[ { "id": "authors:en9tt-2np72", "collection": "authors", "collection_id": "en9tt-2np72", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210908-171123816", "type": "article", "title": "Alterations in the gut microbiota contribute to cognitive impairment induced by the ketogenic diet and hypoxia", "author": [ { "family_name": "Olson", "given_name": "Christine A.", "orcid": "0000-0002-5382-1393", "clpid": "Olson-Christine-A" }, { "family_name": "I\u00f1iguez", "given_name": "Alonso J.", "orcid": "0000-0002-4869-3278", "clpid": "I\u00f1iguez-Alonso-J" }, { "family_name": "Yang", "given_name": "Grace E.", "orcid": "0000-0001-8346-908X", "clpid": "Yang-Grace-E" }, { "family_name": "Fang", "given_name": "Ping", "orcid": "0000-0003-4379-3787", "clpid": "Fang-Ping" }, { "family_name": "Pronovost", "given_name": "Geoffrey N.", "clpid": "Pronovost-Geoffrey-N" }, { "family_name": "Jameson", "given_name": "Kelly G.", "orcid": "0000-0002-9972-9138", "clpid": "Jameson-Kelly-G" }, { "family_name": "Rendon", "given_name": "Tomiko K.", "clpid": "Rendon-Tomiko-K" }, { "family_name": "Paramo", "given_name": "Jorge", "clpid": "Paramo-Jorge" }, { "family_name": "Barlow", "given_name": "Jacob T.", "orcid": "0000-0002-1842-4835", "clpid": "Barlow-Jacob-T" }, { "family_name": "Ismagilov", "given_name": "Rustem F.", "orcid": "0000-0002-3680-4399", "clpid": "Ismagilov-R-F" }, { "family_name": "Hsiao", "given_name": "Elaine Y.", "orcid": "0000-0002-1633-588X", "clpid": "Hsiao-Elaine-Y-Bio" } ], "abstract": "Many genetic and environmental factors increase susceptibility to cognitive impairment (CI), and the gut microbiome is increasingly implicated. However, the identity of gut microbes associated with CI risk, their effects on CI, and their mechanisms remain unclear. Here, we show that a carbohydrate-restricted (ketogenic) diet potentiates CI induced by intermittent hypoxia in mice and alters the gut microbiota. Depleting the microbiome reduces CI, whereas transplantation of the risk-associated microbiome or monocolonization with Bilophila wadsworthia confers CI in mice fed a standard diet. B. wadsworthia and the risk-associated microbiome disrupt hippocampal synaptic plasticity, neurogenesis, and gene expression. The CI is associated with microbiome-dependent increases in intestinal interferon-gamma (IFNg)-producing Th1 cells. Inhibiting Th1 cell development abrogates the adverse effects of both B. wadsworthia and environmental risk factors on CI. Together, these findings identify select gut bacteria that contribute to environmental risk for CI in mice by promoting inflammation and hippocampal dysfunction.", "doi": "10.1016/j.chom.2021.07.004", "pmcid": "PMC8429275", "issn": "1931-3128", "publisher": "Cell Press", "publication": "Cell Host and Microbe", "publication_date": "2021-09-08", "series_number": "9", "volume": "29", "issue": "9", "pages": "1378-1392" }, { "id": "authors:vmejn-ca491", "collection": "authors", "collection_id": "vmejn-ca491", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181105-100651058", "type": "article", "title": "Defining Dysbiosis in Disorders of Movement and Motivation", "author": [ { "family_name": "Fields", "given_name": "Christopher T.", "orcid": "0000-0002-2054-7316", "clpid": "Fields-Christopher-T" }, { "family_name": "Sampson", "given_name": "Timothy R.", "orcid": "0000-0002-2486-8766", "clpid": "Sampson-Timothy-R" }, { "family_name": "Bruce-Keller", "given_name": "Annadora J.", "clpid": "Bruce-Keller-Annadora-J" }, { "family_name": "Kiraly", "given_name": "Drew D.", "orcid": "0000-0002-4818-5169", "clpid": "Kiraly-Drew-D" }, { "family_name": "Hsiao", "given_name": "Elaine Y.", "orcid": "0000-0002-1633-588X", "clpid": "Hsiao-Elaine-Y-Bio" }, { "family_name": "de Vries", "given_name": "Geert J.", "clpid": "de-Vries-Geert-J" } ], "abstract": "The gut microbiota has emerged as a critical player in shaping and modulating brain function and has been shown to influence numerous behaviors, including anxiety and depression-like behaviors, sociability, and cognition. However, the effects of the gut microbiota on specific disorders associated with thalamo-cortico-basal ganglia circuits, ranging from compulsive behavior and addiction to altered sensation and motor output, are only recently being explored. Wholesale depletion and alteration of gut microbial communities in rodent models of disorders, such as Parkinson's disease, autism, and addiction, robustly affect movement and motivated behavior. A new frontier therefore lies in identifying specific microbial alterations that affect these behaviors and understanding the underlying mechanisms of action. Comparing alterations in gut microbiota across multiple basal-ganglia associated disease states allows for identification of common mechanistic pathways that may interact with distinct environmental and genetic risk factors to produce disease-specific