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Primate Models as a Translational Tool for Understanding Prenatal Origins of Neurodevelopmental Disorders Associated With Maternal Infection

Published:March 08, 2022DOI:https://doi.org/10.1016/j.bpsc.2022.02.012

      Abstract

      Pregnant women represent a uniquely vulnerable population during an infectious disease outbreak, such as the COVID-19 pandemic. Although we are at the early stages of understanding the specific impact of SARS-CoV-2 exposure during pregnancy, mounting epidemiological evidence strongly supports a link between exposure to a variety of maternal infections and an increased risk for offspring neurodevelopmental disorders. Inflammatory biomarkers identified from archived or prospectively collected maternal biospecimens suggest that the maternal immune response is the critical link between infection during pregnancy and altered offspring neurodevelopment. This maternal immune activation (MIA) hypothesis has been tested in animal models by artificially activating the immune system during pregnancy and evaluating the neurodevelopmental consequences in MIA-exposed offspring. Although the vast majority of MIA model research is carried out in rodents, the nonhuman primate model has emerged in recent years as an important translational tool. In this review, we briefly summarize human epidemiological studies that have prompted the development of translationally relevant MIA models. We then highlight notable similarities between humans and nonhuman primates, including placental structure, pregnancy physiology, gestational timelines, and offspring neurodevelopmental stages, that provide an opportunity to explore the MIA hypothesis in species more closely related to humans. Finally, we provide a comprehensive review of neurodevelopmental alterations reported in current nonhuman primate models of maternal infection and discuss future directions for this promising area of research.

      Keywords

      Maternal Infection and Offspring Neurodevelopment

      As this review has been written in the midst of the ongoing COVID-19 pandemic, it is sobering to note that exposure to maternal infection during pregnancy is associated with increased risk of offspring neurodevelopmental disorders (NDDs) (
      • Knuesel I.
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      • Britschgi M.
      • Schobel S.A.
      • Bodmer M.
      • Hellings J.A.
      • et al.
      Maternal immune activation and abnormal brain development across CNS disorders.
      ). Decades of converging evidence from epidemiological and preclinical research suggest that the maternal immune response is the critical link between exposure to a variety of viral and bacterial infections during pregnancy and alterations in fetal brain development (
      • Meyer U.
      Neurodevelopmental resilience and susceptibility to maternal immune activation.
      ). Although most women report experiencing at least one infection during pregnancy (
      • Collier S.A.
      • Rasmussen S.A.
      • Feldkamp M.L.
      • Honein M.A.
      National Birth Defects Prevention Study
      Prevalence of self-reported infection during pregnancy among control mothers in the National Birth Defects Prevention Study.
      ), it is also important to note that the vast majority of exposed offspring will not experience significant neurodevelopmental changes. However, for a subset of women, maternal infection and the subsequent immune response may serve as a disease primer into an altered trajectory of fetal brain development that, in combination with other genetic and environmental factors, increases the likelihood of offspring NDDs (
      • Meyer U.
      Prenatal poly(I:C) exposure and other developmental immune activation models in rodent systems.
      ).
      Not only is the immune system critical in mediating successful pregnancy (
      • Yang F.
      • Zheng Q.
      • Jin L.
      Dynamic function and composition changes of immune cells during normal and pathological pregnancy at the maternal-fetal interface.
      ), but immune signaling molecules, such as cytokines, also play a critical role in fetal brain development (
      • Deverman B.E.
      • Patterson P.H.
      Cytokines and CNS development.
      ). Thus, the complex cascade of changes associated with maternal infection and the subsequent maternal immune response (
      • Yockey L.J.
      • Iwasaki A.
      Interferons and proinflammatory cytokines in pregnancy and fetal development.
      ) is uniquely positioned to influence the developing fetal brain. Even in the absence of an acute inflammatory event triggered by infection, variations in maternal cytokine levels during pregnancy have been associated with offspring neurobehavioral outcomes, including early alterations in brain growth, functional connectivity, behavioral development (
      • Spann M.N.
      • Monk C.
      • Scheinost D.
      • Peterson B.S.
      Maternal immune activation during the third trimester is associated with neonatal functional connectivity of the salience network and fetal to toddler behavior.
      ,
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      • Feczko E.
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      • et al.
      Maternal IL-6 during pregnancy can be estimated from newborn brain connectivity and predicts future working memory in offspring.
      ,
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      • Fair D.A.
      • et al.
      Maternal interleukin-6 concentration during pregnancy is associated with variation in frontolimbic white matter and cognitive development in early life.
      ,
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      • Gilmore J.H.
      • Styner M.
      • et al.
      Maternal systemic interleukin-6 during pregnancy is associated with newborn amygdala phenotypes and subsequent behavior at 2 years of age.
      ,
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      • Roder S.
      • Borte M.
      • von Bergen M.
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      Elevated gestational IL-13 during fetal development is associated with hyperactivity and inattention in eight-year-old children.
      ), and long-lasting dysregulation of stress response circuitry (
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      • Whitfield-Gabrieli S.
      • Gilman S.E.
      • et al.
      Impact of prenatal maternal cytokine exposure on sex differences in brain circuitry regulating stress in offspring 45 years later.
      ). Collectively, these studies suggest that changes in the maternal-fetal immune environment during pregnancy can have long-lasting consequences, ranging from subtle differences in offspring brain and behavioral development to severe NDDs.
      There is a critical need to understand factors that determine risk and resilience to changes in the maternal-placental-fetal immune environment and to develop evidence-based guidelines to manage infection during pregnancy (
      • Bauman M.D.
      • Van de Water J.
      Translational opportunities in the prenatal immune environment: Promises and limitations of the maternal immune activation model.
      ). While previous gestational therapeutic strategies have focused on preventing vertical transmission of congenital disease–associated TORCH pathogens (Toxoplasma gondii, other, rubella virus, cytomegalovirus, and herpes simplex virus) (
      • Coyne C.B.
      • Lazear H.M.
      Zika virus—reigniting the TORCH.
      ), new approaches are needed to address potential insults associated with the maternal immune response that is a common feature of many viral and bacterial infections. In this review, we first discuss epidemiological data linking maternal infection and offspring NDDs, with a focus on seroepidemiological approaches that provide mechanistic hypotheses that can be tested in preclinical models. We next describe the role of translationally relevant maternal immune activation (MIA) models and highlight relevant features of the nonhuman primate (NHP) that closely resemble human pregnancy and offspring neurodevelopment. We then provide a comprehensive summary of NHP MIA models and conclude by summarizing current knowledge gaps and future directions.

