Wheeler, M. A. & Quintana, F. J. The neuroimmune connectome in health and disease. Nature 638, 333–342 (2025).
Poller, W. C. et al. Brain motor and fear circuits regulate leukocytes during acute stress. Nature 607, 578–584 (2022).
Chan, K. L., Poller, W. C., Swirski, F. K. & Russo, S. J. Central regulation of stress-evoked peripheral immune responses. Nat. Rev. Neurosci. https://doi.org/10.1038/s41583-023-00729-2 (2023).
Cathomas, F. et al. Beyond the neuron: role of non-neuronal cells in stress disorders. Neuron 110, 1116–1138 (2022).
Fan, K.-Q. et al. Stress-induced metabolic disorder in peripheral CD4+ T cells leads to anxiety-like behavior. Cell 179, 864–879 (2019).
Cathomas, F. et al. Circulating myeloid-derived MMP8 in stress susceptibility and depression. Nature 626, 1108–1115 (2024).
Pape, K., Tamouza, R., Leboyer, M. & Zipp, F. Immunoneuropsychiatry—novel perspectives on brain disorders. Nat. Rev. Neurol. 15, 317–328 (2019).
Hodes, G. E., Kana, V., Menard, C., Merad, M. & Russo, S. J. Neuroimmune mechanisms of depression. Nat. Neurosci. 18, 1386–1393 (2015).
Wohleb, E. S., Franklin, T., Iwata, M. & Duman, R. S. Integrating neuroimmune systems in the neurobiology of depression. Nat. Rev. Neurosci. 17, 497–511 (2016).
Qing, H. et al. Origin and function of stress-induced IL-6 in murine models. Cell 182, 372–387 (2020).
Lee, H.-G., Wheeler, M. A. & Quintana, F. J. Function and therapeutic value of astrocytes in neurological diseases. Nat. Rev. Drug Discov. 21, 339–358 (2022).
Byun, Y. G. et al. Stress induces behavioral abnormalities by increasing expression of phagocytic receptor, MERTK, in astrocytes to promote synapse phagocytosis. Immunity 56, 2105–2120 (2023).
Leng, L. et al. Menin deficiency leads to depressive-like behaviors in mice by modulating astrocyte-mediated neuroinflammation. Neuron 100, 551–563 (2018).
Guayasamin, M. et al. Early-life stress induces persistent astrocyte dysfunction associated with fear generalisation. eLife https://doi.org/10.7554/eLife.99988.2 (2024).
Dudek, K. A. et al. Astrocytic cannabinoid receptor 1 promotes resilience by dampening stress-induced blood–brain barrier alterations. Nat. Neurosci. https://doi.org/10.1038/s41593-025-01891-9 (2025).
Ollivier, M. et al. Crym-positive striatal astrocytes gate perseverative behaviour. Nature 627, 358–366 (2024).
Yu, X. et al. Reducing astrocyte calcium signaling in vivo alters striatal microcircuits and causes repetitive behavior. Neuron 99, 1170–1187 (2018).
Suthard, R. L. et al. Basolateral amygdala astrocytes are engaged by the acquisition and expression of a contextual fear memory. J. Neurosci. 43, 4997–5013 (2023).
Martin-Fernandez, M. et al. Synapse-specific astrocyte gating of amygdala-related behavior. Nat. Neurosci. 20, 1540–1548 (2017).
Cui, Y. et al. Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature 554, 323–327 (2018).
Wheeler, M. A. et al. Droplet-based forward genetic screening of astrocyte–microglia cross-talk. Science 379, 1023–1030 (2023).
Clark, I. C. et al. Identification of astrocyte regulators by nucleic acid cytometry. Nature 614, 326–333 (2023).
Wheeler, M. A. et al. Environmental control of astrocyte pathogenic activities in CNS inflammation. Cell 176, 581–596 (2019).
Wheeler, M. A. et al. MAFG-driven astrocytes promote CNS inflammation. Nature 578, 593–599 (2020).
Sanmarco, L. M. et al. Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes. Nature 590, 473–479 (2021).
