Extracellular free water elevations are associated with brain volume and maternal cytokine response in a longitudinal nonhuman primate maternal immune activation model
Maternal infection has emerged as an important environmental risk factor for neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Animal model systems of maternal immune activation (MIA) suggest that the maternal immune response plays a significant role in the offspri...
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| Veröffentlicht in: | Molecular psychiatry 2023-10, Vol.28 (10), p.4185-4194 |
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| creator | Lesh, Tyler A. Iosif, Ana-Maria Tanase, Costin Vlasova, Roza M. Ryan, Amy M. Bennett, Jeffrey Hogrefe, Casey E. Maddock, Richard J. Geschwind, Daniel H. Van de Water, Judy McAllister, A. Kimberley Styner, Martin A. Bauman, Melissa D. Carter, Cameron S. |
| description | Maternal infection has emerged as an important environmental risk factor for neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Animal model systems of maternal immune activation (MIA) suggest that the maternal immune response plays a significant role in the offspring’s neurodevelopment and behavioral outcomes. Extracellular free water is a measure of freely diffusing water in the brain that may be associated with neuroinflammation and impacted by MIA. The present study evaluates the brain diffusion characteristics of male rhesus monkeys (
Macaca mulatta
) born to MIA-exposed dams (
n
= 14) treated with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the end of the first trimester (
n
= 10) or were untreated (
n
= 4). Offspring underwent diffusion MRI scans at 6, 12, 24, 36, and 45 months. Offspring born to MIA-exposed dams showed significantly increased extracellular free water in cingulate cortex gray matter starting as early as 6 months of age and persisting through 45 months. In addition, offspring gray matter free water in this region was significantly correlated with the magnitude of the maternal IL-6 response in the MIA-exposed dams. Significant correlations between brain volume and extracellular free water in the MIA-exposed offspring also indicate converging, multimodal evidence of the impact of MIA on brain development. These findings provide strong evidence for the construct validity of the nonhuman primate MIA model as a system of relevance for investigating the pathophysiology of human neurodevelopmental psychiatric disorders. Elevated free water in individuals exposed to immune activation in utero could represent an early marker of a perturbed or vulnerable neurodevelopmental trajectory. |
| doi_str_mv | 10.1038/s41380-023-02213-w |
| format | Article |
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Macaca mulatta
) born to MIA-exposed dams (
n
= 14) treated with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the end of the first trimester (
n
= 10) or were untreated (
n
= 4). Offspring underwent diffusion MRI scans at 6, 12, 24, 36, and 45 months. Offspring born to MIA-exposed dams showed significantly increased extracellular free water in cingulate cortex gray matter starting as early as 6 months of age and persisting through 45 months. In addition, offspring gray matter free water in this region was significantly correlated with the magnitude of the maternal IL-6 response in the MIA-exposed dams. Significant correlations between brain volume and extracellular free water in the MIA-exposed offspring also indicate converging, multimodal evidence of the impact of MIA on brain development. These findings provide strong evidence for the construct validity of the nonhuman primate MIA model as a system of relevance for investigating the pathophysiology of human neurodevelopmental psychiatric disorders. Elevated free water in individuals exposed to immune activation in utero could represent an early marker of a perturbed or vulnerable neurodevelopmental trajectory.</description><identifier>ISSN: 1359-4184</identifier><identifier>EISSN: 1476-5578</identifier><identifier>DOI: 10.1038/s41380-023-02213-w</identifier><identifier>PMID: 37582858</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/21 ; 59/57 ; 631/378 ; 692/699/476/1799 ; Animal models ; Animals ; Autism ; Behavior ; Behavior, Animal - physiology ; Behavioral Sciences ; Biological Psychology ; Brain ; Brain research ; Cortex (cingulate) ; Cytokines ; Disease Models, Animal ; Dopamine ; Female ; Humans ; Immune response ; Inflammation ; Male ; Medicine ; Medicine & Public Health ; Mental disorders ; Monkeys & apes ; Neurodevelopment ; Neurodevelopmental disorders ; Neurosciences ; Offspring ; Pharmacotherapy ; Prenatal Exposure Delayed Effects ; Primates ; Psychiatry ; Psychosis ; Risk factors ; Schizophrenia ; Substantia grisea</subject><ispartof>Molecular psychiatry, 2023-10, Vol.28 (10), p.4185-4194</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2023. The Author(s), under exclusive licence to Springer Nature Limited.