      Human Maternal Immune Response

      The majority of studies investigating prenatal origins of NDDs have focused on schizophrenia (SZ) and autism spectrum disorder (ASD) (
      • Brown A.S.
      Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism.
      ), though the association between maternal infection may extend to other NDDs (
      • Knuesel I.
      • Chicha L.
      • Britschgi M.
      • Schobel S.A.
      • Bodmer M.
      • Hellings J.A.
      • et al.
      Maternal immune activation and abnormal brain development across CNS disorders.
      ). Initial evidence linking maternal infection with SZ stemmed from the observation that birth during the winter and spring months was associated with an increased risk of SZ, possibly owing to seasonal viral exposures [reviewed in (
      • Kepinska A.P.
      • Iyegbe C.O.
      • Vernon A.C.
      • Yolken R.
      • Murray R.M.
      • Pollak T.A.
      Schizophrenia and influenza at the centenary of the 1918-1919 Spanish influenza pandemic: Mechanisms of psychosis risk.
      )]. Subsequent studies using large birth cohorts reported increased risk of SZ in offspring born to women who experienced infections during pregnancy (
      • Khandaker G.M.
      • Zimbron J.
      • Lewis G.
      • Jones P.B.
      Prenatal maternal infection, neurodevelopment and adult schizophrenia: A systematic review of population-based studies.
      ,
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      • Babulas V.
      • Malaspina D.
      • Gorman J.M.
      • et al.
      A.E. Bennett Research Award. Prenatal rubella, premorbid abnormalities, and adult schizophrenia.
      ,
      • Buka S.L.
      • Cannon T.D.
      • Torrey E.F.
      • Yolken R.H.
      Collaborative Study Group on the Perinatal Origins of Severe Psychiatric Disorders
      Maternal exposure to herpes simplex virus and risk of psychosis among adult offspring.
      ,
      • Mortensen P.B.
      • Pedersen C.B.
      • Hougaard D.M.
      • Norgaard-Petersen B.
      • Mors O.
      • Borglum A.D.
      • et al.
      A Danish National Birth Cohort study of maternal HSV-2 antibodies as a risk factor for schizophrenia in their offspring.
      ,
      • Borglum A.D.
      • Demontis D.
      • Grove J.
      • Pallesen J.
      • Hollegaard M.V.
      • Pedersen C.B.
      • et al.
      Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci.
      ,
      • Mortensen P.B.
      • Norgaard-Pedersen B.
      • Waltoft B.L.
      • Sorensen T.L.
      • Hougaard D.
      • Torrey E.F.
      • et al.
      Toxoplasma gondii as a risk factor for early-onset schizophrenia: Analysis of filter paper blood samples obtained at birth.
      ,
      • Brown A.S.
      • Schaefer C.A.
      • Quesenberry Jr., C.P.
      • Liu L.
      • Babulas V.P.
      • Susser E.S.
      Maternal exposure to toxoplasmosis and risk of schizophrenia in adult offspring.
      ,
      • Babulas V.
      • Factor-Litvak P.
      • Goetz R.
      • Schaefer C.A.
      • Brown A.S.
      Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia.
      ,
      • Sørensen H.J.
      • Mortensen E.L.
      • Reinisch J.M.
      • Mednick S.A.
      Association between prenatal exposure to bacterial infection and risk of schizophrenia.
      ). Likewise, initial associations between maternal infection and ASD were primarily based on case studies following in utero exposure to maternal infections (
      • Chess S.
      Autism in children with congenital rubella.
      ,
      • Desmond M.M.
      • Wilson G.S.
      • Melnick J.L.
      • Singer D.B.
      • Zion T.E.
      • Rudolph A.J.
      • et al.
      Congenital rubella encephalitis. Course and early sequelae.
      ,
      • Deykin E.Y.
      • MacMahon B.
      Viral exposure and autism.
      ,
      • Ivarsson S.A.
      • Bjerre I.
      • Vegfors P.
      • Ahlfors K.
      Autism as one of several disabilities in two children with congenital cytomegalovirus infection.
      ,
      • Markowitz P.I.
      Autism in a child with congenital cytomegalovirus infection.
      ,
      • Sweeten T.L.
      • Posey D.J.
      • McDougle C.J.
      Brief report: Autistic disorder in three children with cytomegalovirus infection.
      ). Large-scale epidemiological studies further strengthened this association, though factors such as type of infectious agent and the timing of the gestational exposure have emerged as important considerations (
      • Atladottir H.O.
      • Thorsen P.
      • Ostergaard L.
      • Schendel D.E.
      • Lemcke S.
      • Abdallah M.
      • et al.
      Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders.
      ,
      • Atladóttir H.Ó.
      • Henriksen T.B.
      • Schendel D.E.
      • Parner E.T.
      Autism after infection, febrile episodes, and antibiotic use during pregnancy: An exploratory study.
      ,
      • Zerbo O.
      • Iosif A.M.
      • Walker C.
      • Ozonoff S.
      • Hansen R.L.
      • Hertz-Picciotto I.
      Is maternal influenza or fever during pregnancy associated with autism or developmental delays? Results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) study.
      ,
      • Zerbo O.
      • Qian Y.
      • Yoshida C.
      • Grether J.K.
      • Van de Water J.
      • Croen L.A.
      Maternal infection during pregnancy and autism spectrum disorders.
      ,
      • Lee B.K.
      • Magnusson C.
      • Gardner R.M.
      • Blomstrom A.
      • Newschaffer C.J.
      • Burstyn I.
      • et al.
      Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders.
      ,
      • Al-Haddad B.J.S.
      • Jacobsson B.
      • Chabra S.
      • Modzelewska D.
      • Olson E.M.
      • Bernier R.
      • et al.
      Long-term risk of neuropsychiatric disease after exposure to infection in utero.
      ,
      • Croen L.A.
      • Qian Y.
      • Ashwood P.
      • Zerbo O.
      • Schendel D.
      • Pinto-Martin J.
      • et al.
      Infection and fever in pregnancy and autism spectrum disorders: Findings from the Study to Explore Early Development.
      ,
      • Frazier T.W.
      • Thompson L.
      • Youngstrom E.A.
      • Law P.
      • Hardan A.Y.
      • Eng C.
      • et al.
      A twin study of heritable and shared environmental contributions to autism.
      ,
      • Szatmari P.
      • White J.
      • Merikangas K.R.
      The use of genetic epidemiology to guide classification in child and adult psychopathology.
      ). Recent studies also indicate that the magnitude of the maternal immune response also plays a critical role (
      • Al-Haddad B.J.S.
      • Jacobsson B.
      • Chabra S.
      • Modzelewska D.
      • Olson E.M.
      • Bernier R.
      • et al.
      Long-term risk of neuropsychiatric disease after exposure to infection in utero.
      ), as associations with offspring ASD have been linked to maternal fever episodes (
      • Atladóttir H.Ó.
      • Henriksen T.B.
      • Schendel D.E.
      • Parner E.T.
      Autism after infection, febrile episodes, and antibiotic use during pregnancy: An exploratory study.
      ,
      • Croen L.A.
      • Qian Y.
      • Ashwood P.
      • Zerbo O.
      • Schendel D.
      • Pinto-Martin J.
      • et al.
      Infection and fever in pregnancy and autism spectrum disorders: Findings from the Study to Explore Early Development.
      ), particularly episodes not treated with antifever medication (
      • Zerbo O.
      • Iosif A.M.
      • Walker C.
      • Ozonoff S.
      • Hansen R.L.
      • Hertz-Picciotto I.
      Is maternal influenza or fever during pregnancy associated with autism or developmental delays? Results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) study.
      ) or when diagnosed in hospitals (
      • Zerbo O.
      • Qian Y.
      • Yoshida C.
      • Grether J.K.
      • Van de Water J.
      • Croen L.A.
      Maternal infection during pregnancy and autism spectrum disorders.
      ). These studies suggest that the acute maternal immune response associated with more severe infections may serve as the common biological pathway linking various maternal infections and aberrant fetal brain development (Figure 1).
      Figure thumbnail gr1
      Figure 1Schematic representation of associations between maternal infection, biomarkers of maternal inflammation, and changes in human fetal brain development.
      The association between maternal infection and offspring neurodevelopment is further supported by a growing body of seroepidemiological studies that use archived or prospectively collected maternal biospecimens from mothers of individuals in whom an NDD was later diagnosed. Maternal inflammatory biomarkers generated in response to infection may cross the placenta and/or indirectly stimulate additional downstream changes in the maternal-placental-fetal immune environment that disrupt finely orchestrated events of fetal brain development (
      • Zaretsky M.V.
      • Alexander J.M.
      • Byrd W.
      • Bawdon R.E.
      Transfer of inflammatory cytokines across the placenta.
      ,
      • Ashdown H.
      • Dumont Y.
      • Ng M.
      • Poole S.
      • Boksa P.
      • Luheshi G.N.
      The role of cytokines in mediating effects of prenatal infection on the fetus: Implications for schizophrenia.
      ,
      • Samuelsson A.M.
      • Jennische E.
      • Hansson H.A.
      • Holmang A.
      Prenatal exposure to interleukin-6 results in inflammatory neurodegeneration in hippocampus with NMDA/GABA(A) dysregulation and impaired spatial learning.
      ,
      • Hauguel-de Mouzon S.
      • Guerre-Millo M.
      The placenta cytokine network and inflammatory signals.
      ,
      • Estes M.L.
      • McAllister A.K.
      Immune mediators in the brain and peripheral tissues in autism spectrum disorder.
      ). Biomarkers of maternal infection, including influenza antibodies (
      • Brown A.S.
      • Begg M.D.
      • Gravenstein S.
      • Schaefer C.A.
      • Wyatt R.J.
      • Bresnahan M.
      • et al.
      Serologic evidence of prenatal influenza in the etiology of schizophrenia.
      ), cytokines (
      • Buka S.L.
      • Tsuang M.T.
      • Torrey E.F.
      • Klebanoff M.A.
      • Wagner R.L.
      • Yolken R.H.
      Maternal cytokine levels during pregnancy and adult psychosis.
      ,
      • Brown A.S.
      • Hooton J.
      • Schaefer C.A.
      • Zhang H.
      • Petkova E.
      • Babulas V.
      • et al.
      Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring.
      ,
      • Allswede D.M.
      • Yolken R.H.
      • Buka S.L.
      • Cannon T.D.
      Cytokine concentrations throughout pregnancy and risk for psychosis in adult offspring: A longitudinal case-control study.
      ), and levels of maternal complement components (
      • Severance E.G.
      • Gressitt K.L.
      • Buka S.L.
      • Cannon T.D.
      • Yolken R.H.
      Maternal complement C1q and increased odds for psychosis in adult offspring.
      ), have been associated with offspring psychosis. Likewise, quantification of cytokines, chemokines, and other inflammatory markers obtained from archived maternal sera (
      • Goines P.E.
      • Croen L.A.
      • Braunschweig D.
      • Yoshida C.K.
      • Grether J.
      • Hansen R.
      • et al.
      Increased mid-gestational IFN-gamma, IL-4, and IL-5 in women giving birth to a child with autism: A case-control study.
      ,
      • Jones K.L.
      • Croen L.A.
      • Yoshida C.K.
      • Heuer L.
      • Hansen R.
      • Zerbo O.
      • et al.
      Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation.
      ) and amniotic fluid (
      • Abdallah M.W.
      • Larsen N.
      • Grove J.
      • Nørgaard-Pedersen B.
      • Thorsen P.
      • Mortensen E.L.
      • et al.
      Amniotic fluid chemokines and autism spectrum disorders: An exploratory study utilizing a Danish Historic Birth Cohort.
      ,
      • Abdallah M.W.
      • Larsen N.
      • Grove J.
      • Nørgaard-Pedersen B.
      • Thorsen P.
      • Mortensen E.L.
      • et al.
      Amniotic fluid inflammatory cytokines: Potential markers of immunologic dysfunction in autism spectrum disorders.
      ) lends further support to the link between maternal infection and increased ASD risk, though not all studies have found positive associations (
      • Egorova O.
      • Myte R.
      • Schneede J.
      • Hagglof B.
      • Bolte S.
      • Domellof E.
      • et al.
      Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: A study of 62 serum biomarkers.
      ). Recent efforts have focused on exploring disease-specific maternal inflammatory pathways associated with other NDDs, including attention-deficit/hyperactivity disorder, depression, bipolar disorder, and other neuropsychiatric conditions (
      • Parboosing R.
      • Bao Y.
      • Shen L.
      • Schaefer C.A.
      • Brown A.S.
      Gestational influenza and bipolar disorder in adult offspring.
      ,
      • Canetta S.E.
      • Bao Y.
      • Co M.D.
      • Ennis F.A.
      • Cruz J.
      • Terajima M.
      • et al.
      Serological documentation of maternal influenza exposure and bipolar disorder in adult offspring.
      ,
      • Canetta S.
      • Sourander A.
      • Surcel H.M.
      • Hinkka-Yli-Salomaki S.
      • Leiviska J.
      • Kellendonk C.
      • et al.
      Elevated maternal C-reactive protein and increased risk of schizophrenia in a national birth cohort.
      ,
      • Brown A.S.
      • Sourander A.
      • Hinkka-Yli-Salomaki S.
      • McKeague I.W.
      • Sundvall J.
      • Surcel H.M.
      Elevated maternal C-reactive protein and autism in a national birth cohort.
      ,
      • Chudal R.
      • Brown A.S.
      • Gyllenberg D.
      • Hinkka-Yli-Salomaki S.
      • Sucksdorff M.
      • Surcel H.M.
      • et al.
      Maternal serum C-reactive protein (CRP) and offspring attention deficit hyperactivity disorder (ADHD).
      ,
      • Cheslack-Postava K.
      • Cremers S.
      • Bao Y.
      • Shen L.
      • Schaefer C.A.
      • Brown A.S.
      Maternal serum cytokine levels and risk of bipolar disorder.
      ). Collectively, the growing epidemiological literature provides compelling evidence linking the maternal immune response to offspring NDDs, though underlying mechanisms are difficult to ascertain owing to constraints associated with human research, including differences in study design, timing of biospecimen collection, methods for determining maternal infection exposure, and long delays before clinical diagnosis of affected offspring. Preclinical models have emerged as complementary translational tools to explore the impact of acute exposure to maternal inflammatory biomarkers identified in these seroepidemiological studies.

