key: cord-0752622-60ie0uuk
authors: Ryan, Amy M.; Bauman, Melissa D.
title: Primate models as a translational tool for understanding prenatal origins of neurodevelopmental disorders associated with maternal infection
date: 2022-03-08
journal: Biol Psychiatry Cogn Neurosci Neuroimaging
DOI: 10.1016/j.bpsc.2022.02.012
sha: 5eed52e4643364a066c09cf80e2f372b4cade220
doc_id: 752622
cord_uid: 60ie0uuk

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 (NDDs). 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 (NHP) 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 NHPs 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 NHP models of maternal infection and discuss future directions for this promising area of research.

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) (1) . 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 (2) . Although most women report experiencing at least one infection during pregnancy (3) , 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, increase the likelihood of offspring NDDs (4) .

Not only is the immune system critical in mediating successful pregnancy (5) , immune signaling molecules, such as cytokines, also play a critical role in fetal brain development (6) . Thus, the complex cascade of changes associated with maternal infection and the subsequent maternal immune response (7) is uniquely positioned to influence the developing fetal brain. Even in the absence of an acute inflammatory event triggered by infection, variation in maternal cytokine levels during pregnancy have been associated with offspring neurobehavioral outcomes, including early alterations in brain growth, functional connectivity, behavioral development (8) (9) (10) (11) (12) , and long-lasting dysregulation of stress response circuitry (13) . Collectively, these studies suggest that changes in 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 maternalplacental-fetal immune environment and to develop evidence-based guidelines to manage infection during pregnancy (14) . 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) (15) 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 sero-epidemiological 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.

The majority of studies investigating prenatal origins of NDDs have focused on schizophrenia (SZ) and autism spectrum disorder (ASD) (16) , though the association between maternal infection may extend to other NDDs (1) . Initial evidence linking maternal infection with SZ stemmed from the observation that birth during the winter and spring months J o u r n a l P r e -p r o o f was associated with an increased risk of SZ, possibly due to seasonal viral exposures (reviewed in (17) ). Subsequent studies utilizing large birth cohorts reported increased risk of SZ in offspring born to women who experienced infections during pregnancy (18) (19) (20) (21) (22) (23) (24) (25) (26) . Likewise, initial associations between maternal infection and ASD were primarily based on case studies following in utero exposure to maternal infections (27) (28) (29) (30) (31) (32) . 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 (33-41). Recent studies also indicate that the magnitude of the maternal immune response also plays a critical role (38), as associations with offspring ASD have been linked to maternal fever episodes (34, 39), particularly episodes not treated with anti-fever medication (35), or when diagnosed in hospitals (36). 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 ).

The association between maternal infection and offspring neurodevelopment is further supported by a growing body of sero-epidemiological studies that utilize archived or prospectively collected maternal biospecimens from mothers of individuals later diagnosed with an NDD. 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 (42-46). Biomarkers of maternal infection, including influenza antibodies (47) , cytokines (48) (49) (50) , and levels of maternal complement components (51) have all been associated with offspring psychosis. Likewise, quantification of cytokines, chemokines, and other inflammatory markers obtained from archived maternal sera (52, 53) and amniotic fluid (54, 55) lends further support to the link between maternal infection and increased ASD risk, though not all studies have found positive associations (56) . Recent efforts have focused on exploring disease-specific maternal inflammatory pathways associated with other NDDs, including ADHD, depression, bipolar disorder and other neuropsychiatric conditions (57) (58) (59) (60) (61) (62) . Collectively, the growing epidemiological literature provides compelling evidence linking the maternal immune response to offspring NDDs, though underlying mechanisms are difficult to ascertain due 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 sero-epidemiological studies.

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 (63, 64) and prompted widespread interest in the MIA model. In spite of significant challenges associated with methodological variability, offspring born to MIAtreated dams exhibit many reproducible changes in brain and behavioral development relevant to human NDDs (65) . The vast majority of MIA models have used rodent model systems to provide foundational knowledge on the neurodevelopmental consequences of MIA exposure (for review, (66) (67) (68) ), though there is increasing interest in J o u r n a l P r e -p r o o f developing MIA models in other species, including ferrets and pigs (69, 70) . 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 US (71), with the majority of NHP studies performed in macaques (72) . We focus this review primarily on the rhesus macaque (Macaca mulatta), but also incorporate the common marmoset (Callithrix jacchus) that is playing an increasing role in gestational research (73) .

NHPs are the closest model to human pregnancy, sharing similarities in placental and pregnancy physiology, maternalfetal 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 described in Tarantal et al (this issue).

3.1 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 (74) and sex differences (75) 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 (76, 77) . 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 (77, 78) . 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 (79), striking differences can be found when comparing the anatomy, cell types and molecular biology of rodent versus primate placentas (80, 81) .

Identifying gestational timepoints 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 mice/rats (18-23 days) is not always straightforward and offspring are also 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 (82) . Rhesus monkey gestation can be divided into first (gestational days, or GD, 0-55), second (GD 56-110) and third (GD 111-165) trimesters that closely parallel stages of human fetal brain development. Peak periods of neurogenesis for subcortical structures, including the amygdala (83) and thalamus (84) , as well as the early stages of neurogenesis for the striatum (85) and hippocampus (86) , 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 (87) . 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 (88) . Although J o u r n a l P r e -p r o o f 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 (89-91).