outcomes.", "doi": "10.1523/jneurosci.1672-18.2018", "pmcid": "PMC6209841", "issn": "0270-6474", "publisher": "Society for Neuroscience", "publication": "Journal of Neuroscience", "publication_date": "2018-10-31", "series_number": "44", "volume": "38", "issue": "44", "pages": "9414-9422" }, { "id": "authors:647wd-8bg68", "collection": "authors", "collection_id": "647wd-8bg68", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20161114-135126065", "type": "article", "title": "The Placental Interleukin-6 Signaling Controls Fetal Brain Development and Behavior", "author": [ { "family_name": "Wu", "given_name": "Wei-Li", "orcid": "0000-0003-2610-1881", "clpid": "Wu-Wei-Li" }, { "family_name": "Hsiao", "given_name": "Elaine Y.", "orcid": "0000-0002-1633-588X", "clpid": "Hsiao-Elaine-Y-Bio" }, { "family_name": "Yan", "given_name": "Zihao", "clpid": "Yan-Zihao" }, { "family_name": "Mazmanian", "given_name": "Sarkis K.", "orcid": "0000-0003-2713-1513", "clpid": "Mazmanian-S-K" }, { "family_name": "Patterson", "given_name": "Paul H.", "clpid": "Patterson-P-H" } ], "abstract": "Epidemiological studies show that maternal immune activation (MIA) during pregnancy is a risk factor for autism. However, mechanisms for how MIA affects brain development and behaviors in offspring remain poorly described. To determine whether placental interleukin-6 (IL-6) signaling is required for mediating MIA on the offspring, we generated mice with restricted deletion of the receptor for IL-6 (IL-6R_) in placental trophoblasts (Cyp19-Cre^(+);Il6ra^(fl/fl)), and tested offspring of Cyp19-Cre^(+);Il6ra^(fl/fl) mothers for immunological, pathological and behavioral abnormalities following induction of MIA. We reveal that MIA results in acute inflammatory responses in the fetal brain. Lack of IL-6 signaling in trophoblasts effectively blocks MIA-induced inflammatory responses in the placenta and the fetal brain. Furthermore, behavioral abnormalities and cerebellar neuropathologies observed in MIA control offspring are prevented in Cyp19-Cre^(+);Il6ra^(fl/fl) offspring. Our results demonstrate that IL-6 activation in placenta is required for relaying inflammatory signals to the fetal brain and impacting behaviors and neuropathologies relevant to neurodevelopmental disease.", "doi": "10.1016/j.bbi.2016.11.007", "pmcid": "PMC5373986", "issn": "0889-1591", "publisher": "Elsevier", "publication": "Brain, Behavior, and Immunity", "publication_date": "2017-05", "volume": "62", "pages": "11-23" }, { "id": "authors:1n749-wdv15", "collection": "authors", "collection_id": "1n749-wdv15", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150409-093248232", "type": "article", "title": "Indigenous Bacteria from the Gut Microbiota Regulate Host Serotonin Biosynthesis", "author": [ { "family_name": "Yano", "given_name": "Jessica M.", "clpid": "Yano-Jessica-M" }, { "family_name": "Yu", "given_name": "Kristie", "orcid": "0000-0001-6735-3968", "clpid": "Yu-Kristie-B" }, { "family_name": "Donaldson", "given_name": "Gregory P.", "orcid": "0000-0002-8551-374X", "clpid": "Donaldson-Gregory-P" }, { "family_name": "Shastri", "given_name": "Gauri G.", "clpid": "Shastri-Gauri-G" }, { "family_name": "Ann", "given_name": "Phoebe", "clpid": "Ann-Phoebe" }, { "family_name": "Ma", "given_name": "Liang", "clpid": "Ma-Liang" }, { "family_name": "Nagler", "given_name": "Cathryn R.", "orcid": "0000-0001-7254-6617", "clpid": "Nagler-Cathryn-R" }, { "family_name": "Ismagilov", "given_name": "Rustem F.", "orcid": "0000-0002-3680-4399", "clpid": "Ismagilov-R-F" }, { "family_name": "Mazmanian", "given_name": "Sarkis K.", "orcid": "0000-0003-2713-1513", "clpid": "Mazmanian-S-K" }, { "family_name": "Hsiao", "given_name": "Elaine Y.", "orcid": "0000-0002-1633-588X", "clpid": "Hsiao-Elaine-Y-Bio" } ], "abstract": "The gastrointestinal (GI) tract contains much of the body's serotonin (5-hydroxytryptamine, 5-HT), but mechanisms controlling the metabolism of gut-derived 5-HT remain unclear. Here, we demonstrate that the microbiota plays a critical role in regulating host 5-HT. Indigenous spore-forming bacteria (Sp) from the mouse and human microbiota promote 5-HT biosynthesis from colonic enterochromaffin cells (ECs), which supply 5-HT to the mucosa, lumen, and circulating platelets. Importantly, microbiota-dependent effects on gut 5-HT significantly impact host physiology, modulating GI motility and platelet function. We identify select fecal metabolites that are increased by Sp and that elevate 5-HT in chromaffin cell cultures, suggesting direct metabolic signaling of gut microbes to ECs. Furthermore, elevating luminal concentrations of particular microbial metabolites increases colonic and blood 5-HT in germ-free mice. Altogether, these findings demonstrate that Sp are important modulators of host 5-HT and further highlight a key role for host-microbiota interactions in regulating fundamental 5-HT-related biological processes.", "doi": "10.1016/j.cell.2015.02.047", "pmcid": "PMC4393509", "issn": "0092-8674", "publisher": "Cell