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c431t-fdaaa5091b3cac2c613c0c01d5c81b2c7aa577b4543642c73f9ad4f6672daee63</citedby><cites>FETCH-LOGICAL-c431t-fdaaa5091b3cac2c613c0c01d5c81b2c7aa577b4543642c73f9ad4f6672daee63</cites><orcidid>0000-0001-6392-5519 ; 0000-0001-9177-9889 ; 0000-0003-1193-5875 ; 0000-0002-3255-5663 ; 0000-0001-7283-2015 ; 0000-0002-6160-3927 ; 0000-0003-2896-3450 ; 0000-0003-0701-3851</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37582858$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lesh, Tyler A.</creatorcontrib><creatorcontrib>Iosif, Ana-Maria</creatorcontrib><creatorcontrib>Tanase, Costin</creatorcontrib><creatorcontrib>Vlasova, Roza M.</creatorcontrib><creatorcontrib>Ryan, Amy M.</creatorcontrib><creatorcontrib>Bennett, Jeffrey</creatorcontrib><creatorcontrib>Hogrefe, Casey E.</creatorcontrib><creatorcontrib>Maddock, Richard J.</creatorcontrib><creatorcontrib>Geschwind, Daniel H.</creatorcontrib><creatorcontrib>Van de Water, Judy</creatorcontrib><creatorcontrib>McAllister, A. Kimberley</creatorcontrib><creatorcontrib>Styner, Martin A.</creatorcontrib><creatorcontrib>Bauman, Melissa D.</creatorcontrib><creatorcontrib>Carter, Cameron S.</creatorcontrib><title>Extracellular free water elevations are associated with brain volume and maternal cytokine response in a longitudinal nonhuman primate maternal immune activation model</title><title>Molecular psychiatry</title><addtitle>Mol Psychiatry</addtitle><addtitle>Mol Psychiatry</addtitle><description>Maternal infection has emerged as an important environmental risk factor for neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Animal model systems of maternal immune activation (MIA) suggest that the maternal immune response plays a significant role in the offspring’s neurodevelopment and behavioral outcomes. Extracellular free water is a measure of freely diffusing water in the brain that may be associated with neuroinflammation and impacted by MIA. The present study evaluates the brain diffusion characteristics of male rhesus monkeys (
Macaca mulatta
) born to MIA-exposed dams (
n
= 14) treated with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the end of the first trimester (
n
= 10) or were untreated (
n
= 4). Offspring underwent diffusion MRI scans at 6, 12, 24, 36, and 45 months. Offspring born to MIA-exposed dams showed significantly increased extracellular free water in cingulate cortex gray matter starting as early as 6 months of age and persisting through 45 months. In addition, offspring gray matter free water in this region was significantly correlated with the magnitude of the maternal IL-6 response in the MIA-exposed dams. Significant correlations between brain volume and extracellular free water in the MIA-exposed offspring also indicate converging, multimodal evidence of the impact of MIA on brain development. These findings provide strong evidence for the construct validity of the nonhuman primate MIA model as a system of relevance for investigating the pathophysiology of human neurodevelopmental psychiatric disorders. Elevated free water in individuals exposed to immune activation in utero could represent an early marker of a perturbed or vulnerable neurodevelopmental trajectory.</description><subject>13/21</subject><subject>59/57</subject><subject>631/378</subject><subject>692/699/476/1799</subject><subject>Animal models</subject><subject>Animals</subject><subject>Autism</subject><subject>Behavior</subject><subject>Behavior, Animal - physiology</subject><subject>Behavioral Sciences</subject><subject>Biological Psychology</subject><subject>Brain</subject><subject>Brain research</subject><subject>Cortex (cingulate)</subject><subject>Cytokines</subject><subject>Disease Models, Animal</subject><subject>Dopamine</subject><subject>Female</subject><subject>Humans</subject><subject>Immune response</subject><subject>Inflammation</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mental disorders</subject><subject>Monkeys & apes</subject><subject>Neurodevelopment</subject><subject>Neurodevelopmental disorders</subject><subject>Neurosciences</subject><subject>Offspring</subject><subject>Pharmacotherapy</subject><subject>Prenatal Exposure Delayed Effects</subject><subject>Primates</subject><subject>Psychiatry</subject><subject>Psychosis</subject><subject>Risk factors</subject><subject>Schizophrenia</subject><subject>Substantia grisea</subject><issn>1359-4184</issn><issn>1476-5578</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9ks1u1DAUhSMEoqXwAiyQJTZsAnYcJ84Koar8SJXYwNq649zMuDj2YCcz9Il4TW6a0gILFpZtne8c29e3KJ4L_lpwqd_kWkjNS15JGpWQ5fFBcSrqtimVavVDWkvVlbXQ9UnxJOcrzhdRPS5OZKt0pZU-LX5e_JgSWPR-9pDYkBDZESZMDD0eYHIxZAYJGeQcrSOlZ0c37dgmgQvsEP08khh6Ni6uAJ7Z6yl-cwFZwrwnOzICgfkYtm6ae7cwIYbdPEJg--QW473bjeNMXrCTW49nY-zRPy0eDeAzPrudz4qv7y--nH8sLz9_-HT-7rK0tRRTOfQAoHgnNtKCrWwjpOWWi15ZLTaVbUlt202tatnUtJVDB309NE1b9YDYyLPi7Zq7nzcj9hYDlcebm2umaxPBmb-V4HZmGw9GcE0huqaEV7cJKX6fMU9mdHkpMASMczZUd6Eb3ShN6Mt_0Ks4L1UgqhNd13LRKaKqlbIp5pxwuLuN4GZpBLM2gqFGMDeNYI5kevHnO-4sv3-eALkCmaSwxXR_9n9ifwHjzcVm</recordid><startdate>20231001</startdate><enddate>20231001</enddate><creator>Lesh, Tyler A.