Regions of the human brain commonly implicated in NDDs are well-developed in the NHP (92) . The prefrontal cortex, for example, has expanded during primate evolution and is considered one of the key regions for regulating social cognition in primates (93, 94) . Cytoarchectonic regions identifiable in human and NHP brains that are not present in rodents bring into question the existence of the homologous prefrontal cortex region in rodents (95, 96) . Likewise, the amygdala exhibits similar patterns of connectivity and nuclei distribution in human and NHPs (97, 98) that differs substantially from rodents (99) . The rhesus monkey exhibits a protracted period of brain and behavioral development uniquely suited to explore the emergence of MIA-induced changes (100) (101) (102) . Pubertal onset for male and female macaques generally begins at 2.5 and 3.5 years, respectively (103, 104) , and coincides with a sensitive period of dramatic neural reorganization and plasticity (105) . 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 (106) . Although the brain of the common marmoset is considerably smaller compared to larger primates, marmosets also share many of the basic neuroanatomical organizational features described above (107) . 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 (108), white matter (109) and the recently released population-based in-vivo standard templates and tools (110) .

Behavioral deficits in rodent MIA models initially focused on "adult onset" changes in behavior (111, 112) , though increasing attention has been paid to the developmental progression of MIA-induced behavioral changes (113) (114) (115) . 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 (116, 117) . Macaques live in large social groups of related animals and, like humans, use vision as their primary sensory modality (118) and rely on facial expressions and body postures for communication (119) . Recent advances in more naturalistic eye-tracking methods have increased our understanding of how monkeys process social information (120) and provide a translational opportunity to human eye tracking studies that have documented changes in individuals with NDDs, including both ASD and SZ (121, 122) . Moreover, rhesus monkeys develop increasingly sophisticated problem-solving skills as they mature, which can be assessed with translationally relevant cognitive paradigms (123, 124) . While rhesus monkeys have traditionally been the standard NHP model species for humans, marmoset social organization and behavior allows for new opportunities for studying social behavior not easily carried out in rhesus monkeys. Marmosets are monkeys that are more distantly related to humans (40mya) than rhesus monkeys (25mya), but like many humans and unlike rhesus monkeys, live in small family groups with pair-bonding and engage in cooperative rearing of young, including paternal and intergenerational sibling care (125, 126) . This social organization may contribute to the tendency for marmosets to perform prosocial behaviors, such as food sharing and imitation (for review, J o u r n a l P r e -p r o o f see (127)). Furthermore, separation of an individual from the family group in an experimental context can reliably serve as a psychosocial stressor to assess reactivity (128) . While their capabilities have not been as widely explored as rhesus macaques, marmosets can perform discrimination tasks early in development (129) and have been used in more complex cognitive paradigms using eye fixations under restraint, using touchscreens (130, 131) , and visual detection and discrimination tasks requiring complex motor behavior (132, 133) .

The greater physical, psychological, and social needs of laboratory housed NHPs is 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 model "of" ASD or SZ towards a more hypothesis-based model "for" examining the effects of maternal inflammation on neural systems relevant to multiple neurodevelopmental conditions (134) . 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 polyinosinic:polycytidylic acid (Poly IC), a synthetic double-stranded RNA molecule that mimics the genetic information for many viruses and is recognized by toll-like receptor 3 (TLR3) or lipopolysaccharide (LPS), the cell-wall component of gram-negative bacteria recognized by TLR4 (135, 136) . 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 nonhuman primate. However, we expect that neurodevelopmental outcomes in the nonhuman primate 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.

Coe and colleagues developed the first NHP model to investigate the impact of prenatal influenza exposure on offspring development (137) . Pregnant monkeys were intranasally exposed to human-derived H3N2 strain of influenza during the early third trimester. Maternal infection was verified, and influenzaexposed 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 grey 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 grey matter reduction was reduced after ICV correction, volumetric decreases were still evident in the frontal and parietal lobes and J o u r n a l P r e -p r o o f 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.

In parallel, Coe and colleagues also developed the first rhesus monkey MIA model using LPS to elicit a maternal immune response in the early third trimester (138) . 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 old, followed by less reactivity during an anxiety assessment at 8-9 months of age. 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 controls at 1 year of age. Although global grey matter did not differ statistically between groups, selective grey 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 LPSexposed monkeys compared to controls. The study provided the first evidence that artificially stimulating the maternal immune response in NHPs results in changes in offspring brain and behavioral development. obtained from the offspring of the dosing cohort at 3.5 years of age 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 prefrontal cortex (DLPFC). Our results show that MIA-treated offspring have a narrower apical dendritic diameter and more oblique dendrites compared to control offspring, and highlighted the frontal cortex as a potentially vulnerable region in NHPs exposed to prenatal immune challenge.