Maddox, S. A., Hartmann, J., Ross, R. A. & Ressler, K. J. Deconstructing the gestalt: mechanisms of fear, threat, and trauma memory encoding. Neuron 102, 60–74 (2019).
Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999–1014 (2018).
LeDoux, J. The amygdala. Curr. Biol. 17, R868–R874 (2007).
Wohleb, E. S., Powell, N. D., Godbout, J. P. & Sheridan, J. F. Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. J. Neurosci. 33, 13820–13833 (2013).
Zheng, Z.-H. et al. Neuroinflammation induces anxiety- and depressive-like behavior by modulating neuronal plasticity in the basolateral amygdala. Brain Behav. Immun. 91, 505–518 (2021).
Linnerbauer, M. et al. The astrocyte-produced growth factor HB-EGF limits autoimmune CNS pathology. Nat. Immunol. 25, 432–447 (2024).
Sun, W. et al. Spatial transcriptomics reveal neuron–astrocyte synergy in long-term memory. Nature 627, 374–381 (2024).
Luo, F. et al. Modulation of proteoglycan receptor PTPσ enhances MMP-2 activity to promote recovery from multiple sclerosis. Nat. Commun. 9, 4126 (2018).
Tonks, N. K. Protein tyrosine phosphatases: from genes, to function, to disease. Nat. Rev. Mol. Cell Biol. 7, 833–846 (2006).
Won, S. Y., Lee, P. & Kim, H. M. Synaptic organizer: slitrks and type IIa receptor protein tyrosine phosphatases. Curr. Opin. Struct. Biol. 54, 95–103 (2019).
Hochgerner, H. et al. Neuronal types in the mouse amygdala and their transcriptional response to fear conditioning. Nat. Neurosci. https://doi.org/10.1038/s41593-023-01469-3 (2023).
Santiago, A. C. & Shammah-Lagnado, S. J. Efferent connections of the nucleus of the lateral olfactory tract in the rat. J. Comp. Neurol. 471, 314–332 (2004).
Menard, C. et al. Social stress induces neurovascular pathology promoting depression. Nat. Neurosci. 20, 1752–1760 (2017).
Clark, S. M., Soroka, J. A., Song, C., Li, X. & Tonelli, L. H. CD4+ T cells confer anxiolytic and antidepressant-like effects, but enhance fear memory processes in Rag2–/– mice. Stress 19, 303–311 (2016).
Rustenhoven, J. & Kipnis, J. Brain borders at the central stage of neuroimmunology. Nature 612, 417–429 (2022).
Marin-Rodero, M. et al. The meninges host a distinct compartment of regulatory T cells that preserves brain homeostasis. Sci. Immunol. 10, eadu2910 (2025).
Barron, J. J. et al. Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior. Science 386, eadi1025 (2024).
Dai, W. et al. A functional role of meningeal lymphatics in sex difference of stress susceptibility in mice. Nat. Commun. 13, 4825 (2022).
McKim, D. B. et al. Sympathetic release of splenic monocytes promotes recurring anxiety following repeated social defeat. Biol. Psychiatry 79, 803–813 (2015).
Kwan, A. C., Olson, D. E., Preller, K. H. & Roth, B. L. The neural basis of psychedelic action. Nat. Neurosci. 25, 1407–1419 (2022).
Green, A. R., Mechan, A. O., Elliott, J. M., O’Shea, E. & Colado, M. I. The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol. Rev. 55, 463–508 (2003).
Shao, L.-X. et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron 109, 2535–2544 (2021).
Goodwin, G. M. et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N. Engl. J. Med. 387, 1637–1648 (2022).
Mitchell, J. M. et al. MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nat. Med. https://doi.org/10.1038/s41591-023-02565-4 (2023).
Nardou, R. et al. Psychedelics reopen the social reward learning critical period. Nature 618, 790–798 (2023).
Nardou, R. et al. Oxytocin-dependent reopening of a social reward learning critical period with MDMA. Nature 569, 116–120 (2019).
Flanagan, T. W. & Nichols, C. D. Psychedelics as anti-inflammatory agents. Int. Rev. Psychiatry 30, 363–375 (2018).