Press", "publication": "Cell", "publication_date": "2015-04-09", "series_number": "2", "volume": "161", "issue": "2", "pages": "264-276" }, { "id": "authors:qmrnh-m6595", "collection": "authors", "collection_id": "qmrnh-m6595", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150609-074625307", "type": "article", "title": "Maternal Immune Activation Perturbs Fetal Brain Development and Adult Behaviors Through Placental Trophoblast IL-6 Activation", "author": [ { "family_name": "Wu", "given_name": "Wei-Li", "orcid": "0000-0003-2610-1881", "clpid": "Wu-Wei-Li" }, { "family_name": "Hsiao", "given_name": "Elaine Y.", "orcid": "0000-0002-1633-588X", "clpid": "Hsiao-Elaine-Y-Bio" }, { "family_name": "Yan", "given_name": "Zihao", "clpid": "Yan-Zihao" }, { "family_name": "Mazmanian", "given_name": "Sarkis", "orcid": "0000-0003-2713-1513", "clpid": "Mazmanian-S-K" }, { "family_name": "Patterson", "given_name": "Paul H.", "clpid": "Patterson-P-H" } ], "abstract": "Background: Epidemiologic studies indicate maternal infection as a risk factor for autism and schizophrenia in the offspring. Maternal immune activation (MIA) in the dam, an animal model for maternal infection, leads the offspring exhibiting autistic- and schizophrenia-like behaviors.\nHowever, the mechanism of how MIA perturbs fetal brain development and precipitates the offspring behavior deficits and brain neuropathologies remains elusive. Prior works demonstrate maternal interleukin-6 (IL-6) is a key cytokine that mediates the effect of MIA on the offspring. Placenta as an interface between dam and fetus presumably plays a role in mediating the acute response to MIA in maternal-placental-fetal axis. Here, we are investigating the role of placental IL-6 activation in the etiology of MIA\ncaused autistic and schizophrenia-like phenotypes.\nMethods: Induction of MIA is done by injecting viral mimic poly(I:C) into the dam at mid-gestation. The inflammatory responses in the fetal brain after poly(I:C) injection is examined to understand the impact of MIA to the brain development. To further investigate the role of placental\nIL-6 activation in MIA model, we specifically delete the receptor for IL-6, IL-6Ra, in the placenta of mice. By using placenta-specific IL-6Ra knockout mice, we are allowed to ask whether blocking placental IL-6 activation\ncan prevent the acute inflammation in the placental-fetal axis and offspring behavioral abnormalities and neuropathologies.\nResults: We demonstrate MIA causes acute inflammatory responses in the fetal brain, including increased IL-6 expression and activated IL-6 downstream signaling in fetal prepontine and pontine hindbrain. The acute inflammatory response in the fetal brain following by MIA is found to\ndepend on IL-6 level in the dam. Knockout of IL-6Ra in the placental trophoblast effectively blocks the inflammation in the placenta and ceases the inflammatory signaling in the fetal brain. Furthermore, the behavioral abnormalities and loss of cerebellar Purkinje cells seen in MIA offspring\nwere successfully prevented by knockout IL-6Ra in the placental trophoblast.\nConclusion: IL-6 activation in the placenta during maternal infection is indispensible for relaying the inflammatory signal from mother to fetal brain and impacting brain development and adult behaviors. Intervention of IL-6 activation in the placenta after infection could be a potential precaution for offspring developing autism and schizophrenia.", "issn": "0586-7614", "publisher": "Oxford University Press", "publication": "Schizophrenia Bulletin", "publication_date": "2015-03", "series_number": "S1", "volume": "41", "issue": "S1", "pages": "Art. No. S216" }, { "id": "authors:csgkw-4jm50", "collection": "authors", "collection_id": "csgkw-4jm50", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140421-091942025", "type": "article", "title": "Gastrointestinal Issues in Autism Spectrum Disorder", "author": [ { "family_name": "Hsiao", "given_name": "Elaine Y.", "orcid": "0000-0002-1633-588X", "clpid": "Hsiao-Elaine-Y-Bio" } ], "abstract": "While autism spectrum disorder (ASD) is characterized by communication impairments, social abnormalities, and stereotypic behaviors, several medical comorbidities are observed in autistic individuals. Of these, gastrointestinal (GI) abnormalities are of particular interest given their reported prevalence and correlation with the severity of core autism-related behavioral abnormalities. This review discusses the GI pathologies seen in ASD individuals and the association of particular GI conditions with known genetic and environmental risk factors for autism. It further addresses how GI abnormalities can affect the neuropathological and behavioral features of ASD, as well as the development of autism-related endophenotypes such as immune dysregulation, hyperserotonemia, and metabolic dysfunction. Finally, it presents