [DOI] [PubMed] [PMC]

99.

Furlan VA, MacAuslan D, Ha K, Patel N, Adam S, Zanagar B, et al. Microglial Dyshomeostasis: A Common Substrate in Neurodevelopmental and Neurodegenerative Diseases. Neuroglia. 2024;5:119–28. [DOI]

100.

Yokokura M, Takebasashi K, Takao A, Nakaizumi K, Yoshikawa E, Futatsubashi M, et al. In vivo imaging of dopamine D1 receptor and activated microglia in attention-deficit/hyperactivity disorder: a positron emission tomography study. Mol Psychiatry. 2020;26:4958–67. [DOI] [PubMed]

101.

Uygun SD, Kose TB, Bahadir-Varol A, Uzay B, Eren-Kocak E. Attention-related impairment and contributing neuroinflammatory signalling in the prefrontal cortex of perinatal nicotine-exposed mice. Acta Neuropsychiatr. 2025;37:e12. [DOI] [PubMed] [PMC]

102.

Song Y, Yuan H, Chen T, Lu M, Lei S, Han X. An Shen Ding Zhi Ling Alleviates Symptoms of Attention Deficit Hyperactivity Disorder via Anti-Inflammatory Effects in Spontaneous Hypertensive Rats. Front Pharmacol. 2021;11:617581. [DOI] [PubMed] [PMC]

103.

Anand D, Colpo GD, Zeni G, Zeni CP, Teixeira AL. Attention-Deficit/Hyperactivity Disorder And Inflammation: What Does Current Knowledge Tell Us? A Systematic Review. Front Psychiatry. 2017;8:228. [DOI] [PubMed] [PMC]

104.

Wohleb ES. Neuron–Microglia Interactions in Mental Health Disorders: “For Better, and For Worse”. Front Immunol. 2016;7:544. [DOI] [PubMed] [PMC]

105.

Ghosh S, Castillo E, Frias ES, Swanson RA. Bioenergetic regulation of microglia. Glia. 2017;66:1200–12. [DOI] [PubMed] [PMC]

106.

Whitelaw BS, Stoessel MB, Majewska AK. Movers and shakers: Microglial dynamics and modulation of neural networks. Glia. 2022;71:1575–91. [DOI] [PubMed] [PMC]

107.

Lacabanne C. Inflammation and immune-mediated neurobehavioral alterations: a critical role for microglia [dissertation]. Montréal (Canada): McGill University; 2018. [DOI]

108.

Abudara V, Roux L, Dallérac G, Matias I, Dulong J, Mothet JP, et al. Activated microglia impairs neuroglial interaction by opening Cx43 hemichannels in hippocampal astrocytes. Glia. 2015;63:795–811. [DOI] [PubMed]

109.

Hoshino K, Hasegawa K, Kamiya H, Morimoto Y. Synapse-specific effects of IL-1β on long-term potentiation in the mouse hippocampus. Biomed Res. 2017;38:183–8. [DOI]

110.

Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun. 2011;25:181–213. [DOI] [PubMed]

111.

Prieto GA, Cotman CW. Cytokines and cytokine networks target neurons to modulate long-term potentiation. Cytokine Growth Factor Rev. 2017;34:27–33. [DOI] [PubMed] [PMC]

112.

Zhang H, Dougherty PM. Acute inhibition of signalling phenotype of spinal GABAergic neurons by tumour necrosis factor‐α. J Physiol. 2011;589:4511–26. [DOI] [PubMed] [PMC]

113.

Carrillo JA, de la Plata JAC, Schneider R. Nonlinear noisy integrate and fire neuron models: delay and excitatory-inhibitory populations. In: Proceedings of the first International Conference on Mathematical NeuroScience (ICMNS); 2015 Jun 8–10; Antibes - Juan les Pins, France. ICNMS 2015; 2015.

114.

Mahmoud S, Gharagozloo M, Simard C, Amrani A, Gris D. NLRX1 Enhances Glutamate Uptake and Inhibits Glutamate Release by Astrocytes. Cells. 2019;8:400. [DOI] [PubMed] [PMC]

115.

Tilleux S, Hermans E. Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. J Neurosci Res. 2007;85:2059–70. [DOI] [PubMed]

116.