Lehmann, M. L., Poffenberger, C. N., Elkahloun, A. G. & Herkenham, M. Analysis of cerebrovascular dysfunction caused by chronic social defeat in mice. Brain Behav. Immun. 88, 735–747 (2020).
Daskalakis, N. P. et al. Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood. Science 384, eadh3707 (2024).
Cugurra, A. et al. Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma. Science 373, eabf7844 (2021).
Singh, V. et al. Microbiota dysbiosis controls the neuroinflammatory response after stroke. J. Neurosci. 36, 7428–7440 (2016).
Endo, F. et al. Molecular basis of astrocyte diversity and morphology across the CNS in health and disease. Science 378, eadc9020 (2022).
Kyzar, E. J., Nichols, C. D., Gainetdinov, R. R., Nichols, D. E. & Kalueff, A. V. Psychedelic drugs in biomedicine. Trends Pharmacol. Sci. 38, 992–1005 (2017).
Chiu, Y.-T. et al. A suite of engineered mice for interrogating psychedelic drug actions. Preprint at bioRxiv https://doi.org/10.1101/2023.09.25.559347 (2023).
Muir, J. et al. Isolation of psychedelic-responsive neurons underlying anxiolytic behavioral states. Science 386, 802–810 (2024).
Shultz, L. D. et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2Rγnull mice engrafted with mobilized human hemopoietic stem cells. J. Immunol. 174, 6477–6489 (2005).
Coughlan, A. M. et al. Myeloid engraftment in humanized mice: impact of granulocyte-colony stimulating factor treatment and transgenic mouse strain. Stem Cells Dev. 25, 530–541 (2016).
Srinivasan, R. et al. New transgenic mouse lines for selectively targeting astrocytes and studying calcium signals in astrocyte processes in situ and in vivo. Neuron 92, 1181–1195 (2016).
Madisen, L. et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat. Neurosci. 13, 133–140 (2010).
Buch, T. et al. A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nat. Methods 2, 419–426 (2005).
Xu, Z. et al. Efficient strategies for microglia replacement in the central nervous system. Cell Rep. 32, 108041 (2020).
Tomura, M. et al. Monitoring cellular movement in vivo with photoconvertible fluorescence protein “Kaede” transgenic mice. Proc. Natl Acad. Sci. USA 105, 10871–10876 (2008).
Chu, C. et al. The microbiota regulate neuronal function and fear extinction learning. Nature 574, 543–548 (2019).
Shen, Y. et al. CCR5 closes the temporal window for memory linking. Nature 606, 146–152 (2022).
Woodburn, S. C., Levitt, C. M., Koester, A. M. & Kwan, A. C. Psilocybin facilitates fear extinction: importance of dose, context, and serotonin receptors. ACS Chem. Neurosci. 15, 3034–3043 (2024).
Clark, I. C. et al. Barcoded viral tracing of single-cell interactions in central nervous system inflammation. Science 372, eabf1230 (2021).
Macosko, E. Z. et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell 161, 1202–1214 (2015).
Bergen, V., Lange, M., Peidli, S., Wolf, F. A. & Theis, F. J. Generalizing RNA velocity to transient cell states through dynamical modeling. Nat. Biotechnol. 38, 1408–1414 (2020).
Hunker, A. C. et al. Conditional single vector CRISPR/SaCas9 viruses for efficient mutagenesis in the adult mouse nervous system. Cell Rep. 30, 4303–4316 (2020).
Lee, J.-H. et al. Astrocytes phagocytose adult hippocampal synapses for circuit homeostasis. Nature 590, 612–617 (2020).
Challis, R. C. et al. Systemic AAV vectors for widespread and targeted gene delivery in rodents. Nat. Protoc. 14, 379–414 (2019).
Mathis, A. et al. DeepLabCut: markerless pose estimation of user-defined body parts with deep learning. Nat. Neurosci. 21, 1281–1289 (2018).
Nath, T. et al. Using DeepLabCut for 3D markerless pose estimation across species and behaviors. Nat. Protoc. 14, 2152–2176 (2019).