emerging evidence for a gut-brain connection in autism, wherein GI dysfunction may contribute to the pathogenesis or severity of ASD symptoms.", "doi": "10.1097/HRP.0000000000000029", "issn": "1067-3229", "publisher": "Lippincott, Williams & Wilkins", "publication": "Harvard Review of Psychiatry", "publication_date": "2014-03", "series_number": "2", "volume": "22", "issue": "2", "pages": "104-111" }, { "id": "authors:2p6nf-pg047", "collection": "authors", "collection_id": "2p6nf-pg047", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20131205-105756544", "type": "article", "title": "Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders", "author": [ { "family_name": "Hsiao", "given_name": "Elaine Y.", "orcid": "0000-0002-1633-588X", "clpid": "Hsiao-Elaine-Y-Bio" }, { "family_name": "McBride", "given_name": "Sara W.", "clpid": "McBride-S-W" }, { "family_name": "Hsien", "given_name": "Sophia", "clpid": "Hsien-Sophia" }, { "family_name": "Sharon", "given_name": "Gil", "orcid": "0000-0002-4605-9943", "clpid": "Sharon-G" }, { "family_name": "Hyde", "given_name": "Embriette R.", "orcid": "0000-0002-9370-0051", "clpid": "Hyde-E-R" }, { "family_name": "McCue", "given_name": "Tyler", "clpid": "McCue-T" }, { "family_name": "Codelli", "given_name": "Julian A.", "clpid": "Codelli-J-A" }, { "family_name": "Chow", "given_name": "Janet", "clpid": "Chow-Janet" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Petrosino", "given_name": "Joseph F.", "orcid": "0000-0002-4046-6898", "clpid": "Petrosino-J-F" }, { "family_name": "Patterson", "given_name": "Paul H.", "clpid": "Patterson-P-H" }, { "family_name": "Mazmanian", "given_name": "Sarkis K.", "orcid": "0000-0003-2713-1513", "clpid": "Mazmanian-S-K" } ], "abstract": "Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.", "doi": "10.1016/j.cell.2013.11.024", "pmcid": "PMC3897394", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "2013-12-19", "series_number": "7", "volume": "155", "issue": "7", "pages": "1451-1463" }, { "id": "authors:j3f9k-04092", "collection": "authors", "collection_id": "j3f9k-04092", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130716-140239217", "type": "article", "title": "Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development", "author": [ { "family_name": "Garay", "given_name": "Paula A.", "clpid": "Garay-P-A" }, { "family_name": "Hsiao", "given_name": "Elaine Y.", "orcid": "0000-0002-1633-588X", "clpid": "Hsiao-Elaine-Y-Bio" }, { "family_name": "Patterson", "given_name": "Paul H.", "clpid": "Patterson-P-H" }, { "family_name": "McAllister", "given_name": "A. K.", "clpid": "McAllister-A-K" } ], "abstract": "Maternal infection is a risk factor for autism spectrum disorder (ASD) and schizophrenia (SZ). Indeed, modeling this risk factor in mice through maternal immune activation (MIA) causes ASD- and SZ-like neuropathologies and behaviors in the offspring. Although MIA upregulates pro-inflammatory cytokines in the fetal brain, whether MIA leads to long-lasting changes in brain cytokines during postnatal development remains unknown. Here, we tested this possibility by measuring protein levels of 23 cytokines in the blood and three brain regions from offspring of poly(I:C)- and saline-injected mice at five postnatal ages using multiplex arrays. Most cytokines examined are present in sera and brains throughout development. MIA induces changes in the levels of many cytokines in the brains and sera of offspring in a region- and age-specific manner. These MIA-induced changes follow a few, unexpected and distinct patterns. In frontal and cingulate cortices, several, mostly pro-inflammatory, cytokines are elevated at birth, followed by decreases during periods of synaptogenesis and plasticity, and increases again in the adult. Cytokines are also altered in postnatal hippocampus, but in a pattern distinct from the other regions. The MIA-induced changes in brain cytokines do not correlate with changes in serum cytokines from the same animals. Finally, these MIA-induced cytokine changes are not accompanied by breaches in the blood\u2013brain barrier, immune cell infiltration or increases in microglial density. Together, these data indicate that MIA leads to long-lasting, region-specific changes in brain cytokines in offspring\u2014similar to those reported for ASD and SZ\u2014that may alter CNS development and behavior.", "doi": "10.1016/j.bbi.2012.07.008", "pmcid": "PMC3529133", "issn": "1090-2139", "publisher": "Elsevier", "publication": "Brain, Behavior, and Immunity", "publication_date": "2013-07", "volume": "31", "pages": "54-68" }, { "id": "authors:mpe1b-y6206", "collection": "authors", "collection_id": "mpe1b-y6206", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130208-111652259", "type": "article", "title": "Neuroimmune changes in a mouse model of the maternal infection risk factor for schizophrenia and autism", "author": [ { "family_name": "Hsiao", "given_name": "Elaine