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

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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 behavior, such as spatial learning and memory 1 . Here we show that meningeal immunity is also critical for social behavior; 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 behavior and interferon-gamma (IFN-γ) driven responses. Concordantly, we demonstrate that inhibitory neurons respond to IFN-γ and increase GABAergic currents in projection neurons, suggesting that IFN-γ is a molecular link between meningeal immunity and neural circuits recruited for social behavior. Meta-analysis on the transcriptomes of a range of organisms revealed that rodents, fish, and flies elevate IFN-γ/JAK-STAT–dependent gene signatures in a social context, suggesting that the IFN-γ signaling pathway could mediate a co-evolutionary link between social/aggregation behavior 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 behavior and an anti-pathogen immune response driven by IFN-γ signaling.

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          Most cited references 48

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          Is Open Access

          featureCounts: An efficient general-purpose program for assigning sequence reads to genomic features

           ,  ,   (2013)
          Next-generation sequencing technologies generate millions of short sequence reads, which are usually aligned to a reference genome. In many applications, the key information required for downstream analysis is the number of reads mapping to each genomic feature, for example to each exon or each gene. The process of counting reads is called read summarization. Read summarization is required for a great variety of genomic analyses but has so far received relatively little attention in the literature. We present featureCounts, a read summarization program suitable for counting reads generated from either RNA or genomic DNA sequencing experiments. featureCounts implements highly efficient chromosome hashing and feature blocking techniques. It is considerably faster than existing methods (by an order of magnitude for gene-level summarization) and requires far less computer memory. It works with either single or paired-end reads and provides a wide range of options appropriate for different sequencing applications. featureCounts is available under GNU General Public License as part of the Subread (http://subread.sourceforge.net) or Rsubread (http://www.bioconductor.org) software packages.
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            R: A language and environment for statistical computing

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              Behavioural phenotyping assays for mouse models of autism.

              Autism is a heterogeneous neurodevelopmental disorder of unknown aetiology that affects 1 in 100-150 individuals. Diagnosis is based on three categories of behavioural criteria: abnormal social interactions, communication deficits and repetitive behaviours. Strong evidence for a genetic basis has prompted the development of mouse models with targeted mutations in candidate genes for autism. As the diagnostic criteria for autism are behavioural, phenotyping these mouse models requires behavioural assays with high relevance to each category of the diagnostic symptoms. Behavioural neuroscientists are generating a comprehensive set of assays for social interaction, communication and repetitive behaviours to test hypotheses about the causes of autism. Robust phenotypes in mouse models hold great promise as translational tools for discovering effective treatments for components of autism spectrum disorders.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                9 June 2016
                21 July 2016
                21 January 2017
                : 535
                : 7612
                : 425-429
                Affiliations
                [1 ]Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA
                [2 ]Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA
                [3 ]Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA
                [4 ]Neuroscience Graduate Program, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA
                [5 ]Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA
                [6 ]Department of Radiology and Medical Imaging, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA
                [7 ]Department of Neurosurgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA
                [8 ]Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA
                [9 ]Department of Public Health Sciences, School of Medicine University of Virginia, Charlottesville, VA 22908, USA
                [10 ]Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
                Author notes
                [* ]Correspondence to: A.J.F. ( ajf5v@ 123456virginia.edu ), V.L. ( Vladimir.Litvak@ 123456umassmed.edu ), or J.K. ( kipnis@ 123456virginia.edu ); Tel: +1 434-982-3858, Fax: +1 434-982-4380

                J.K. and V.L. are co-senior authors

                Article
                NIHMS793134
                10.1038/nature18626
                4961620
                27409813

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