</creator><creator>Iosif, Ana-Maria</creator><creator>Tanase, Costin</creator><creator>Vlasova, Roza M.</creator><creator>Ryan, Amy M.</creator><creator>Bennett, Jeffrey</creator><creator>Hogrefe, Casey E.</creator><creator>Maddock, Richard J.</creator><creator>Geschwind, Daniel H.</creator><creator>Van de Water, Judy</creator><creator>McAllister, A. 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Kimberley</au><au>Styner, Martin A.</au><au>Bauman, Melissa D.</au><au>Carter, Cameron S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Extracellular free water elevations are associated with brain volume and maternal cytokine response in a longitudinal nonhuman primate maternal immune activation model</atitle><jtitle>Molecular psychiatry</jtitle><stitle>Mol Psychiatry</stitle><addtitle>Mol Psychiatry</addtitle><date>2023-10-01</date><risdate>2023</risdate><volume>28</volume><issue>10</issue><spage>4185</spage><epage>4194</epage><pages>4185-4194</pages><issn>1359-4184</issn><eissn>1476-5578</eissn><abstract>Maternal infection has emerged as an important environmental risk factor for neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Animal model systems of maternal immune activation (MIA) suggest that the maternal immune response plays a significant role in the offspring’s neurodevelopment and behavioral outcomes. Extracellular free water is a measure of freely diffusing water in the brain that may be associated with neuroinflammation and impacted by MIA. The present study evaluates the brain diffusion characteristics of male rhesus monkeys (
Macaca mulatta
) born to MIA-exposed dams (
n
= 14) treated with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the end of the first trimester (
n
= 10) or were untreated (
n
= 4). Offspring underwent diffusion MRI scans at 6, 12, 24, 36, and 45 months. Offspring born to MIA-exposed dams showed significantly increased extracellular free water in cingulate cortex gray matter starting as early as 6 months of age and persisting through 45 months. In addition, offspring gray matter free water in this region was significantly correlated with the magnitude of the maternal IL-6 response in the MIA-exposed dams. Significant correlations between brain volume and extracellular free water in the MIA-exposed offspring also indicate converging, multimodal evidence of the impact of MIA on brain development. These findings provide strong evidence for the construct validity of the nonhuman primate MIA model as a system of relevance for investigating the pathophysiology of human neurodevelopmental psychiatric disorders. Elevated free water in individuals exposed to immune activation in utero could represent an early marker of a perturbed or vulnerable neurodevelopmental trajectory.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>37582858</pmid><doi>10.1038/s41380-023-02213-w</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-6392-5519</orcidid><orcidid>https://orcid.org/0000-0001-9177-9889</orcidid><orcidid>https://orcid.org/0000-0003-1193-5875</orcidid><orcidid>https://orcid.org/0000-0002-3255-5663</orcidid><orcidid>https://orcid.org/0000-0001-7283-2015</orcidid><orcidid>https://orcid.org/0000-0002-6160-3927</orcidid><orcidid>https://orcid.org/0000-0003-2896-3450</orcidid><orcidid>https://orcid.org/0000-0003-0701-3851</orcidid></addata></record> |
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| ispartof | Molecular psychiatry, 2023-10, Vol.28 (10), p.4185-4194 |
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| source | MEDLINE; Alma/SFX Local Collection |
| subjects | 13/21 59/57 631/378 692/699/476/1799 Animal models Animals Autism Behavior Behavior, Animal - physiology Behavioral Sciences Biological Psychology Brain Brain research Cortex (cingulate) Cytokines Disease Models, Animal Dopamine Female Humans Immune response Inflammation Male Medicine Medicine & Public Health Mental disorders Monkeys & apes Neurodevelopment Neurodevelopmental disorders Neurosciences Offspring Pharmacotherapy Prenatal Exposure Delayed Effects Primates Psychiatry Psychosis Risk factors Schizophrenia Substantia grisea |
| title | Extracellular free water elevations are associated with brain volume and maternal cytokine response in a longitudinal nonhuman primate maternal immune activation model |
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