Y.", "orcid": "0000-0002-1633-588X", "clpid": "Hsiao-Elaine-Y-Bio" }, { "family_name": "McBride", "given_name": "Sara W.", "clpid": "McBride-S-W" }, { "family_name": "Chow", "given_name": "Janet", "clpid": "Chow-Janet" }, { "family_name": "Garbett", "given_name": "Krassimira A.", "clpid": "Garbett-K-A" }, { "family_name": "K\u00e1lm\u00e1n", "given_name": "S\u00e1ra", "clpid": "K\u00e1lm\u00e1n-S" }, { "family_name": "Mirnics", "given_name": "K\u00e1roly", "clpid": "Mirnics-K" }, { "family_name": "Mazmanian", "given_name": "Sarkis K.", "orcid": "0000-0003-2713-1513", "clpid": "Mazmanian-S-K" }, { "family_name": "Patterson", "given_name": "Paul H.", "clpid": "Patterson-P-H" } ], "abstract": "Objective: Infection in pregnant women is associated with increased risk\nfor autism and schizophrenia in the offspring. In a mouse model of this\nrisk factor, activation of the maternal immune system by injection of\nthe viral mimic poly(I:C) sets in motion a cascade of molecular events\nthat ultimately results in autism- and schizophrenia-related behaviors\nin offspring. The finding that interleukin-6 (IL-6) is a crucial mediator\nof these effects led us to examine themechanism by which this cytokine\ninfluences fetal development in vivo. Here we examine the placenta and\nfetal brain as sites of early IL-6 action. We further assess whether MIA\noffspring display altered postnatal immune profiles and function as a potential\nlater-life consequence of maternal immune activation (MIA).", "doi": "10.1016/j.jneuroim.2012.10.001", "issn": "0165-5728", "publisher": "Elsevier", "publication": "Journal of Neuroimmunology", "publication_date": "2012-12-15", "series_number": "1-2", "volume": "253", "issue": "1-2", "pages": "48" }, { "id": "authors:76vn0-yj497", "collection": "authors", "collection_id": "76vn0-yj497", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130208-111108964", "type": "article", "title": "Gastrointestinal symptoms and probiotic treatment in a mouse model of an autism risk factor", "author": [ { "family_name": "Hsiao", "given_name": "Elaine Y.", "orcid": "0000-0002-1633-588X", "clpid": "Hsiao-Elaine-Y-Bio" }, { "family_name": "McBride", "given_name": "Sara W.", "clpid": "McBride-S-W" }, { "family_name": "Hsien", "given_name": "Sophia", "clpid": "Hsien-Sophia" }, { "family_name": "Chow", "given_name": "Janet", "clpid": "Chow-Janet" }, { "family_name": "Mazmanian", "given_name": "Sarkis K.", "orcid": "0000-0003-2713-1513", "clpid": "Mazmanian-S-K" }, { "family_name": "Patterson", "given_name": "Paul H.", "clpid": "Patterson-P-H" } ], "abstract": "Objective: While autism is a neurodevelopmental disorder characterized\nby language and social deficits, recent studies have highlighted\nstriking dysregulation in the neural, peripheral, and enteric immune\nsystems of autistic individuals. There are also reports that subsets of\nchildren with autism spectrum disorder (ASD) display gastrointestinal\n(GI) abnormalities, including chronic inflammation of the colon,\nincreased intestinal permeability and altered composition of GI\nmicrobiota. Moreover, antibiotic treatment and restricted diet are\nreported to provide behavioral improvements for some ASD children.\nWe use a mouse model of an ASD risk factor, maternal immune activation\n(MIA), to assess whether offspring, which display core behavioral\nand neuropathological features of autism, also display ASD-associated\nGI symptoms. To explore the potential connections between GI problems\nand the brain and behavior,we test whether postnatal administration\nof a probiotic influences GI and ASD-related behaviors.", "doi": "10.1016/j.jneuroim.2012.10.001", "issn": "0165-5728", "publisher": "Elsevier", "publication": "Journal of Neuroimmunology", "publication_date": "2012-12-15", "series_number": "1-2", "volume": "253", "issue": "1-2", "pages": "47-48" }, { "id": "authors:kgprs-q5253", "collection": "authors", "collection_id": "kgprs-q5253", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130221-100432479", "type": "article", "title": "Maternal immune activation induces IL-6-dependent alterations in cytokine and gene expression profiles in the offspring", "author": [ { "family_name": "Hsiao", "given_name": "E. Y.", "orcid": "0000-0002-1633-588X", "clpid": "Hsiao-Elaine-Y-Bio" }, { "family_name": "Patterson", "given_name": "P. H.", "clpid": "Patterson-P-H" } ], "abstract": "Infection in pregnant women is associated with increased risk\nfor autism and schizophrenia in the offspring. In a mouse model\nof this risk factor, activation of the maternal immune system sets\nin motion a cascade of molecular events that ultimately result in\nautism- and schizophrenia-related behaviors in offspring. The finding\nthat interleukin-6 (IL-6) is a crucial mediator of these effects\nled us to examine the mechanism by which this cytokine influences\nfetal development in vivo. We find that maternal immune\nactivation (MIA) with