Sturman, O. et al. Deep learning-based behavioral analysis reaches human accuracy and is capable of outperforming commercial solutions. Neuropsychopharmacology 45, 1942–1952 (2020).
Gradinaru, V. et al. Molecular and cellular approaches for diversifying and extending optogenetics. Cell 141, 154–165 (2010).
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 (2022).
Leites, E. P. & Morais, V. A. Protocol for the isolation and culture of microglia, astrocytes, and neurons from the same mouse brain. STAR Protoc. 5, 102804 (2024).
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2012).
Chen, S., Zhou, Y., Chen, Y. & Gu, J. fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 34, i884–i890 (2018).
Ewels, P., Magnusson, M., Lundin, S. & Käller, M. MultiQC: summarize analysis results for multiple tools and samples in a single report. Bioinformatics 32, 3047–3048 (2016).
Liao, Y., Smyth, G. K. & Shi, W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30, 923–930 (2014).
Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).
Chen, E. Y. et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14, 128 (2013).
Kuleshov, M. V. et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 44, W90–W97 (2016).
Xie, Z. et al. Gene set knowledge discovery with Enrichr. Curr. Protoc. 1, e90 (2021).
Szklarczyk, D. et al. The STRING database in 2023: protein–protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 51, D638–D646 (2023).
Laricchiuta, D. et al. Optogenetic stimulation of prelimbic pyramidal neurons maintains fear memories and modulates amygdala pyramidal neuron transcriptome. Int. J. Mol. Sci. 22, 810 (2021).
Namburi, P. et al. A circuit mechanism for differentiating positive and negative associations. Nature 520, 675–678 (2015).
Samineni, V. K. et al. Cellular, circuit and transcriptional framework for modulation of itch in the central amygdala. eLife 10, e68130 (2021).
Levitan, D. et al. Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory. eLife 9, e61036 (2020).
Knoedler, J. R. et al. A functional cellular framework for sex and estrous cycle-dependent gene expression and behavior. Cell 185, 654–671 (2022).
Yamaguchi, T. et al. Posterior amygdala regulates sexual and aggressive behaviors in male mice. Nat. Neurosci. 23, 1111–1124 (2020).
Golden, S. A. et al. Basal forebrain projections to the lateral habenula modulate aggression reward. Nature 534, 688–692 (2016).
Buenrostro, J. D., Wu, B., Chang, H. Y. & Greenleaf, W. J. ATAC-seq: a method for assaying chromatin accessibility genome-wide. Curr. Protoc. Mol. Biol. 109, 21.29.1–21.29.9 (2015).
Chen, A. et al. Spatiotemporal transcriptomic atlas of mouse organogenesis using DNA nanoball-patterned arrays. Cell 185, 1777–1792 (2022).
Chen, A. et al. Single-cell spatial transcriptome reveals cell-type organization in the macaque cortex. Cell 186, 3726–3743 (2023).
van der Walt, S. et al. scikit-image: image processing in Python. PeerJ 2, e453 (2014).
Wolf, F. A., Angerer, P. & Theis, F. J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 19, 15 (2018).
Waclaw, R. R., Ehrman, L. A., Pierani, A. & Campbell, K. Developmental origin of the neuronal subtypes that comprise the amygdalar fear circuit in the mouse. J. Neurosci. 30, 6944–6953 (2010).
Kuerbitz, J. et al. Loss of intercalated cells (ITCs) in the mouse amygdala of Tshz1 mutants correlates with fear, depression, and social interaction phenotypes. J. Neurosci. 38, 1160–1177 (2018).
Garcia-Calero, E., Martínez-de-la-Torre, M. & Puelles, L. A radial histogenetic model of the mouse pallial amygdala. Brain Struct. Funct. 225, 1921–1956 (2020).
Glendining, K. A., Fisher, L. C. & Jasoni, C. L. Maternal high fat diet alters offspring epigenetic regulators, amygdala glutamatergic profile and anxiety. Psychoneuroendocrinology 96, 132–141 (2018).
Nery, S., Fishell, G. & Corbin, J. G. The caudal ganglionic eminence is a source of distinct cortical and subcortical cell populations. Nat. Neurosci. 5, 1279–1287 (2002).