Simpson DSA, Oliver PL. ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease. Antioxidants. 2020;9:743. [DOI] [PubMed] [PMC]

117.

Gimeno-Bayón J, López-López A, Rodríguez MJ, Mahy N. Glucose pathways adaptation supports acquisition of activated microglia phenotype. J Neurosci Res. 2014;92:723–31. [DOI] [PubMed]

118.

Stauch KL, Purnell PR, Fox HS. Quantitative Proteomics of Synaptic and Nonsynaptic Mitochondria: Insights for Synaptic Mitochondrial Vulnerability. J Proteome Res. 2014;13:2620–36. [DOI] [PubMed] [PMC]

119.

Nicholls DG, Budd SL. Mitochondria and Neuronal Survival. Physiol Rev. 2000;80:315–60. [DOI] [PubMed]

120.

Picard M, McEwen BS. Psychological Stress and Mitochondria: A Conceptual Framework. Psychosom Med. 2018;80:126–40. [DOI] [PubMed] [PMC]

121.

Anglin RE, Tarnopolsky MA, Mazurek MF, Rosebush PI. The Psychiatric Presentation of Mitochondrial Disorders in Adults. J Neuropsychiatry Clin Neurosci. 2012;24:394–409. [DOI] [PubMed]

122.

Morris G, Berk M. The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders. BMC Med. 2015;13:68. [DOI] [PubMed] [PMC]

123.

Papathanasiou IV, Fradelos EC, Malli F, Stefanidis I, Zintzaras E, Doxani C. A SYSTEMATIC REVIEW OF OBSERVATIONAL STUDIES ASSESSING THE IMPACT OF OXIDATIVE STRESS IN COGNITIVE DECLINE. Wiad Lek. 2021;74:1995–2003. [DOI]

124.

Verosky BG, Bailey MT, Gur TL. The Metabolomic Mind: Microbial Metabolite Programming of Microglia. Neuroimmunomodulation. 2025;32:139–49. [DOI] [PubMed] [PMC]

125.

Camberos-Barraza J, Guadrón-Llanos AM, De la Herrán-Arita AK. The Gut Microbiome-Neuroglia Axis: Implications for Brain Health, Inflammation, and Disease. Neuroglia. 2024;5:254–73. [DOI]

126.

Abdel-Haq R, Schlachetzki JCM, Glass CK, Mazmanian SK. Microbiome–microglia connections via the gut–brain axis. J Exp Med. 2018;216:41–59. [DOI] [PubMed] [PMC]

127.

Colombo AV, Sadler RK, Llovera G, Singh V, Roth S, Heindl S, et al. Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition. eLife. 2021;10:e59826. [DOI]

128.

Wenzel TJ, Le J, He J, Alcorn J, Mousseau DD. Fundamental Neurochemistry Review: Incorporating a greater diversity of cell types, including microglia, in brain organoid cultures improves clinical translation. J Neurochem. 2023;164:560–82. [DOI]

129.

Li X, Ramos-Rolón AP, Kass G, Pereira-Rufino LS, Shifman N, Shi Z, et al. Imaging neuroinflammation in individuals with substance use disorders. J Clin Investig. 2024;134:e134. [DOI] [PubMed] [PMC]

130.

Coughlin J, Notter T, Du Y, Pomper M, Sawa A, Meyer U. 6.1 STUDY OF ALTERED NEUROIMMUNITY IN PSYCHOSIS USING PET-BASED IMAGING OF THE TRANSLOCATOR PROTEIN 18 KDA: PROMISES, PITFALLS, AND FUTURE DIRECTIONS. Schizophr Bull. 2018;44:S8. [DOI]

131.

Ran W, Hu K, Ye W, Zhang L, Chen J, Ji B, et al. Radiofluorination of 2-Arylquinolin-4-yl Oxypropanamide Derivatives for TSPO Imaging in Neuroinflammatory Murine, Nonhuman Primates, and Human Brain Autoradiography with Insensitivity to the rs6971 Polymorphism. J Med Chem. 2025;68:12457–72. [DOI] [PubMed]

132.

Hagens M, van Berckel B, Barkhof F. Novel MRI and PET markers of neuroinflammation in multiple sclerosis. Curr Opin Neurol. 2016;29:229–36. [DOI] [PubMed]

133.