a viral mimic, synthetic double-stranded\nRNA (poly(I:C)), increases IL-6 mRNA as well as maternally derived\nIL-6 protein in the placenta.", "doi": "10.1016/j.ijdevneu.2012.03.304", "issn": "0736-5748", "publisher": "Elsevier", "publication": "International Journal of Developmental Neuroscience", "publication_date": "2012-12", "series_number": "8", "volume": "30", "issue": "8", "pages": "662-663" }, { "id": "authors:1n2nh-a5y03", "collection": "authors", "collection_id": "1n2nh-a5y03", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20121008-084130309", "type": "article", "title": "Placental regulation of maternal-fetal interactions and brain development", "author": [ { "family_name": "Hsiao", "given_name": "Elaine Y.", "orcid": "0000-0002-1633-588X", "clpid": "Hsiao-Elaine-Y-Bio" }, { "family_name": "Patterson", "given_name": "Paul H.", "clpid": "Patterson-P-H" } ], "abstract": "A variety prenatal insults are associated with the incidence of neurodevelopmental disorders such as schizophrenia, autism and cerebral palsy. While the precise mechanisms underlying how transient gestational challenges can lead to later life dysfunctions are largely unknown, the placenta is likely to play a key role. The literal interface between maternal and fetal cells resides in the placenta, and disruptions to the maternal or intrauterine environment are necessarily conveyed to the developing embryo via the placenta. Placental cells bear the responsibility of promoting maternal tolerance of the semiallogeneic fetus and regulating selective permeability of nutrients, gases, and antibodies, while still providing physiological protection of the embryo from adversity. The placenta's critical role in modulating immune protection and the availability of nutrients and endocrine factors to the offspring implicates its involvement in autoimmunity, growth restriction and hypoxia, all factors associated with the development of neurological complications. In this review, we summarize primary maternal-fetal interactions that occur in the placenta and describe pathways by which maternal insults can impair these processes and disrupt fetal brain development. We also review emerging evidence for placental dysfunction in the prenatal programming of neurodevelopmental disorders.", "doi": "10.1002/dneu.22045", "issn": "1932-8451", "publisher": "Wiley", "publication": "Developmental Neurobiology", "publication_date": "2012-10", "series_number": "10", "volume": "72", "issue": "10", "pages": "1317-1326" }, { "id": "authors:pw7mc-qvq46", "collection": "authors", "collection_id": "pw7mc-qvq46", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120924-131641114", "type": "article", "title": "Modeling an autism risk factor in mice leads to permanent immune dysregulation", "author": [ { "family_name": "Hsiao", "given_name": "Elaine Y.", "orcid": "0000-0002-1633-588X", "clpid": "Hsiao-Elaine-Y-Bio" }, { "family_name": "McBride", "given_name": "Sara W.", "clpid": "McBride-S-W" }, { "family_name": "Chow", "given_name": "Janet", "clpid": "Chow-Janet" }, { "family_name": "Mazmanian", "given_name": "Sarkis K.", "orcid": "0000-0003-2713-1513", "clpid": "Mazmanian-S-K" }, { "family_name": "Patterson", "given_name": "Paul H.", "clpid": "Patterson-P-H" } ], "abstract": "Increasing evidence highlights a role for the immune system in the pathogenesis of autism spectrum disorder (ASD), as immune dysregulation is observed in the brain, periphery, and gastrointestinal tract of ASD individuals. Furthermore, maternal infection (maternal immune activation, MIA) is a risk factor for ASD. Modeling this risk factor in mice yields offspring with the cardinal behavioral and neuropathological symptoms of human ASD. In this study, we find that offspring of immune-activated mothers display altered immune profiles and function, characterized by a systemic deficit in CD4^+ TCR\u03b2^+ Foxp3^+ CD25^+ T regulatory cells, increased IL-6 and IL-17 production by CD4^+ T cells, and elevated levels of peripheral Gr-1^+ cells. In addition, hematopoietic stem cells from MIA offspring exhibit altered myeloid lineage potential and differentiation. Interestingly, repopulating irradiated control mice with bone marrow derived from MIA offspring does not confer MIA-related immunological deficits, implicating the peripheral environmental context in long-term programming of immune dysfunction. Furthermore, behaviorally abnormal MIA offspring that have been irradiated and transplanted with immunologically normal bone marrow from either MIA or control offspring no longer exhibit deficits in stereotyped/repetitive and anxiety-like behaviors, suggesting that immune abnormalities in MIA offspring can contribute to ASD-related behaviors. These studies support a link between cellular immune dysregulation and ASD-related behavioral deficits in a mouse model of an autism risk