Huang, W.-C., Chen, Y. & Page, D. T. Hyperconnectivity of prefrontal cortex to amygdala projections in a mouse model of macrocephaly/autism syndrome. Nat. Commun. 7, 13421 (2016).
Stenman, J., Yu, R. T., Evans, R. M. & Campbell, K. Tlx and Pax6 co-operate genetically to establish the pallio-subpallial boundary in the embryonic mouse telencephalon. Development 130, 1113–1122 (2003).
Tosches, M. A. et al. Evolution of pallium, hippocampus, and cortical cell types revealed by single-cell transcriptomics in reptiles. Science 360, 881–888 (2018).
Boyle, M. P. et al. Cell-type-specific consequences of Reelin deficiency in the mouse neocortex, hippocampus, and amygdala. J. Comp. Neurol. 519, 2061–2089 (2011).
Ressler, K. J. et al. Post-traumatic stress disorder: clinical and translational neuroscience from cells to circuits. Nat. Rev. Neurol. 18, 273–288 (2022).
Rothhammer, V. et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat. Med. 22, 586–597 (2016).
Pinho-Ribeiro, F. A. et al. Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion. Nature 615, 472–481 (2023).
Wilk, C. M. et al. Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disorders. Immunity 56, 2790–2802 (2023).
Barnes, N. M. et al. International Union of Basic and Clinical Pharmacology. CX. Classification of receptors for 5-hydroxytryptamine; pharmacology and function. Pharmacol. Rev. 73, 310–520 (2021).
Gumpper, R. H. & Roth, B. L. SnapShot: psychedelics and serotonin receptor signaling. Cell 186, 232–232 (2023).
Baumann, M. H. et al. Effects of dose and route of administration on pharmacokinetics of (±)-3,4-methylenedioxymethamphetamine in the rat. Drug Metab. Dispos. 37, 2163–2170 (2009).
Lyon, R. A., Glennon, R. A. & Titeler, M. 3,4-Methylenedioxymethamphetamine (MDMA): stereoselective interactions at brain 5-HT1 and 5-HT2 receptors. Psychopharmacology 88, 525–526 (1986).
Nash, J., Roth, B., Brodkin, J., Nichols, D. & Gudelsky, G. Effect of the R(−) and S(+) isomers of MDA and MDMA on phosphotidyl inositol turnover in cultured cells expressing 5-HT2A or 5-HT2C receptors. Neurosci. Lett. 177, 111–115 (1994).
Setola, V. et al. 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol. Pharmacol. 63, 1223–1229 (2003).
Doly, S. et al. Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro. J. Neurosci. 28, 2933–2940 (2008).
Moliner, R. et al. Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nat. Neurosci. https://doi.org/10.1038/s41593-023-01316-5 (2023).
McClure-Begley, T. D. & Roth, B. L. The promises and perils of psychedelic pharmacology for psychiatry. Nat. Rev. Drug Discov. 21, 463–473 (2022).
Cameron, L. P. et al. Beyond the 5-HT2A receptor: classic and nonclassic targets in psychedelic drug action. J. Neurosci. 43, 7472–7482 (2023).
Nichols, D. E., Nichols, C. D. & Hendricks, P. S. Proposed consensus statement on defining psychedelic drugs. Psychedelic Med. 1, 12–13 (2023).
Schneider, K. M. et al. The enteric nervous system relays psychological stress to intestinal inflammation. Cell 186, 2823–2838 (2023).
Wheeler, M. A. et al. TNF-α/TNFR1 signaling is required for the development and function of primary nociceptors. Neuron 82, 587–602 (2014).
Glebova, N. O. & Ginty, D. D. Heterogeneous requirement of NGF for sympathetic target innervation in vivo. J. Neurosci. 24, 743–751 (2004).
Heng, T. S. P., Painter, M. W. & Immunological Genome Project Consortium. The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008).
Sanmarco, L. M. et al. Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells. Nature 620, 881–889 (2023).
Zeisel, A. Amy_FC_allcells_with_metadata_31-Jul-2022.txt. Figshare https://doi.org/10.6084/m9.figshare.20412573 (2022).