Nutma E, Fancy N, Weinert M, Tsartsalis S, Marzin MC, Muirhead RCJ, et al. Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases. Nat Commun. 2023;14:5247. [DOI] [PubMed] [PMC]

134.

Meyer JH, Cervenka S, Kim MJ, Kreisl WC, Henter ID, Innis RB. Neuroinflammation in psychiatric disorders: PET imaging and promising new targets. Lancet Psychiatry. 2020;7:1064–74. [DOI] [PubMed] [PMC]

135.

Chang L, Munsaka SM, Kraft-Terry S, Ernst T. Magnetic Resonance Spectroscopy to Assess NeuroInflammation and Neuropathic Pain. J Neuroimmune Pharmacol. 2013;8:576–93. [DOI] [PubMed] [PMC]

136.

Cumbers GA, Harvey-Latham ED, Kassiou M, Werry EL, Danon JJ. Emerging TSPO-PET Radiotracers for Imaging Neuroinflammation: A Critical Analysis. Semin Nucl Med. 2024;54:856–74. [DOI] [PubMed]

137.

Burke NN, Kerr DM, Moriarty O, Finn DP, Roche M. Minocycline modulates neuropathic pain behaviour and cortical M1–M2 microglial gene expression in a rat model of depression. Brain Behav Immun. 2014;42:147–56. [DOI] [PubMed]

138.

Dong Yang M, Ming Jie W, Hui Zhou L, Zhao L, Xin L, Xiu Li W, et al. Spinal microglial M1 polarization contributes paclitaxel‐induced neuropathic pain by triggering cells necroptosis. J Biochem Mol Toxicol. 2024;38:e23669. [DOI] [PubMed]

139.

Chen X, Xiong Z, Li Z, Yang Y, Zheng Z, Li Y, et al. Minocycline as adjunct therapy for a male patient with deficit schizophrenia. Neuropsychiatr Dis Treat. 2018;14:2697–701. [DOI] [PubMed] [PMC]

140.

Bell RL, Lopez MF, Cui C, Egli M, Johnson KW, Franklin KM, et al. Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence. Addctn Biol. 2013;20:38–42. [DOI] [PubMed] [PMC]

141.

Burnette EM, Baskerville WA, Grodin EN, Ray LA. Ibudilast for alcohol use disorder: study protocol for a phase II randomized clinical trial. Trials. 2020;21:779. [DOI] [PubMed] [PMC]

142.

Barca C, Foray C, Hermann S, Herrlinger U, Remory I, Laoui D, et al. The Colony Stimulating Factor-1 Receptor (CSF-1R)-Mediated Regulation of Microglia/Macrophages as a Target for Neurological Disorders (Glioma, Stroke). Front Immunol. 2021;12:787307. [DOI] [PubMed] [PMC]

143.

Boland R, Kokiko-Cochran ON. Deplete and repeat: microglial CSF1R inhibition and traumatic brain injury. Front Cell Neurosci. 2024;18:1352790. [DOI] [PubMed] [PMC]

144.

Olmos-Alonso A, Schetters ST, Sri S, Askew K, Mancuso R, Vargas-Caballero M, et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain. 2016;139:891–907. [DOI] [PubMed] [PMC]

145.

Siva Venkatesh IP, Majumdar A, Basu A. Prophylactic Administration of Gut Microbiome Metabolites Abrogated Microglial Activation and Subsequent Neuroinflammation in an Experimental Model of Japanese Encephalitis. ACS Chem Neurosci. 2024;15:1712–27. [DOI] [PubMed]

146.

Qu H, Liu R, Chen J, Zheng L, Chen R. Aerobic Exercise Inhibits CUMS-Depressed Mice Hippocampal Inflammatory Response via Activating Hippocampal miR-223/TLR4/MyD88-NF-κB Pathway. Int J Environ Res Public Health. 2020;17:2676. [DOI] [PubMed] [PMC]

147.

Mee-Inta O, Zhao ZW, Kuo YM. Physical Exercise Inhibits Inflammation and Microglial Activation. Cells. 2019;8:691. [DOI] [PubMed] [PMC]

148.

