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Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour

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Abstract

Immune dysfunction is commonly associated with several neurological and mental disorders. Although the mechanisms by which peripheral immunity may influence neuronal function are largely unknown, recent findings implicate meningeal immunity influencing behaviour, such as spatial learning and memory1. Here we show that meningeal immunity is also critical for social behaviour; mice deficient in adaptive immunity exhibit social deficits and hyper-connectivity of fronto-cortical brain regions. Associations between rodent transcriptomes from brain and cellular transcriptomes in response to T-cell-derived cytokines suggest a strong interaction between social behaviour and interferon-γ (IFN-γ)-driven responses. Concordantly, we demonstrate that inhibitory neurons respond to IFN-γ and increase GABAergic (γ-aminobutyric-acid) currents in projection neurons, suggesting that IFN-γ is a molecular link between meningeal immunity and neural circuits recruited for social behaviour. Meta-analysis of the transcriptomes of a range of organisms reveals that rodents, fish, and flies elevate IFN-γ/JAK-STAT-dependent gene signatures in a social context, suggesting that the IFN-γ signalling pathway could mediate a co-evolutionary link between social/aggregation behaviour and an efficient anti-pathogen response. This study implicates adaptive immune dysfunction, in particular IFN-γ, in disorders characterized by social dysfunction and suggests a co-evolutionary link between social behaviour and an anti-pathogen immune response driven by IFN-γ signalling.

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Figure 1: Meningeal T-cell compartment is necessary for supporting neuronal connectivity and social behaviour.
Figure 2: IFN-γ supports proper neural connectivity and social behaviour.
Figure 3: Over-representation of IFN-γ transcriptional signature genes in social behaviour-associated brain transcriptomes of rat, mouse, zebrafish, and Drosophila.

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Gene Expression Omnibus

Data deposits

RNA-seq data have been deposited in the Gene Expression Omnibus under accession number GSE81783.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (AG034113 and NS081026 to J.K.), (T32-AI007496 to A.J.F.), and the Hartwell Foundation (to A.J.F.). We thank all the members of the Center for Brain Immunology and Glia (BIG) for their comments during numerous discussions of this manuscript. We also thank J. Roy for his expertise in MRI, B. Tomlin and N. Al Hamadani for animal care, as well as S. Rich, S. Onengut-Gumuscu, and E. Farber for sequencing the cDNA library.

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Authors and Affiliations

Authors

Contributions

A.J.F. and J.K. designed and performed experiments and wrote the manuscript. Y.X. and V.L. provided intellectual contributions and analysed all transcriptome data. S.D.T., Z.W., S.N.P., and H.C. analysed transcriptome data. N.T. and C.C.O. analysed BOLD data. R.L.M., W.B., I.S., S.P.G., M.M.S. and M.P.B. provided intellectual contributions and assisted with experimental procedures. M.P.B. performed all electrophysiological experiments. K.S.L. critically reviewed the manuscript.

Corresponding authors

Correspondence to Anthony J. Filiano, Vladimir Litvak or Jonathan Kipnis.

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The authors declare no competing financial interests.

Additional information

Reviewer Information Nature thanks M. Kano, L. Steinman and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data figures and tables

Extended Data Figure 1 SCID mice have no observable anxiety, motor, or olfactory deficits.

a, The three-chamber sociability assay was used to test social behaviour. b, Neither wild-type nor SCID mice had a side bias in the habituation phase (empty cups) of the three-chamber assay (n = 6; repeated at least three times). c, There was no effect of genotype on distance travelled in the three-chamber assay during the habituation phase (n = 6; repeated at least three times). d, Both wild-type and SCID mice had an olfactory preference to urine, suggesting normal olfactory behaviour (n = 8 mice per group; ANOVA for urine preference F1,28 = 31.01; P < 0.0001; ***P < 0.001, **P < 0.01, Sidak’s post hoc test; single experiment). e, Percentage time spent in the open arms of plus-maze (n = 22 mice per group; pooled two independent experiments). f, Number of entries into the open arms of the plus-maze (n = 22 mice per group; pooled two independent experiments). g, Total arm entries of plus-maze (n = 22 mice per group; pooled two independent experiments). h, Percentage time spent in the centre of the open field (n = 22 mice per group; pooled two independent experiments). i, Total ambulatory distance in the open field (n = 22 mice per group; pooled two independent experiments). j, Latency to fall off the accelerating rotarod (n = 8 mice per group; single experiment). k, SCID mice spent less time investigating each other than wild-type mice spent investigating each other when placed into a novel social environment (n = 5 mice per group; repeated-measures ANOVA for genotype F1,21 = 5.708 *P < 0.05; single experiment). l, Repopulated SCID mice have similar numbers (m) and percentages (n) of meningeal T cells as wild-type mice (n = 4–5 mice per group; repeated at least three times). Cells were gated on singlets, live, CD45+, and TCR.