factor.", "doi": "10.1073/pnas.1202556109", "pmcid": "PMC3411999", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2012-07-31", "series_number": "31", "volume": "109", "issue": "31", "pages": "12776-12781" }, { "id": "authors:hm1mp-yyw31", "collection": "authors", "collection_id": "hm1mp-yyw31", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120522-110955497", "type": "article", "title": "Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism", "author": [ { "family_name": "Malkova", "given_name": "Natalia V.", "clpid": "Malkova-N-V" }, { "family_name": "Yu", "given_name": "Collin Z.", "clpid": "Yu-Collin-Z" }, { "family_name": "Hsiao", "given_name": "Elaine Y.", "orcid": "0000-0002-1633-588X", "clpid": "Hsiao-Elaine-Y-Bio" }, { "family_name": "Moore", "given_name": "Marlyn J.", "clpid": "Moore-M-J" }, { "family_name": "Patterson", "given_name": "Paul H.", "clpid": "Patterson-P-H" } ], "abstract": "The core symptoms of autism are deficits in social interaction and language, and the presence of repetitive/stereotyped behaviors. We demonstrate that behaviors related to these symptoms are present in a mouse model of an environmental risk factor for autism, maternal infection. We stimulate the maternal immune system by injecting the viral mimic poly(I:C) during pregnancy, and analyze the social and communicative behaviors of the offspring. In one test, young pups respond to a brief separation from the mother with ultrasonic vocalizations (USVs). We find that, compared to pups born to saline-injected mothers, pups born to maternal immune activation (MIA) mothers produce a lower rate of USVs in the isolation test starting at day 8. The quality of the vocalizations is also different; analysis of sound spectrograms of 10 day-old pups shows that male pups from MIA mothers emit significantly fewer harmonic and more complex and short syllables. These communication differences are also apparent in adult offspring. Compared to controls, adult MIA males emit significantly fewer USVs in response to social encounters with females or males, and display reduced scent marking in response to female urine. Regarding a second autism symptom, MIA males display decreased sociability. In a third test of characteristic autism behaviors, MIA offspring exhibit increased repetitive/stereotyped behavior in both marble burying and self-grooming tests. In sum, these results indicate that MIA yields male offspring with deficient social and communicative behavior, as well as high levels of repetitive behaviors, all of which are hallmarks of autism.", "doi": "10.1016/j.bbi.2012.01.011", "pmcid": "PMC3322300", "issn": "0889-1591", "publisher": "Elsevier", "publication": "Brain, Behavior and Immunity", "publication_date": "2012-05", "series_number": "4", "volume": "26", "issue": "4", "pages": "607-616" }, { "id": "authors:vntzd-abp57", "collection": "authors", "collection_id": "vntzd-abp57", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120803-134745067", "type": "article", "title": "Effects of maternal immune activation on gene expression patterns in the fetal brain", "author": [ { "family_name": "Garbett", "given_name": "K. A.", "clpid": "Garbett-K-A" }, { "family_name": "Hsiao", "given_name": "E. Y.", "orcid": "0000-0002-1633-588X", "clpid": "Hsiao-Elaine-Y-Bio" }, { "family_name": "K\u00e1lm\u00e1n", "given_name": "S.", "clpid": "K\u00e1lm\u00e1n-S" }, { "family_name": "Patterson", "given_name": "P. H.", "clpid": "Patterson-P-H" }, { "family_name": "Mirnics", "given_name": "K.", "clpid": "Mirnics-K" } ], "abstract": "We are exploring the mechanisms underlying how maternal infection increases the risk for schizophrenia and autism in the offspring. Several mouse models of maternal immune activation (MIA) were used to examine the immediate effects of MIA induced by influenza virus, poly(I:C) and interleukin IL-6 on the fetal brain transcriptome. Our results indicate that all three MIA treatments lead to strong and common gene expression changes in the embryonic brain. Most notably, there is an acute and transient upregulation of the \u03b1, \u03b2 and \u03b3 crystallin gene family. Furthermore, levels of crystallin gene expression are correlated with the severity of MIA as assessed by placental weight. The overall gene expression changes suggest that the response to MIA is a neuroprotective attempt by the developing brain to counteract environmental stress, but at a cost of disrupting typical neuronal differentiation and axonal growth. We propose that this cascade of events might parallel the mechanisms by which environmental insults contribute to the risk of neurodevelopmental disorders such as schizophrenia and autism.", "doi": "10.1038/tp.2012.24", "pmcid": "PMC3337077", "issn": "2158-3188", "publisher": "Nature Publishing Group", "publication": "Translational Psychiatry", "publication_date": "2012-04", "volume": "2", "pages": "Art. No. e98" }, { "id": "authors:h7y3f-tg295", "collection": "authors", "collection_id": "h7y3f-tg295", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20110531-100559236", "type": "article", "title": "Activation