      Translationally Relevant MIA Models

      Pioneering studies in mice suggested that artificially stimulating the maternal immune response during pregnancy yielded offspring with deficits similar to those born to influenza-exposed dams (
      • Shi L.M.
      • Fatemi H.
      • Sidwell R.W.
      • Patterson P.H.
      Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring.
      ,
      • Smith S.E.
      • Li J.
      • Garbett K.
      • Mirnics K.
      • Patterson P.H.
      Maternal immune activation alters fetal brain development through interleukin-6.
      ) and prompted widespread interest in the MIA model. Despite significant challenges associated with methodological variability, offspring born to MIA-treated dams exhibit many reproducible changes in brain and behavioral development relevant to human NDDs (
      • Kentner A.C.
      • Bilbo S.D.
      • Brown A.S.
      • Hsiao E.Y.
      • McAllister A.K.
      • Meyer U.
      • et al.
      Maternal immune activation: Reporting guidelines to improve the rigor, reproducibility, and transparency of the model.
      ). The vast majority of MIA models have used rodent model systems to provide foundational knowledge on the neurodevelopmental consequences of MIA exposure [for review, see (
      • Bergdolt L.
      • Dunaevsky A.
      Brain changes in a maternal immune activation model of neurodevelopmental brain disorders.
      ,
      • Brown A.S.
      • Meyer U.
      Maternal immune activation and neuropsychiatric illness: A translational research perspective.
      ,
      • Careaga M.
      • Murai T.
      • Bauman M.D.
      Maternal immune activation and autism spectrum disorder: From rodents to nonhuman and human primates.
      )], though there is increasing interest in developing MIA models in other species, including ferrets and pigs (
      • Li Y.
      • Dugyala S.R.
      • Ptacek T.S.
      • Gilmore J.H.
      • Frohlich F.
      Maternal immune activation alters adult behavior, gut microbiome and juvenile brain oscillations in ferrets.
      ,
      • Rymut H.E.
      • Bolt C.R.
      • Caputo M.P.
      • Houser A.K.
      • Antonson A.M.
      • Zimmerman J.D.
      • et al.
      Long-lasting impact of maternal immune activation and interaction with a second immune challenge on pig behavior.
      ). Here, we focus specifically on the translational potential of the NHP model to bridge the gap between rodent MIA models and patient populations with respect to physiological similarity in gestation and development as well as an expanded repertoire of social and cognitive outcomes to measure in offspring. NHP models account for a very small percentage of research in the United States (
      United States Department of Agriculture Animal and Plant Health Inspection Service
      Annual Report Animal Usage by Fiscal Year.
      ), with the majority of NHP studies performed in macaques (
      • Lankau E.W.
      • Turner P.V.
      • Mullan R.J.
      • Galland G.G.
      Use of nonhuman primates in research in North America.
      ). We focus this review primarily on the rhesus macaque (Macaca mulatta), but also incorporate the common marmoset (Callithrix jacchus), which is playing an increasing role in gestational research (
      • Li M.
      • Brokaw A.
      • Furuta A.M.
      • Coler B.
      • Obregon-Perko V.
      • Chahroudi A.
      • et al.
      Non-human primate models to investigate mechanisms of infection-associated fetal and pediatric injury, teratogenesis and stillbirth.
      ). NHPs are the closest model to human pregnancy, sharing similarities in placental and pregnancy physiology, maternal-fetal interface, gestational timeline, and fetal brain development. Moreover, the neuroanatomical complexity and sophisticated behavioral repertoire of NHP offspring allow us to test hypotheses about prenatal immune challenge, from molecular mechanisms through complex behavior, with assays that correspond more closely to behavior or neurobiology observed in humans (Figure 2). NHP features most germane to the MIA model are briefly described below, with a more comprehensive review of the translational utility of the NHP model provided by Tarantal et al. (
      • Tarantal A.F.
      • Hartigan-O’Connor D.J.
      • Noctor S.C.
      Translational utility of the nonhuman primate model.
      ).
      Figure thumbnail gr2
      Figure 2Schematic representation of nonhuman primate models of maternal infection.

      Placental Structure and Pregnancy Physiology

      Determining which pregnancies are at risk and which are resilient to the impact of maternal infection is a major challenge for the MIA model field. Given that rodent MIA models exhibit within-litter variability (
      • Mueller F.S.
      • Scarborough J.
      • Schalbetter S.M.
      • Richetto J.
      • Kim E.
      • Couch A.
      • et al.
      Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation.
      ) and sex differences (
      • Braun A.E.
      • Carpentier P.A.
      • Babineau B.A.
      • Narayan A.R.
      • Kielhold M.L.
      • Moon H.M.
      • et al.
      “Females are not just ‘protected’ males”: Sex-specific vulnerabilities in placenta and brain after prenatal immune disruption.
      ) associated with placental physiology, the ability to extend the model into NHPs that give birth to one offspring, such as the rhesus macaque, or bear small twin or triplet litters sometimes with a chimeric placenta, such as the common marmoset, provide important translational opportunities (
      • Stouffer R.L.
      • Woodruff T.K.
      Nonhuman primates: A vital model for basic and applied research on female reproduction, prenatal development, and women’s health.
      ,
      • Riesche L.
      • Tardif S.D.
      • Ross C.N.
      • deMartelly V.A.
      • Ziegler T.
      • Rutherford J.N.
      The common marmoset monkey: Avenues for exploring the prenatal, placental, and postnatal mechanisms in developmental programming of pediatric obesity.
      ). Moreover, the pronounced differences in placental structure and physiology between rodents and primates influences the maternal-placental-fetal immune environment and is thus an important consideration (
      • Riesche L.
      • Tardif S.D.
      • Ross C.N.
      • deMartelly V.A.
      • Ziegler T.
      • Rutherford J.N.
      The common marmoset monkey: Avenues for exploring the prenatal, placental, and postnatal mechanisms in developmental programming of pediatric obesity.
      ,
      • Carter A.M.
      Animal models of human placentation—a review.
      ). Although humans, rats, mice, and many NHPs possess a hemochorial placenta in which the trophoblast layer is in direct contact with the maternal blood and not separated by endothelium and/or epithelium (
      • Soares M.J.
      • Varberg K.M.
      • Iqbal K.
      Hemochorial placentation: Development, function, and adaptations.
      ), striking differences can be found when comparing the anatomy, cell types, and molecular biology of rodent versus primate placentas (
      • Schmidt A.
      • Morales-Prieto D.M.
      • Pastuschek J.
      • Frohlich K.
      • Markert U.R.
      Only humans have human placentas: Molecular differences between mice and humans.
      ,
      • Moffett A.
      • Loke C.
      Immunology of placentation in eutherian mammals.
      ).