Extended Data Figure 2 Neuroanatomical structures analysed by rsfMRI.

a, Regions of interests (ROIs) were generated using The Mouse Brain by Paxinos and Franklin as a reference. Representative slices were extracted from ref. 32. Abbreviations are as follows: FrA, frontal association cortex; PrL, prelimbic cortex; OrbC, orbital cortex; OB, olfactory bulb; MC, motor cortex; SocC, somatosensory cortex; Ins, insula; PirF, piriform cortex; CpU, caudate putamen; Acb, accumbens; ACC, anterior cingulate cortex; dHip, dorsal hippocampus; T, thalamus; Amyg, amygdala; EntC, entorhinal cortex; Hyp, hypothalamus; VisC, visual cortex; SupC, superior colliculus; PAG, periductal grey; DpMe, deep mesencephalic nucleus; vHip, ventral hippocampus; SNR, substantia nigra; VTA, ventral tegmental area; CB, cerebellum; BS, brain stem. b, Connectivity of local PFC/insular nodes. Correlation thresholds were applied to visualize the strength of the connection. Connections that pass a high threshold are shown in red; connections that pass a lower threshold are shown in dashed grey. SCID mice have aberrant hyper-connectivity in the PFC (n = 8–9 mice per group; P < 0.05, Jennrich test; two pooled independent experiments). c, c-fos+ cells in the hippocampus (n = 9–10 mice per group; single experiment).

Extended Data Figure 3 Acute reduction of meningeal T cells with anti-VLA4.

a, Anti-VLA4 depletes meningeal T cells. Meninges were dissected and single-cell suspensions were immunostained. T cells were gated on live, single, CD45+, TCR+ events and counted by flow cytometry. b, Acute injection of anti-VLA4 reduced the amount of TCR+ T cells in the meninges (n = 4 mice per group; *P < 0.01; repeated at least twice).

Extended Data Figure 4 Circos plot showing the connectivity of Th1 response and social aggregation.

Labels are shown for the data sets analysed and presented in Fig. 1h.

Extended Data Figure 5 T cells in the meninges produce IFN-γ and IFN-γ-deficient mice have normal levels of anxiety and motor behaviour.

a, A substantial percentage of meningeal T cells produce IFN-γ. Cells were gated for live, singlets, CD45+, and TCR+. Ifng-/- mice were used to gate for IFN-γ staining. b, Percentage time spent in open arms of the plus-maze (n = 20 mice per group; pooled two independent experiments). c, Entries into the open arms of plus-maze (n = 20 mice per group; pooled two independent experiments). d, Total entries into all arms of the plus-maze (n = 20 mice per group; pooled two independent experiments). e, Percentage time spent in the centre of the open field (n = 20 mice per group; pooled two independent experiments). f, Total ambulatory distance in the open field (n = 20 mice per group; pooled two independent experiments). g, Latency to fall off the accelerating rotarod (n = 8 mice per group; single experiment).

Extended Data Figure 6 IFN-γ signalling is necessary for normal social behaviour.

a, Repopulating SCID mice with wild-type lymphocytes rescued a social preference; repopulating with Ifng-/- lymphocytes did not rescue a social preference; ANOVA for social behaviour F1,14 = 11.99; P = 0.0038 (**P < 0.01; n = 8 mice per group; single experiment). b, Connectivity of local PFC/insular nodes. Correlation thresholds were applied to visualize the strength of the connection. Connections that pass a high threshold are shown in red; connections that pass a lower threshold are shown in dashed grey. Ifng-/- mice have more connections than wild-type mice (Jennerich test; P = 0.0006). These connections were reduced by IFN-γ (Jennerich test; P = 0.02; pooled two independent experiments). c, Ifngr1-/- mice have social deficits (n = 6 mice per group; ANOVA for interaction P = 0.01; **P < 0.01 Sidak’s post hoc test) that were not rescued by injecting IFN-γ into the CSF (d; n = 5–6 mice per group; ANOVA for interaction P = 0.01; **P < 0.01 Sidak’s post hoc test; single experiment). e, Il4-/- mice spend more time than wild-type mice investigating a novel mouse; ANOVA for genotype F1,32 = 5.397; P = 0.0267 (*P < 0.05 Sidak’s post hoc test; n = 16–18 mice per group; pooled three independent experiments).