Meyer JD, Hayney MS, Coe CL, Ninos CL, Barrett BP. Differential Reduction of IP-10 and C-Reactive Protein via Aerobic Exercise or Mindfulness-Based Stress-Reduction Training in a Large Randomized Controlled Trial. J Sport Exerc Psychol. 2019;41:96–106. [DOI] [PubMed] [PMC]

149.

Darwish SF, Elbadry AMM, Elbokhomy AS, Salama GA, Salama RM. The dual face of microglia (M1/M2) as a potential target in the protective effect of nutraceuticals against neurodegenerative diseases. Front Aging. 2023;4:1231706. [DOI] [PubMed] [PMC]

150.

Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530:177–83. [DOI] [PubMed] [PMC]

151.

Donohoe G, Holland J, Mothersill D, McCarthy-Jones S, Cosgrove D, Harold D, et al. Genetically predicted complement component 4A expression: effects on memory function and middle temporal lobe activation. Psychol Med. 2018;48:1608–15. [DOI] [PubMed]

152.

Benusa SD, George NM, Dupree JL. Microglial heterogeneity: distinct cell types or differential functional adaptation? Neuroimmunol Neuroinflammation. 2020;2020:248–63. [DOI]

153.

Chen Z, Haider A, Chen J, Xiao Z, Gobbi L, Honer M, et al. The Repertoire of Small-Molecule PET Probes for Neuroinflammation Imaging: Challenges and Opportunities beyond TSPO. J Med Chem. 2021;64:17656–89. [DOI] [PubMed] [PMC]

154.

Ahn I, Chang S, Lee J, Choi SH, Han J, Kim Y. Exploration of Novel Biomarkers Through a Precision Medicine Approach Using Multi‐Omics and Brain Organoids in Patients With Atypical Depression and Psychotic Symptoms. Adv Sci. 2025;13:e08383. [DOI] [PubMed] [PMC]

155.

Antic SD, Baker BJ, Canepari M. Editorial: New Insights on Neuron and Astrocyte Function From Cutting-Edge Optical Techniques. Front Cell Neurosci. 2019;13:463. [DOI] [PubMed] [PMC]

156.

Streit WJ, Xue QS, Tischer J, Bechmann I. Microglial pathology. Acta Neuropathol Commun. 2014;2:142. [DOI] [PubMed] [PMC]

157.

Wohleb ES, Franklin T, Iwata M, Duman RS. Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci. 2016;17:497–511. [DOI] [PubMed]

158.

van Kesteren CF, Gremmels H, de Witte LD, Hol EM, Van Gool AR, Falkai PG, et al. Immune involvement in the pathogenesis of schizophrenia: a meta-analysis on postmortem brain studies. Transl Psychiatry. 2017;7:e1075. [DOI] [PubMed] [PMC]

159.

Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nat Med. 2017;23:1018–27. [DOI] [PubMed]

160.

Watkins LR, Hutchinson MR, Rice KC, Maier SF. The “Toll” of Opioid-Induced Glial Activation: Improving the Clinical Efficacy of Opioids by Targeting Glia. Trends Pharmacol Sci. 2009;30:581–91. [DOI] [PubMed] [PMC]

161.

Crews FT, Vetreno RP. Mechanisms of neuroimmune gene induction in alcoholism. Psychopharmacology. 2015;233:1543–57. [DOI] [PubMed] [PMC]

162.

Paolicelli RC, Sierra A, Stevens B, Tremblay ME, Aguzzi A, Ajami B, et al. Microglia states and nomenclature: A field at its crossroads. Neuron. 2022;110:3458–83. [DOI] [PubMed] [PMC]

163.

Abels ER, Nieland L, Hickman S, Broekman MLD, El Khoury J, Maas SLN. Comparative Analysis Identifies Similarities between the Human and Murine Microglial Sensomes. Int J Mol Sci. 2021;22:1495. [DOI] [PubMed] [PMC]

164.

Ritzel RM, Li Y, Jiao Y, Lei Z, Doran SJ, He J, et al. Brain injury accelerates the onset of a reversible age-related microglial phenotype associated with inflammatory neurodegeneration. Sci Adv. 2023;9:eadd1101. [DOI] [PubMed] [PMC]

165.