      Gestational Timelines and Prenatal Brain Development

      Identifying gestational time points that are most vulnerable to prenatal immune challenge presents another translational challenge for the MIA model field. Although extrapolating gestational timing of humans (280 days) to other species such as mice/rats (18–23 days) is not always straightforward, and offspring are born at different stages of later brain development, rhesus monkey gestation (165 days) and marmoset gestation (144 days) are more similar to that of humans (
      • Clancy B.
      • Darlington R.B.
      • Finlay B.L.
      Translating developmental time across mammalian species.
      ). Rhesus monkey gestation can be divided into first (gestational days 0–55), second (gestational days 56–110), and third (gestational days 111–165) trimesters that closely parallel stages of human fetal brain development. Peak periods of neurogenesis for subcortical structures, including the amygdala (
      • Kordower J.H.
      • Piecinski P.
      • Rakic P.
      Neurogenesis of the amygdaloid nuclear complex in the rhesus monkey.
      ) and thalamus (
      • Ogren M.P.
      • Racic P.
      The prenatal development of the pulvinar in the monkey: 3H-thymidine autoradiographic and morphometric analyses.
      ), as well as the early stages of neurogenesis for the striatum (
      • Brand S.
      • Rakic P.
      Genesis of the primate neostriatum: [3H]thymidine autoradiographic analysis of the time of neuron origin in the rhesus monkey.
      ) and hippocampus (
      • Rakic P.
      • Nowakowski R.S.
      The time of origin of neurons in the hippocampal region of the rhesus monkey.
      ), occur in the macaque first trimester, while the early stages of corticogenesis begin at the end of the first trimester and continue through the second trimester (
      • Rakic P.
      Specification of cerebral cortical areas.
      ). Emerging evidence from macaques indicates that microglia play a critical role in regulating cell production during this time and raises the possibility that MIA-induced changes in the maternal-fetal immune environment could alter the timing and trajectory of these critical neurodevelopmental processes (
      • Barger N.
      • Keiter J.
      • Kreutz A.
      • Krishnamurthy A.
      • Weidenthaler C.
      • Martinez-Cerdeno V.
      • et al.
      Microglia: An intrinsic component of the proliferative zones in the fetal rhesus monkey (Macaca mulatta) cerebral cortex.
      ). Although less is known about fetal development of the marmoset, the near-lissencephalic (i.e., lacking cortical folds) marmoset brain presents new opportunities to bridge the gap between rodent models and studies in primates with gyrencephalic brains (i.e., brains with a folded cerebral cortex), including humans and rhesus monkeys (
      • Kelava I.
      • Reillo I.
      • Murayama A.Y.
      • Kalinka A.T.
      • Stenzel D.
      • Tomancak P.
      • et al.
      Abundant occurrence of basal radial glia in the subventricular zone of embryonic neocortex of a lissencephalic primate, the common marmoset Callithrix jacchus.
      ,
      • Sawada K.
      • Hikishima K.
      • Murayama A.Y.
      • Okano H.J.
      • Sasaki E.
      • Okano H.
      Fetal sulcation and gyrification in common marmosets (Callithrix jacchus) obtained by ex vivo magnetic resonance imaging.
      ,
      • Heide M.
      • Haffner C.
      • Murayama A.
      • Kurotaki Y.
      • Shinohara H.
      • Okano H.
      • et al.
      Human-specific ARHGAP11B increases size and folding of primate neocortex in the fetal marmoset.
      ).

      Neuroanatomical Organization

      Regions of the human brain commonly implicated in NDDs are well developed in the NHP (
      • Varghese M.
      • Keshav N.
      • Jacot-Descombes S.
      • Warda T.
      • Wicinski B.
      • Dickstein D.L.
      • et al.
      Autism spectrum disorder: Neuropathology and animal models.
      ). The prefrontal cortex (PFC), for example, has expanded during primate evolution and is considered one of the key regions for regulating social cognition in primates (
      • Amodio D.M.
      • Frith C.D.
      Meeting of minds: The medial frontal cortex and social cognition.
      ,
      • Smaers J.B.
      • Steele J.
      • Case C.R.
      • Cowper A.
      • Amunts K.
      • Zilles K.
      Primate prefrontal cortex evolution: Human brains are the extreme of a lateralized ape trend.
      ). Cytoarchitectonic regions identifiable in human and NHP brains that are not present in rodents bring into question the existence of the homologous PFC region in rodents (
      • Geschwind D.H.
      • Rakic P.
      Cortical evolution: Judge the brain by its cover.
      ,
      • Carlen M.
      What constitutes the prefrontal cortex?.
      ). Likewise, the amygdala exhibits similar patterns of connectivity and nuclei distribution in humans and NHPs (
      • Rutishauser U.
      • Mamelak A.N.
      • Adolphs R.
      The primate amygdala in social perception—insights from electrophysiological recordings and stimulation.
      ,
      • Schumann C.M.
      • Vargas M.V.
      • Lee A.
      A synopsis of primate amygdala neuroanatomy.
      ) that differ substantially from rodents (
      • Chareyron L.J.
      • Banta Lavenex P.
      • Amaral D.G.
      • Lavenex P.
      Stereological analysis of the rat and monkey amygdala.
      ). The rhesus monkey exhibits a protracted period of brain and behavioral development uniquely suited to explore the emergence of MIA-induced changes (
      • Hunsaker M.R.
      • Scott J.A.
      • Bauman M.D.
      • Schumann C.M.
      • Amaral D.G.
      Postnatal development of the hippocampus in the Rhesus macaque (Macaca mulatta): A longitudinal magnetic resonance imaging study.
      ,
      • Schumann C.M.
      • Scott J.A.
      • Lee A.
      • Bauman M.D.
      • Amaral D.G.
      Amygdala growth from youth to adulthood in the macaque monkey.
      ,
      • Scott J.A.
      • Grayson D.
      • Fletcher E.
      • Lee A.
      • Bauman M.D.
      • Schumann C.M.
      • et al.
      Longitudinal analysis of the developing rhesus monkey brain using magnetic resonance imaging: Birth to adulthood.
      ). Pubertal onset for male and female macaques generally begins at 2.5 and 3.5 years, respectively (
      • Herman R.A.
      • Zehr J.L.
      • Wallen K.
      Prenatal androgen blockade accelerates pubertal development in male rhesus monkeys.
      ,
      • Wilson M.E.
      • Bounar S.
      • Godfrey J.
      • Michopoulos V.
      • Higgins M.
      • Sanchez M.
      Social and emotional predictors of the tempo of puberty in female rhesus monkeys.
      ), and coincides with a sensitive period of dramatic neural reorganization and plasticity (
      • Hoftman G.D.
      • Lewis D.A.
      Postnatal developmental trajectories of neural circuits in the primate prefrontal cortex: Identifying sensitive periods for vulnerability to schizophrenia.
      ). Moreover, there are areas of the brain that are important for advanced social cognition, such as face-selective patches identified in macaque inferotemporal cortex, that appear to be unique to higher-order primates (
      • Hesse J.K.
      • Tsao D.Y.
      The macaque face patch system: A turtle’s underbelly for the brain.
      ). Although the brain of the common marmoset is considerably smaller compared with larger primates, marmosets also share many of the basic neuroanatomical organizational features described above (
      • Vogt N.
      A detailed marmoset brain atlas.
      ). Recent advances to promote neuroimaging studies of marmosets facilitated through the Marmoset Brain Mapping Project (marmosetbrainmapping.org) have produced comprehensive brain atlases focused on cortex (
      • Liu C.
      • Ye F.Q.
      • Yen C.C.
      • Newman J.D.
      • Glen D.
      • Leopold D.A.
      • et al.
      A digital 3D atlas of the marmoset brain based on multi-modal MRI.
      ), white matter (
      • Liu C.
      • Ye F.Q.
      • Newman J.D.
      • Szczupak D.
      • Tian X.
      • Yen C.C.
      • et al.
      A resource for the detailed 3D mapping of white matter pathways in the marmoset brain.
      ), and the recently released population-based in vivo standard templates and tools (
      • Liu C.
      • Yen C.C.
      • Szczupak D.
      • Tian X.
      • Glen D.
      • Silva A.C.
      Marmoset Brain Mapping V3: Population multi-modal standard volumetric and surface-based templates.
      ).