Extended Data Figure 7 Gating strategy for neurons and microglia.

Brain homogenates were stained and analysed by flow cytometry. Cells were gated on nucleated, singlets, and live. Neurons were then gated on NeuN-positive and microglia on CD11B-positive cells.

Extended Data Figure 8 IFN-γ signalling in microglia is not necessary for normal social function.

Mice deficient for STAT1 in microglia have normal social preference (n = 9 mice per group; ANOVA for Cre F1,16 = 1.809 and sociability F1,16 = 30.10; P < 0.0001; **P < 0.01; ***P < 0.001 Sidak’s post hoc test; pooled two independent experiments).

Extended Data Figure 9 Deleting IFNGR1 by AAV transduction.

Mice were injected with AVVs expressing Cre and GFP under a synapsin promoter. a, GFP fluorescence in the PFC. Atlas image adapted from 2015 Allen Institute for Brain Science, Allen Brain Atlas. Available from: http://www.brain-map.org. b, GFP fluorescence is only observed in NeuN+ neurons, not Iba+ microglia (top, 20×; bottom 63× objective).

Extended Data Figure 10 IFN-γ increased the number of c-fos+ cells in layer I of the PFC.

a, IFN-γ was injected into the CSF (into the cisterna magna) 2 h before killing and processing brains for immunohistochemistry. Slices were stained for c-fos. Atlas image adapted from 2015 Allen Institute for Brain Science, Allen Brain Atlas. Available from: http://www.brain-map.org. b, Total c-fos+ cells in layer I of the PFC (n = 3 mice per group; *P < 0.05; single experiment). Holding current pre and post IFN-γ application on acute slices from the PFC (c) and somatosensory cortex (d; n = 6 neurons from three mice). c, Vgatcre::Ifngr1fl/fl mice. IFN-γ increased tonic inhibition in Cre mice (n = 6–7 cells from four mice per group; **P < 0.01 Sidak’s post hoc test).

Supplementary information

Supplementary Table 1

R values for ROIs analyzed by rsfMRI. This table contains the raw data of all R-values analyzed from BOLD sequences. (XLSX 1428 kb)

Supplementary Table 2

Custom gene sets. This table shows the list of custom gene sets signatures used to generate the circus plot. These signatures were derived from indicated publicly available datasets. (XLSX 218 kb)

Supplementary Table 3

This table shows metatranscriptome analysis output for Circos plot generation. Pairwise connectivity between transcriptomes was determined by GSEA analysis. Connectivity is determined by GSEA statistical scores of NES > 1.5 and Nominal P-value < 0.05. (XLSX 260 kb)

Supplementary Table 4

IFN-γ and JAK/STAT custom gene set signatures. Shown is the list of custom gene sets of IFN-γ and JAK/STAT signatures derived from indicated publicly available database. (XLSX 48 kb)

Supplementary Table 5

IFN-γ and JAK/STAT signature genes up-regulated in brain transcriptomes. Shown are IFNg and JAK/STAT signature genes that are up-regulated in brain transcriptomes of mice, rats, drosophila flies and zebrafish derived from indicated public available datasets. (XLSX 36 kb)

Supplementary Table 6

GSEA output of transcriptional signatures enriched in the prefrontal cortex transcriptomes of group-housed mice. Shown are the statistical scores of the enrichment of Molecular Signature Database C2 version 4.0 gene sets in the prefrontal cortex transcriptome of group-housed mice. A line showing the over-representation of IFN-γ transcriptional signature in the prefrontal cortex transcriptome of group-housed mice is highlighted in grey. (XLSX 96 kb)

Supplementary Table 7

Over-representation of IFN-γ and JAK/STAT transcriptional signatures in the head transcriptomes of D. rerio and D. melanogaster. Shown is the summary of GSEA output that indicates the statistical scores of the enrichment of IFN-γ and JAK/STAT transcriptional signature genes in the head transcriptome of D. rerio and D. melanogaster derived from indicated publicly available datasets. (XLSX 12 kb)

Supplementary Table 8

Values for statistical analysis. Detailed statistical information is provided including >Ns, F-values, degrees of freedom, and P values. (XLSX 39 kb)

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Filiano, A., Xu, Y., Tustison, N. et al. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature 535, 425–429 (2016). https://doi.org/10.1038/nature18626

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