Palsamy K, Chen JY, Skaggs K, Qadeer Y, Connors M, Cutler N, et al. Microglial depletion after brain injury prolongs inflammation and impairs brain repair, adult neurogenesis and pro‐regenerative signaling. Glia. 2023;71:2642–63. [DOI] [PubMed] [PMC]

166.

Luo EY, Sugimura RR. Taming microglia: the promise of engineered microglia in treating neurological diseases. J Neuroinflammation. 2024;21:19. [DOI] [PubMed]

167.

Wang Y, Yi H, Wang J, Song Y. Early Surgery (Within 24 Hours) Benefits Patients Suffering from Acute Thoracolumbar Spinal Cord Injury. Clin Spine Surg. 2022;36:210–6. [DOI] [PubMed]

168.

Ghosh M, Pearse DD. The Yin and Yang of Microglia-Derived Extracellular Vesicles in CNS Injury and Diseases. Cells. 2024;13:1834. [DOI] [PubMed] [PMC]

169.

Lukiw WJ, Pogue AI. Vesicular Transport of Encapsulated microRNA between Glial and Neuronal Cells. Int J Mol Sci. 2020;21:5078. [DOI] [PubMed] [PMC]

170.

Kanuri SH, Sirrkay PJ. Profiling of microglial-originated microvesicles to unearthing their lurking potential as potent foreseeable biomarkers for the diagnosis of Alzheimer’s disease: A systematic review. Brain Circ. 2024;10:193–204. [DOI]

171.

Gelibter S, Pisa M, Croese T, Finardi A, Mandelli A, Sangalli F, et al. Spinal Fluid Myeloid Microvesicles Predict Disease Course in Multiple Sclerosis. Ann Neurol. 2021;90:253–65. [DOI] [PubMed]

172.

Ceccarelli L, Marchetti L, Rizzo M, Moscardini A, Cappello V, Da Pozzo E, et al. Human Microglia Extracellular Vesicles Derived from Different Microglia Cell Lines: Similarities and Differences. ACS Omega. 2022;7:23127–37. [DOI] [PubMed] [PMC]

173.

Liu Y, Wang M, Hou XO, Hu LF. Roles of microglial mitophagy in neurological disorders. Front Aging Neurosci. 2022;14:979869. [DOI] [PubMed] [PMC]

174.

O'Riordan KJ, Moloney GM, Keane L, Clarke G, Cryan JF. The gut microbiota-immune-brain axis: Therapeutic implications. Cell Rep Med. 2025;6:101982. [DOI] [PubMed] [PMC]

175.

Dias D, Socodato R. Beyond Amyloid and Tau: The Critical Role of Microglia in Alzheimer’s Disease Therapeutics. Biomedicines. 2025;13:279. [DOI] [PubMed] [PMC]

176.

Xia X, Li K, Zou W, Wang L. The central role of microglia in major depressive disorder and its potential as a therapeutic target. Front Behav Neurosci. 2025;19:1598178. [DOI] [PubMed] [PMC]

177.

Dupont AC, Largeau B, Santiago Ribeiro MJ, Guilloteau D, Tronel C, Arlicot N. Translocator Protein-18 kDa (TSPO) Positron Emission Tomography (PET) Imaging and Its Clinical Impact in Neurodegenerative Diseases. Int J Mol Sci. 2017;18:785. [DOI] [PubMed] [PMC]

178.

Szepesi Z, Manouchehrian O, Bachiller S, Deierborg T. Bidirectional Microglia–Neuron Communication in Health and Disease. Front Cell Neurosci. 2018;12:323. [DOI] [PubMed] [PMC]

179.

Friedman BA, Srinivasan K, Ayalon G, Meilandt WJ, Lin H, Huntley MA, et al. Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer’s Disease Not Evident in Mouse Models. Cell Rep. 2018;22:832–47. [DOI] [PubMed]

180.

Beaino W, Janssen B, Vugts DJ, de Vries HE, Windhorst AD. Towards PET imaging of the dynamic phenotypes of microglia. Clin Exp Immunol. 2021;206:282–300. [DOI] [PubMed] [PMC]

181.

Frick LR, Williams K, Pittenger C. Microglial Dysregulation in Psychiatric Disease. Clin Dev Immunol. 2013;2013:608654. [DOI] [PubMed] [PMC]