      Behavioral Repertoire

      Behavioral deficits in rodent MIA models initially focused on adult-onset changes in behavior (
      • Zuckerman L.
      • Rehavi M.
      • Nachman R.
      • Weiner I.
      Immune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: A novel neurodevelopmental model of schizophrenia.
      ,
      • Zuckerman L.
      • Weiner I.
      Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring.
      ), though increasing attention has been paid to the developmental progression of MIA-induced behavioral changes (
      • Vuillermot S.
      • Luan W.
      • Meyer U.
      • Eyles D.
      Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation.
      ,
      • Garay P.A.
      • Hsiao E.Y.
      • Patterson P.H.
      • McAllister A.K.
      Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development.
      ,
      • Giovanoli S.
      • Notter T.
      • Richetto J.
      • Labouesse M.A.
      • Vuillermot S.
      • Riva M.A.
      • et al.
      Late prenatal immune activation causes hippocampal deficits in the absence of persistent inflammation across aging.
      ). With a protracted period of social and cognitive development compared with rodents, monkeys provide an opportunity to explore the postnatal neurodevelopmental trajectory of risk associated with prenatal immune challenge (
      • Ryan A.M.
      • Berman R.F.
      • Bauman M.D.
      Bridging the species gap in translational research for neurodevelopmental disorders.
      ,
      • Phillips K.A.
      • Bales K.L.
      • Capitanio J.P.
      • Conley A.
      • Czoty P.W.
      • ’t Hart B.A.
      • et al.
      Why primate models matter.
      ). Macaques live in large social groups of related animals and, similar to humans, use vision as their primary sensory modality (
      • Ross C.F.
      Into the light: The origin of anthropoidea.
      ) and rely on facial expressions and body postures for communication (
      • Chang S.W.
      • Brent L.J.
      • Adams G.K.
      • Klein J.T.
      • Pearson J.M.
      • Watson K.K.
      • et al.
      Neuroethology of primate social behavior.
      ). Recent advances in more naturalistic eye-tracking methods have increased our understanding of how monkeys process social information (
      • Ryan A.M.
      • Freeman S.M.
      • Murai T.
      • Lau A.R.
      • Palumbo M.C.
      • Hogrefe C.E.
      • et al.
      Non-invasive eye tracking methods for New World and Old World ,onkeys.
      ) and provide a translational opportunity to human eye-tracking studies that have documented changes in individuals with NDDs, including both ASD and SZ (
      • Papagiannopoulou E.A.
      • Chitty K.M.
      • Hermens D.F.
      • Hickie I.B.
      • Lagopoulos J.
      A systematic review and meta-analysis of eye-tracking studies in children with autism spectrum disorders.
      ,
      • Wolf A.
      • Ueda K.
      • Hirano Y.
      Recent updates of eye movement abnormalities in patients with schizophrenia: A scoping review.
      ). Moreover, rhesus monkeys develop increasingly sophisticated problem-solving skills as they mature, which can be assessed with translationally relevant cognitive paradigms (
      • Weed M.R.
      • Bryant R.
      • Perry S.
      Cognitive development in macaques: Attentional set-shifting in juvenile and adult rhesus monkeys.
      ,
      • Weed M.R.
      • Taffe M.A.
      • Polis I.
      • Roberts A.C.
      • Robbins T.W.
      • Koob G.F.
      • et al.
      Performance norms for a rhesus monkey neuropsychological testing battery: Acquisition and long-term performance.
      ). While rhesus monkeys have traditionally been the standard NHP model species for humans, marmoset social organization and behavior allow for new opportunities for studies of social behavior not easily carried out in rhesus monkeys. Marmosets are more distantly related to humans (40 million years ago) than rhesus monkeys (25 million years ago), but, similar to many humans and in contrast to rhesus monkeys, they live in small family groups with pair bonding and engage in cooperative rearing of young, including paternal and intergenerational sibling care (
      Marmoset Genome Sequencing and Analysis Consortium
      The common marmoset genome provides insight into primate biology and evolution.
      ,
      • Schiel N.
      • Souto A.
      The common marmoset: An overview of its natural history, ecology and behavior.
      ). This social organization may contribute to the tendency for marmosets to perform prosocial behaviors, such as food sharing and imitation [for review, see (
      • Miller C.T.
      • Freiwald W.A.
      • Leopold D.A.
      • Mitchell J.F.
      • Silva A.C.
      • Wang X.
      Marmosets: A neuroscientific model of human social behavior.
      )]. Furthermore, separation of an individual from the family group in an experimental context can reliably serve as a psychosocial stressor to assess reactivity (
      • French J.A.
      • Smith A.S.
      • Gleason A.M.
      • Birnie A.K.
      • Mustoe A.
      • Korgan A.
      Stress reactivity in young marmosets (Callithrix geoffroyi): Ontogeny, stability, and lack of concordance among co-twins.
      ). While their capabilities have not been as widely explored as rhesus macaques, marmosets can perform discrimination tasks early in development (
      • Ash H.
      • Ziegler T.E.
      • Colman R.J.
      Early learning in the common marmoset (Callithrix jacchus): Behavior in the family group is related to preadolescent cognitive performance.
      ) and have been used in more complex cognitive paradigms, including using eye fixations under restraint, using touchscreens (
      • Spinelli S.
      • Pennanen L.
      • Dettling A.C.
      • Feldon J.
      • Higgins G.A.
      • Pryce C.R.
      Performance of the marmoset monkey on computerized tasks of attention and working memory.
      ,
      • Takemoto A.
      • Izumi A.
      • Miwa M.
      • Nakamura K.
      Development of a compact and general-purpose experimental apparatus with a touch-sensitive screen for use in evaluating cognitive functions in common marmosets.
      ), and visual detection and discrimination tasks requiring complex motor behavior (
      • Mitchell J.F.
      • Reynolds J.H.
      • Miller C.T.
      Active vision in marmosets: A model system for visual neuroscience.
      ,
      • Pomberger T.
      • Risueno-Segovia C.
      • Gultekin Y.B.
      • Dohmen D.
      • Hage S.R.
      Cognitive control of complex motor behavior in marmoset monkeys.
      ).