of the maternal immune system induces endocrine changes in the placenta via IL-6", "author": [ { "family_name": "Hsiao", "given_name": "Elaine Y.", "orcid": "0000-0002-1633-588X", "clpid": "Hsiao-Elaine-Y-Bio" }, { "family_name": "Patterson", "given_name": "Paul H.", "clpid": "Patterson-P-H" } ], "abstract": "Activation of the maternal immune system in rodent models sets in motion a cascade of molecular pathways that ultimately result in autism- and schizophrenia-related behaviors in offspring. The finding that interleukin-6 (IL-6) is a crucial mediator of these effects led us to examine the mechanism by which this cytokine influences fetal development in vivo. Here we focus on the placenta as the site of direct interaction between mother and fetus and as a principal modulator of fetal development. We find that maternal immune activation (MIA) with a viral mimic, synthetic double-stranded RNA (poly(I:C)), increases IL-6 mRNA as well as maternally-derived IL-6 protein in the placenta. Placentas from MIA mothers exhibit increases in CD69+ decidual macrophages, granulocytes and uterine NK cells, indicating elevated early immune activation. Maternally-derived IL-6 mediates activation of the JAK/STAT3 pathway specifically in the spongiotrophoblast layer of the placenta, which results in expression of acute phase genes. Importantly, this parallels an IL-6-dependent disruption of the growth hormone-insulin-like growth factor (GH-IGF) axis that is characterized by decreased GH, IGFI and IGFBP3 levels. In addition, we observe an IL-6-dependent induction in pro-lactin-like protein-K (PLP-K) expression as well as MIA-related alterations in other placental endocrine factors. Together, these IL-6-mediated effects of MIA on the placenta represent an indirect mechanism by which MIA can alter fetal development.", "doi": "10.1016/j.bbi.2010.12.017", "pmcid": "PMC3081363", "issn": "0889-1591", "publisher": "Elsevier", "publication": "Brain, Behavior, and Immunity", "publication_date": "2011-05", "series_number": "4", "volume": "25", "issue": "4", "pages": "604-615" }, { "id": "authors:55aeb-n1k10", "collection": "authors", "collection_id": "55aeb-n1k10", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20100412-103857089", "type": "article", "title": "Maternal immune activation alters nonspatial information processing in the hippocampus of the adult offspring", "author": [ { "family_name": "Ito", "given_name": "Hiroshi T.", "clpid": "Ito-Hiroshi-T" }, { "family_name": "Smith", "given_name": "Stephen E. P.", "clpid": "Smith-S-E-P" }, { "family_name": "Hsiao", "given_name": "Elaine", "orcid": "0000-0002-1633-588X", "clpid": "Hsiao-Elaine-Y-Bio" }, { "family_name": "Patterson", "given_name": "Paul H.", "clpid": "Patterson-P-H" } ], "abstract": "The observation that maternal infection increases the risk for schizophrenia in the offspring suggests that the maternal immune system plays a key role in the etiology of schizophrenia. In a mouse model, maternal immune activation (MIA) by injection of poly(I:C) yields adult offspring that display abnormalities in a variety of behaviors relevant to schizophrenia. As abnormalities in the hippocampus are a consistent observation in schizophrenia patients, we examined synaptic properties in hippocampal slices prepared from the offspring of poly(I:C)- and saline-treated mothers. Compared to controls, CA1 pyramidal neurons from adult offspring of MIA mothers display reduced frequency and increased amplitude of miniature excitatory postsynaptic currents. In addition, the specific component of the temporoammonic pathway that mediates object-related information displays increased sensitivity to dopamine. To assess hippocampal network function in vivo, we used expression of the immediate-early gene, c-Fos, as a surrogate measure of neuronal activity. Compared to controls, the offspring of poly(I:C)-treated mothers display a distinct c-Fos expression pattern in area CA1 following novel object, but not novel location, exposure. Thus, the offspring of MIA mothers may have an abnormality in modality-specific information processing. Indeed, the MIA offspring display enhanced discrimination in a novel object recognition, but not in an object location, task. Thus, analysis of object and spatial information processing at both synaptic and behavioral levels reveals a largely selective abnormality in object information processing in this mouse model. Our results suggest that altered processing of object-related information may be part of the pathogenesis of schizophrenia-like cognitive behaviors.", "doi": "10.1016/j.bbi.2010.03.004", "pmcid": "PMC2897971", "issn": "1090-2139", "publisher": "Elsevier", "publication": "Brain, Behavior, and Immunity", "publication_date": "2010-08", "series_number": "6", "volume": "24", "issue": "6", "pages": "930-941" } ]