      NHP Models of Maternal Infection

      The greater physical, psychological, and social needs of laboratory-housed NHPs are also associated with greater ethical considerations and increased cost for their care. While studies using NHPs are less common and the number of animals studied is more limited than in rodent or human studies, we provide examples below of ways in which translational NHP models have provided new insight into the impact of acute prenatal immune challenge on offspring neurodevelopment (Table 1). In this section, we summarize the methodological approaches used to induce MIA and evaluate neurobiological outcomes in NHP offspring. It is important to note that even sophisticated NHP models do not recapitulate NDDs observed in humans. In recent years, the MIA model has evolved from the initial characterization as a model of ASD or SZ toward a more hypothesis-based model for examining the effects of maternal inflammation on neural systems relevant to multiple neurodevelopmental conditions (
      • Gordon J.A.
      A Hypothesis-Based Approach: The Use of Animals in Mental Health Research. NIMH Director’s Message.
      ). Our description of neurobehavioral outcomes and comparisons between animal models and clinical disorders reflects this subtle, but important, shift in interpretation. We include maternal influenza exposure models as well as models that artificially stimulate the maternal immune response using poly(I:C) (polyinosinic:polycytidylic acid), a synthetic double-stranded RNA molecule that mimics the genetic information for many viruses and is recognized by toll-like receptor 3 or lipopolysaccharide (LPS), the cell wall component of gram-negative bacteria recognized by toll-like receptor 4 (
      • Arsenault D.
      • St-Amour I.
      • Cisbani G.
      • Rousseau L.S.
      • Cicchetti F.
      The different effects of LPS and poly I:C prenatal immune challenges on the behavior, development and inflammatory responses in pregnant mice and their offspring.
      ,
      • Meyer U.
      • Feldon J.
      • Fatemi S.H.
      In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders.
      ). In contrast to rodent models that can be completed in a matter of months, we are at the earliest stages of exploring the impact of MIA in the NHP model. However, we expect neurodevelopmental outcomes in the NHP MIA model to be influenced by gestational timing, magnitude of the maternal immune response, and additional genetic and environmental insults as described in the rodent MIA model.
      Table 1Summary of Nonhuman Primate Models of Maternal Infection and Maternal Immune Activation (MIA)
      StudiesSpeciesInfection, Design, and TimingAssessmentsMIA Offspring Behavioral DevelopmentMIA Offspring Brain DevelopmentMIA Offspring Other Biological Outcomes
      Short et al. (
      • Short S.J.
      • Lubach G.R.
      • Karasin A.I.
      • Olsen C.W.
      • Styner M.
      • Knickmeyer R.C.
      • et al.
      Maternal influenza infection during pregnancy impacts postnatal brain development in the rhesus monkey.
      )
      Rhesus Macaque (Macaca mulatta)Pregnant rhesus monkeys were exposed to human-derived H3N2 influenza strain intranasally in the third trimester (producing N = 12 offspring, 7 males and 5 females) compared with a combination of saline-treated and untreated control animals (producing N = 7 offspring, 3 males and 4 females)Behavioral Assessments
      • Behavioral maturation, attentional processes, and neuromotor reflexes at 2 weeks
      • Infants observed (1–4 months) with mothers in home cages for three 5-min periods/week
      Neuroimaging
      • MRI (∼1 year)
      Other Outcomes
      • Adrenal activity assessment (1.5 years)
      Neonatal Reflexes and Development
      • No group differences on most measures
      • Males performed more poorly than control animals on orientation subscale
      Mother-Infant Interactions
      • Spent less time in contact with their mothers, were more likely to move off their mother and explore the cage at an earlier age, and demonstrated signs of arousal including an increased likelihood of vocalizing
      Global Measures
      • Reduced ICV
      Gray Matter
      • Less gray matter in prefrontal, frontal (right only), cingulate, insula (right only), parietal, and temporal-auditory regions (before ICV correction); after ICV correction for smaller total brain size, significant differences remained in cingulate and parietal areas
      White Matter
      • Significant differences restricted primarily to parietal lobes and left temporal-auditory region before ICV correction; white matter volume in left parietal region remained significantly smaller after ICV correction, though cingulate white matter was proportionally greater in influenza group
      MIA Correlations
      • Significant negative correlations were found for cingulate volume and magnitude of mothers’ antibody response
      • Size of lateral ventricles was positively correlated with mothers’ antibody response
      Adrenal Activity
      • No group differences in basal and stress-induced cortisol
      Willette et al. (
      • Willette A.A.
      • Lubach G.R.
      • Knickmeyer R.C.
      • Short S.J.
      • Styner M.
      • Gilmore J.H.
      • et al.
      Brain enlargement and increased behavioral and cytokine reactivity in infant monkeys following acute prenatal endotoxemia.
      )
      Rhesus MacaquePregnant rhesus monkeys (N = 9) were given LPS injections (IV) on gestational days 125 and 126 (third trimester) at either 2 ng/kg (n = 1) or 4 ng/kg (n = 8), producing N = 9 LPS-exposed offspring. Control group consisted of saline-treated (n = 2) and untreated (n = 7) animals, producing N = 9 control offspring. There were 4 males and 5 females in each group, although data for both sexes were combinedBehavioral Assessments
      • Behavioral maturation, attentional processes, and neuromotor reflexes (2 weeks)
      • Social interactions between infant and its mother (1–4 months) and with peers (6–7 months)
      • Stress reactivity using a modified human intruder test (8–9months)
      • Response to acoustical startle via PPI paradigm (10–12 months)
      Neuroimaging
      • MRI (∼1 year)
      Other Outcomes
      • Blood collected (2, 4, and 7 months)
      • IL-6 tolerance assessment (1.5 years)
      Neonatal Reflexes and Development
      • Higher emotionality ratings
      Mother-Infant and Peer Interactions
      • No group differences with mothers or peer-rearing groups
      Human Intruder Reactivity
      • Less reactive despite showing more baseline exploration
      Response to Startle
      • As juveniles, demonstrated a dysregulated response characterized by augmented (rather than suppressed) startle to PPI
      Global Measures
      • Marginally larger ICV, results for gray matter and white matter unchanged after ICV correction
      Gray Matter
      • No group differences in global gray matter
      • Selective gray matter increases in parietal and frontal areas and in hippocampus and putamen
      • Marginally thicker gray matter in right parietal and frontal lobes, but thinner gray matter in medial temporal lobe
      White Matter
      • Significant increase in mean global white matter volume
      • All white matter regions were significantly larger
      Cortisol Levels
      • Heightened cortisol levels 2 days after moving to a new cage
      • Following overnight dexamethasone treatment, morning cortisol levels were initially more suppressed, but by afternoon, cortisol levels were elevated compared with control animals
      IL-6 levels
      • Initially had more cellular reactivity when blood was stimulated in vitro with PHA during preweaning phase but showed the opposite pattern 1 month after weaning
      Weir et al. (
      • Frazier T.W.
      • Thompson L.
      • Youngstrom E.A.
      • Law P.
      • Hardan A.Y.
      • Eng C.
      • et al.
      A twin study of heritable and shared environmental contributions to autism.
      )
      Rhesus MacaquePregnant dams (N = 4) received poly(ICLC) injections (IV) on gestational days 43, 44, 46, 47, 49, and 50; 3 doses were evaluated: 0.25 mg/kg (1 female offspring), 0.5 mg/kg (1 male and 1 female offspring), and 1 mg/kg (1 male offspring). Control dams (N = 5) received saline injections, producing N = 5 male offspringBehavioral Assessments
      • General health and development
      • Home cage observations to screen for maladaptive behaviors
      Neuroimaging
      • None
      Other Outcomes
      • DLPFC brain pathology evaluated via Golgi
      Home Cage Observations
      • Exhibited more whole-body stereotypies at 6 months
      N/ADendritic Morphology
      • No group differences in morphological measures of basal dendritic arborization
      • Apical dendrites smaller in diameter and significantly larger number of oblique dendrites
      Bauman et al. (
      • Bauman M.D.
      • Iosif A.M.
      • Smith S.E.
      • Bregere C.
      • Amaral D.G.
      • Patterson P.H.
      Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring.
      ); Machado et al. (
      • Machado C.J.
      • Whitaker A.M.
      • Smith S.E.
      • Patterson P.H.
      • Bauman M.D.
      Maternal immune activation in nonhuman primates alters social attention in juvenile offspring.
      ); Rose et al. (
      • Rose D.R.
      • Careaga M.
      • Van de Water J.
      • McAllister K.
      • Bauman M.D.
      • Ashwood P.
      Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation.
      ); Bauman et al. (
      • Bauman M.D.
      • Lesh T.A.
      • Rowland D.J.
      • Schumann C.M.
      • Smucny J.
      • Kukis D.L.
      • et al.
      Preliminary evidence of increased striatal dopamine in a nonhuman primate model of maternal immune activation.
      ); Page et al. (
      • Page N.F.
      • Gandal M.J.
      • Estes M.L.
      • Cameron S.
      • Buth J.
      • Parhami S.
      • et al.
      Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in nonhuman primates.
      ); Hanson et al. (K.L. Hanson, Ph.D., et al., unpublished data, November 2020)
      Rhesus MacaquePoly(ICLC) injections (0.25 mg/kg IV) comparing first trimester (N = 7, 5 males and 2 females). Control animals received saline injections (N = 8, 3 males and 5 females) or were untreated (n = 3, 1 male and 2 females); first vs. second trimesterBehavioral Assessments

       Bauman et al. (
      • Bauman M.D.
      • Iosif A.M.
      • Smith S.E.
      • Bregere C.
      • Amaral D.G.
      • Patterson P.H.
      Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring.
      ) (see Table S2)
      • Behavioral maturation, attentional processes, and neuromotor reflexes (1 week)
      • Biobehavioral assessment of health, behavior, temperament, and adrenal regulation (3 months)
      • Social interactions between each infant and its mother and with peer-rearing group (1–12 months)
      • Stress reactivity assessed using modified human intruder test (1, 3, and 6 months)
      • Solo observations in a novel cage (10 and 22 months)
      • Response to a novel peer (24 months)


       Machado et al. (
      • Machado C.J.
      • Whitaker A.M.
      • Smith S.E.
      • Patterson P.H.
      • Bauman M.D.
      Maternal immune activation in nonhuman primates alters social attention in juvenile offspring.
      )
      • Eye tracking (first-trimester males)
      Neuroimaging

       Bauman et al. (
      • Bauman M.D.
      • Lesh T.A.
      • Rowland D.J.
      • Schumann C.M.
      • Smucny J.
      • Kukis D.L.
      • et al.
      Preliminary evidence of increased striatal dopamine in a nonhuman primate model of maternal immune activation.
      )
      • PET (first- and second-trimester males)
      Other Outcomes

       Rose et al. (
      • Rose D.R.
      • Careaga M.
      • Van de Water J.
      • McAllister K.
      • Bauman M.D.
      • Ashwood P.
      Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation.
      )
      • Immune system development


       Page et al. (
      • Page N.F.
      • Gandal M.J.
      • Estes M.L.
      • Cameron S.
      • Buth J.
      • Parhami S.
      • et al.
      Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in nonhuman primates.
      )
      • Brain tissue, gene expression


       Hanson et al. (K.L. Hanson, Ph.D., et al., unpublished data, November 2020)
      • Brain tissue, dendritic morphology
      0- to 6-Month Assessments
      • No consistent group differences in physical growth, motor or reflex development, adrenal activity, interactions with mothers, or development of threat detection in first 6 months of life
      Solo Observations
      • At 10 and 22 months, second-trimester MIA offspring produced significantly more repetitive behaviors; first-trimester MIA animals also produced more repetitive behaviors than control animals, but this difference did not reach statistical significance until the latter time point. At 22 months, second-trimester MIA offspring produced significantly fewer affiliative vocalizations than control animals
      Novel Social Partner
      • At 24 months, first-trimester MIA offspring exhibited inappropriate social interactions with unfamiliar animals; first-trimester MIA offspring also produced significantly fewer affiliative vocalizations than control animals
      Social Attention
      • At 2.5 years, first-trimester male MIA offspring differed from control animals on several measures of social attention, particularly when viewing macaque faces depicting the fear grimace facial expression
      • MIA offspring had a longer latency before fixating on the eyes, had fewer fixations directed at the eyes, and spent less total time fixating on the eyes of the fear grimace images
      PET
      • First- and second-trimester MIA groups were not significantly different in age, weight, or FMT index of influx and were considered as one MIA group (N = 9), regardless of trimester of exposure
      • MIA-exposed late adolescent offspring had significantly higher FMT index of influx compared with control animals
      Immune Function
      • Elevated production of innate immune cell associated cytokines early in life, shifting to a more TH2 type response as animals aged
      Gene Expression
      • Changes in a large number of genes across the brain that revealed dysregulated synaptic connectivity and enhanced myelination
      Dendritic Morphology
      • Increase in dendritic branching in pyramidal cells in infra- and supragranular layers in DLPFC
      • Significant decrease in apical dendrite diameter in infragranular layers in DLPFC
      • No significant differences observed in morphology of hippocampus neurons
      Vlasova et al. (
      • Vlasova R.M.
      • Iosif A.M.
      • Ryan A.M.
      • Funk L.H.
      • Murai T.
      • Chen S.
      • et al.
      Maternal immune activation during pregnancy alters postnatal brain growth and cognitive development in nonhuman primate offspring.
      )
      Rhesus MacaquePregnant dams received poly(ICLC) injections (0.25 mg/kg IV) on gestational days 43, 44, and 46 to produce a large (N = 14) cohort of MIA-exposed males; control dams (N = 14) received saline injections (n = 10) or were untreated (n = 4)Behavioral Assessments
      • Behavioral maturation, attentional processes, and neuromotor reflexes (1 week)
      • Social interactions between infant and its mother (0–6 months) and with peers (6–18 months)
      • Reversal learning (18 months) and the following tests (33–45 months): continuous performance task, progressive ratio breakpoint, probabilistic reversal learning, intradimensional/extradimensional shift
      Neuroimaging
      • MRI (∼6, 12, 24, 36, and 45 months)
      Other Outcomes
      • Weight, crown-rump length, head circumference (∼6, 12, 24, 36, and 45 months)
      General Development
      • No group differences in neuromotor reflexes, behavioral maturation, attention, or social interactions with mother or peer in home cage
      Cognitive Development
      • Similar overall cognitive performance to control groups with some subtle differences
      • Increased omission errors in reversal learning, more misses during 2 stages of intradimensional/extradimensional shift (both reversal stages), and had a significantly increased number of false alarms on continuous performance task
      Structural MRI
      • Significant gray matter volume reductions in prefrontal and frontal cortices at 6 months that persisted through the final time point at 45 months along with smaller frontal white matter volumes at 36 and 45 months
      Physical Growth
      • No group differences in overall health or physical development via weight, crown-rump length, and head circumference
      Santana-Coelho et al. (
      • Santana-Coelho D.
      • Layne-Colon D.
      • Valdespino R.
      • Ross C.C.
      • Tardif S.D.
      • O’Connor J.C.
      Advancing autism research from mice to marmosets: Behavioral development of offspring following prenatal maternal immune activation.
      )
      Common Marmoset (Callithrix jacchus)Pregnant dams (N = 8) received 3 poly(ICLC) injections (SC) on gestational days 63, 65, and 67 (5 mg/kg) producing N = 7 (4 female) offspring. Control dams (N = 7) received saline injections (n = 3) or were untreated (n = 4), collectively producing N = 10 (6 female) viable offspringBehavioral Assessments
      • Marmoset Assessment Tests (Matscore) for motor skills, sensory skills, and weight (1–3 days)
      • Isolation-induced vocalization test (2, 4, and 8 weeks)
      • Social preference and stranger interaction tests (3.5 and 9 months)
      Neuroimaging
      • None
      Other Outcomes
      • Weight (before all testing)
      Neonatal Development
      • No group difference in infant health, vitality, and neurodevelopment
      Vocalization Reactivity
      • No group differences in total number of vocalizations
      • Females emitted fewer vocalizations than control females at 8 weeks
      • Males produced less vocal diversity until 8 weeks
      Social Preference
      • No group differences in females at 3.5 months
      • Males at 3.5 months spent more time in the nonsocial chamber than in the social chamber
      • No group difference at 9 months
      Stranger Interaction Reactivity
      • At 3.5 months, males spent significantly more time in the stranger’s chamber
      • At 9 months, males and females spent less time with the stranger than control animals
      N/APhysical Growth
      • Female offspring heavier than control animals at 37 weeks
      DLPFC, dorsolateral prefrontal cortex; ICV, intracranial volume; IL, interleukin; IV, intravenous; LPS, lipopolysaccharide; MRI, magnetic resonance imaging; N/A, not available; PET, positron emission tomography; PHA, phytohemagglutinin; PPI, prepulse inhibition; SC, subcutaneous; TH2, T helper cell type 2.

      Rhesus Monkey Maternal Influenza Models

      Coe’s group developed the first NHP model to investigate the impact of prenatal influenza exposure on offspring development (
      • Short S.J.
      • Lubach G.R.
      • Karasin A.I.
      • Olsen C.W.
      • Styner M.
      • Knickmeyer R.C.
      • et al.
      Maternal influenza infection during pregnancy impacts postnatal brain development in the rhesus monkey.
      ). Pregnant monkeys were intranasally exposed to human-derived H3N2 strain of influenza during the early third trimester. Maternal infection was verified, and influenza-exposed and control offspring were evaluated from birth through 1.5 years. Early behavioral and stress assessments were similar between the two groups, though influenza-exposed offspring demonstrated a more rapid autonomy from the mother by 4 months old. Influenza-exposed offspring also exhibited a reduction in both intracranial volume (ICV) and gray matter in the prefrontal, frontal, cingulate, insula, parietal, and temporal-auditory regions, paired with white matter reductions in the parietal lobes and the left temporal-auditory region. Although the extent of regional gray matter reduction was reduced after ICV correction, volumetric decreases were still evident in the frontal and parietal lobes and the cingulate gyrus of influenza-exposed animals, as were white matter volume reductions in the parietal lobe. This pioneering study both provided evidence linking maternal influenza exposure with alterations in NHP offspring brain and behavioral development, and provided a translational framework to explore the long-term consequences of prenatal immune challenge on NHP neurodevelopment.

      Rhesus Monkey Maternal LPS Models

      In parallel, Coe’s group also developed the first rhesus monkey MIA model using LPS to elicit a maternal immune response in the early third trimester (
      • Willette A.A.
      • Lubach G.R.
      • Knickmeyer R.C.
      • Short S.J.
      • Styner M.
      • Gilmore J.H.
      • et al.
      Brain enlargement and increased behavioral and cytokine reactivity in infant monkeys following acute prenatal endotoxemia.
      ). Rhesus macaques born to dams exposed to LPS exhibited subtle alterations in behavior throughout development, including heightened responsiveness during neonatal development assessments at 2 weeks of age, followed by less reactivity during an anxiety assessment at 8 to 9 months. The LPS-exposed offspring also exhibited periodic findings of physiological differences, including increased cellular reactivity to in vitro blood stimulated early in development and differential response to negative glucocorticoid feedback after an overnight dexamethasone treatment. In contrast to the reduction in ICV described above for influenza-exposed offspring, the LPS-exposed offspring demonstrated marginally larger ICV compared with control offspring at 1 year. Although global gray matter did not differ statistically between groups, selective gray matter increases in LPS monkeys were seen in parietal and frontal areas, in addition to the hippocampus and putamen. LPS monkeys had a significant increase in mean global white matter volume, with nearly all regions significantly larger in LPS-exposed monkeys compared with control offspring. The study provided the first evidence that artificially stimulating the maternal immune response in NHPs results in changes in offspring brain and behavioral development.

      Rhesus Monkey Maternal Poly(I:C) Models

      In collaboration with the late Dr. Paul Patterson, our laboratory developed the first poly(I:C)-based NHP MIA model. Over the past decade, we have generated 3 cohorts of rhesus monkey offspring born to MIA-treated dams: 1) first-trimester dosing cohort, 2) pilot comparison of first- versus second-trimester exposure, and 3) first-trimester male offspring cohort that has recently completed comprehensive brain and behavioral phenotyping from birth through 4 years of age.

      First-Trimester Dosing Cohort

      The first cohort was generated to evaluate 3 doses of a modified form of poly(I:C) stabilized with poly(ICLC) (poly-L-lysine) (
      • Weir R.K.
      • Forghany R.
      • Smith S.E.
      • Patterson P.H.
      • McAllister A.K.
      • Schumann C.M.
      • et al.
      Preliminary evidence of neuropathology in nonhuman primates prenatally exposed to maternal immune activation.
      ). Pregnant dams received 6 injections in the late first trimester of 0.25 mg/kg, 0.5 mg/kg, or 1 mg/kg poly(ICLC) (n = 1 dam, n = 2 dams, n = 1 dam, respectively) or saline (n = 4). Interleukin 6 data confirmed a robust immune response and thus guided our final MIA-induction protocol of 3 injections used for future cohorts. General health and development were monitored along with periodic screening of offspring for maladaptive behaviors, including the increased frequency of whole-body stereotypies exhibited by the MIA-treated offspring at 6 months of age. The brain tissue obtained from the offspring of the dosing cohort at 3.5 years was then used to carry out an initial assessment of brain pathology in the NHP MIA model by quantifying dendritic morphology in layer III pyramidal neurons in the dorsolateral PFC (DLPFC). Our results showed that MIA-treated offspring have a narrower apical dendritic diameter and more oblique dendrites compared with control offspring and highlighted the frontal cortex as a potentially vulnerable region in NHPs exposed to prenatal immune challenge.

      First- Versus Second-Trimester Exposure Cohort

      We then conducted a pilot comparison of NHP offspring born to dams that received 3 poly(ICLC) injections in the late first (n = 6) or second (n = 7) trimesters that included an evaluation of offspring behavior (
      • Bauman M.D.
      • Iosif A.M.
      • Smith S.E.
      • Bregere C.
      • Amaral D.G.
      • Patterson P.H.
      Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring.
      ,
      • Machado C.J.
      • Whitaker A.M.
      • Smith S.E.
      • Patterson P.H.
      • Bauman M.D.
      Maternal immune activation in nonhuman primates alters social attention in juvenile offspring.
      ), immune (
      • Rose D.R.
      • Careaga M.
      • Van de Water J.
      • McAllister K.
      • Bauman M.D.
      • Ashwood P.
      Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation.
      ), and brain [K.L. Hanson, Ph.D., et al., unpublished data, November 2020; (
      • Bauman M.D.
      • Lesh T.A.
      • Rowland D.J.
      • Schumann C.M.
      • Smucny J.
      • Kukis D.L.
      • et al.
      Preliminary evidence of increased striatal dopamine in a nonhuman primate model of maternal immune activation.
      ,
      • Page N.F.
      • Gandal M.J.
      • Estes M.L.
      • Cameron S.
      • Buth J.
      • Parhami S.
      • et al.
      Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in nonhuman primates.
      )] development. Although there were no consistent differences early in development, the offspring exposed to MIA in either trimester displayed increased repetitive behaviors and changes in social development as they matured, with more differences specifically between first- and second-trimester offspring compared with control offspring summarized in Figure S3 in Bauman et al. (
      • Bauman M.D.
      • Iosif A.M.
      • Smith S.E.
      • Bregere C.
      • Amaral D.G.
      • Patterson P.H.
      Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring.
      ). When evaluated with unfamiliar conspecifics, first-trimester MIA offspring also deviated from species-typical social behavior by inappropriately interacting with an unfamiliar animal and later exhibited atypical patterns of social attention when evaluated in a novel eye-tracking paradigm (
      • Machado C.J.
      • Whitaker A.M.
      • Smith S.E.
      • Patterson P.H.
      • Bauman M.D.
      Maternal immune activation in nonhuman primates alters social attention in juvenile offspring.
      ). The male MIA-treated offspring from this cohort also underwent in vivo positron emission tomography scanning at approximately 3.5 years of age using the tracer FMT to measure presynaptic dopamine levels in the striatum (
      • Bauman M.D.
      • Lesh T.A.
      • Rowland D.J.
      • Schumann C.M.
      • Smucny J.
      • Kukis D.L.
      • et al.
      Preliminary evidence of increased striatal dopamine in a nonhuman primate model of maternal immune activation.
      ). Analysis of FMT signal in the striatum showed that MIA-exposed monkeys had a significantly higher FMT index of influx as compared with control animals—a hallmark feature of human psychosis (
      • Fusar-Poli P.
      • Meyer-Lindenberg A.
      Striatal presynaptic dopamine in schizophrenia, part II: Meta-analysis of [(18)F/(11)C]-DOPA PET studies.
      ). The MIA-treated animals also exhibited alterations in immune function relevant to NDDs, characterized by elevated production of innate inflammatory cytokines both at baseline and following stimulation at 1 year and 4 years of age, including elevated interleukin 1β paired with increased production of T helper cell type 2 cytokines, interleukin 4, and interleukin 13 (
      • Rose D.R.
      • Careaga M.
      • Van de Water J.
      • McAllister K.
      • Bauman M.D.
      • Ashwood P.
      Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation.
      ). Finally, RNA sequencing of PFC, anterior cingulate, hippocampus, and primary visual cortex implicated alterations in transposable element biology, synaptic connectivity, and myelination with relative hippocampal vulnerability in the adolescent brain of MIA-exposed NHPs (
      • Page N.F.
      • Gandal M.J.
      • Estes M.L.
      • Cameron S.
      • Buth J.
      • Parhami S.
      • et al.
      Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in nonhuman primates.
      ). We have also recently replicated the findings of aberrant dendritic morphology in the DLPFC (
      • Weir R.K.
      • Forghany R.
      • Smith S.E.
      • Patterson P.H.
      • McAllister A.K.
      • Schumann C.M.
      • et al.
      Preliminary evidence of neuropathology in nonhuman primates prenatally exposed to maternal immune activation.
      ), with both first- and second-trimester MIA-exposed monkeys exhibiting an increase in dendritic branching in pyramidal cells in both infra- and supragranular layers in DLPFC, paired with a significant decrease in apical dendrite diameter in the infragranular layers of the DLPFC. Collectively, these transcriptional and neuropathological changes may provide unique insight into prodromal changes in the brain during a vulnerable period of late adolescent/early adulthood and suggest that the NHP MIA model may provide a translational tool to examine underlying molecular and cellular biology of brain development impacted by prenatal immune challenge.

      First-Trimester Longitudinal Behavior and Neuroimaging Cohort

      To systematically explore the developmental trajectory of risk associated with prenatal immune challenge, we have recently generated a third cohort of first-trimester MIA-exposed (n = 14) and control (n = 14) male monkeys that have undergone longitudinal neuroimaging paired with comprehensive behavioral characterization. These studies are ongoing, including a comprehensive assessment of social and immune system development paired with multimodal neuroimaging. Our preliminary findings indicate that MIA-exposed animals exhibited volumetric reductions in brain growth throughout development paired with subtle changes in cognitive development (
      • Vlasova R.M.
      • Iosif A.M.
      • Ryan A.M.
      • Funk L.H.
      • Murai T.
      • Chen S.
      • et al.
      Maternal immune activation during pregnancy alters postnatal brain growth and cognitive development in nonhuman primate offspring.
      ). Specifically, longitudinal magnetic resonance imaging revealed significant gray matter volume reductions in the frontal and prefrontal cortices of infant MIA-treated offspring that persisted throughout development, along with smaller frontal white matter volumes in MIA-treated offspring that emerged during adolescence. These findings provide the first longitudinal evidence of early postnatal changes in brain development in MIA-exposed NHPs and establish a model system to explore the emergence of brain and behavioral changes from birth through late adolescence. Additional datasets are currently in preparation for publication, including a comprehensive assessment of social and immune system development paired with multimodal neuroimaging.

      Marmoset Maternal Poly(I:C) Models

      The recently established marmoset MIA model (
      • Santana-Coelho D.
      • Layne-Colon D.
      • Valdespino R.
      • Ross C.C.
      • Tardif S.D.
      • O’Connor J.C.
      Advancing autism research from mice to marmosets: Behavioral development of offspring following prenatal maternal immune activation.
      ) provides an opportunity to explore the impact of prenatal immune challenge in a species that is playing an increasing role in neurodevelopmental research. For a NHP, marmosets are comparatively small; have a higher reproductive efficiency with respect to gestation, delivery intervals, and litter size; and overall have a shorter life history and development, becoming sexually mature at around 1.5 years of age (
      • Abbott D.H.
      • Barnett D.K.
      • Colman R.J.
      • Yamamoto M.E.
      • Schultz-Darken N.J.
      Aspects of common marmoset basic biology and life history important for biomedical research.
      ). Similar to the rhesus monkey MIA model, poly(ICLC) was used to elicit a maternal immune response during the late first trimester (administered on days 63, 65, and 67), and offspring were studied through adolescence (9 months old). There was a significant increase in inflammatory cytokines, such as tumor necrosis factor α, in poly(I:C)-treated dams, although notable sickness behaviors were not generally observed. As with the rhesus monkey MIA model, there were no immediate effects of MIA on infant health and development. Yet, subtle and sex-specific behavioral differences emerged as MIA-exposed females demonstrated reduced vocalizations when separated from their social group at 8 weeks of age and MIA-exposed males spent more time in a nonsocial chamber in a modified 3-chamber sociability assay at 3.5 months. Furthermore, both male and female MIA-exposed offspring spent less time with a stranger conspecific at 9 months of age than control offspring. Cross-species comparisons between the marmoset and rhesus monkey MIA models may provide additional opportunities to explore neurobiological underpinnings in NHPs prenatally exposed to immune challenge.

      Future Directions

      Sex as a biological variable has been understudied in the MIA model literature, despite mounting evidence in rodent models indicating that male and female offspring exhibit sex-specific trajectories in neurobehavioral development (
      • Coiro P.
      • Pollak D.D.
      Sex and gender bias in the experimental neurosciences: The case of the maternal immune activation model.
      ). The underrepresentation of female offspring in the current NHP MIA models represents critical gaps in our knowledge, which will be the focus of our next cohort of MIA-exposed offspring. Further, while much progress has been made in our understanding of the link between maternal infection and offspring NDD risk, it has become increasingly clear that we currently do not know which pregnancies are vulnerable and which are resilient to prenatal immune challenge. The preclinical MIA model provides a platform to systematically evaluate susceptibility, resilience, and underlying phenotypic heterogeneity in response to prenatal immune challenge. This, in turn, provides a framework for translating results from preclinical models to evidence-based guidelines to improve women’s health and pregnancy outcomes. Although the prenatal environment might be considered a period of vulnerability for NDD-related insults, we consider it to be a time when preventive strategies and therapeutic interventions may be most effective. Given that millions of pregnant women experience infection each year, even a small decrease in risk could have a significant public health effect on NDD outcomes.

      Acknowledgments and Disclosures

      This work was supported by the National Institute of Mental Health (Grant Nos. P50MH106438 and P50MH106438-06 to University of California Davis Conte Center) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant No. P50HD103526 to University of California Davis Medical Investigation of Neurodevelopmental Disorders Institute Intellectual and Developmental Disabilities Research Center).
      We thank collaborators of the University of California Davis Conte Center and Intellectual and Developmental Disabilities Research Center for conversations on the topic, Dr. Cyndi Schumann for providing insightful comments on an early draft of the manuscript, and Anurupa Kar and Felisa Carbajal for assistance in preparing the manuscript.
      The authors report no biomedical financial interests or potential conflicts of interest.

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