J o u r n a l P r e -p r o o f 4.3.2 1 st versus 2 nd Trimester Exposure Cohort. We then conducted a pilot comparison of NHP offspring born to dams that received three Poly ICLC injections in the late 1 st (N=6) or 2 nd (N=7) trimesters that included an evaluation of offspring behavior (140, 141) , immune (142) , and brain (143) (144) (145) development. Although there were no consistent differences early in development, the MIA 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 with control ones summarized in Table 2 (140) . 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 (141) .

The male MIA-treated offspring from this cohort also underwent in vivo positron emission tomography (PET) scanning at approximately 3.5 years of age using [18F] fluoro-l-m-tyrosine (FMT) to measure presynaptic dopamine levels in the striatum (143) . Analysis of [18F] FMT signal in the striatum showed that MIA-exposed monkeys had a significantly higher

[18F] FMT index of influx as compared with control animals -a hallmark feature of human psychosis (146) . The MIAtreated 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 one year of age, and at four years of age, elevated IL-1b paired with increased production of T-cell helper type (TH)-2 cytokines, IL-4, and IL-13 (142) . Finally, RNA sequencing of prefrontal cortex, 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 (144) . We have also recently replicated the findings of aberrant dendritic morphology in the DLPFC (139), 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.

To systematically explore the developmental trajectory of risk associated with prenatal immune challenge, we have recently generated a third cohort of 1 st 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 MIAexposed animals exhibited volumetric reductions in brain growth throughout development paired with subtle changes in cognitive development (147) . 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 that emerged during adolescence. These findings provide the first longitudinal evidence of early postnatal changes in brain development in MIA-exposed NHPs and J o u r n a l P r e -p r o o f establish a model system to explore the emergence of brain and behavioral changes from birth through late adolescence.

Additional data sets are currently in preparation for publication, including a comprehensive assessment of social and immune system development paired with multimodal neuroimaging.

The recently established marmoset MIA model (148) 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 old (149) . Like in 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 TNF-α in Poly IC-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 old and MIA-exposed males spent more time in a non-social chamber in a modified three-chamber sociability assay at 3.5 months old. Furthermore, both male and female MIA-exposed offspring spent less time with a stranger conspecific at 9 months old than controls. 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.

Sex as a biological variable has been understudied in the MIA model literature, in spite of mounting evidence in rodent models indicating that male and female offspring exhibit sex-specific trajectories in neurobehavioral development (150) . The underrepresentation of female offspring in the current NHP MIA models represents critical gaps in our knowledge that will be the focus of our next cohort of MIA-exposed offspring. Secondly, 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 preventative 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.

The authors report no biomedical financial interests or potential conflicts of interest. 

Although most pregnancies are resilient to prenatal immune challenges, a subset of women exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental disorder.

Biomarkers of maternal inflammation, including cytokines, collected during pregnancy suggest that the maternal immune response is the critical link between maternal infection and altered fetal neurodevelopment.

Cytokines and other immune signaling molecules play critical roles in all stages of fetal brain development. Changes in the maternalfetal immune environment may impact neurodevelopment and lead to long-lasting alteration in brain and behavioral development.

J o u r n a l P r e -p r o o f

Similarities in placental physiology, gestational timelines, preand post-natal brain development and behavioral complexity 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.

Several approaches have been used to activate the nonhuman primate maternal immune response, including exposure to pathogens, such as the influenza virus, or the use of immune activating agents, such as polyinosinic:polycytidylic acid (Poly IC) and lipopolysaccharide (LPS) that elicit an immune response in the absence of an actual pathogen.

Nonhuman primates, including the rhesus macaque (Macaca mulatta) and common marmoset (Callithrix jacchus) provide model systems to explore the impact of maternal immune activation (MIA) on offspring neurodevelopment.

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A resource for the detailed 3D mapping of white matter pathways in the marmoset brain

Marmoset Brain Mapping V3: Population multi-modal standard volumetric and surface-based templates

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

Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring

Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation

Maternal immune activation causes age-and regionspecific changes in brain cytokines in offspring throughout development

Late prenatal immune activation causes hippocampal deficits in the absence of persistent inflammation across aging

Bridging the species gap in translational research for neurodevelopmental disorders

Why primate models matter

Into the Light: The Origin of Anthropoidea

Neuroethology of primate social behavior

Non-invasive Eye Tracking Methods for New World and Old World Monkeys. Frontiers in behavioral neuroscience

A systematic review and metaanalysis of eye-tracking studies in children with autism spectrum disorders

Recent updates of eye movement abnormalities in patients with schizophrenia: A scoping review

Cognitive development in macaques: attentional set-shifting in juvenile and adult rhesus monkeys

Performance norms for a rhesus monkey neuropsychological testing battery: acquisition and long-term performance

The common marmoset genome provides insight into primate biology and evolution

The common marmoset: An overview of its natural history, ecology and behavior

Marmosets: A Neuroscientific Model of Human Social Behavior

Stress reactivity in young marmosets (Callithrix geoffroyi): ontogeny, stability, and lack of concordance among co-twins

Early learning in the common marmoset (Callithrix jacchus): Behavior in the family group is related to preadolescent cognitive performance

Performance of the marmoset monkey on computerized tasks of attention and working memory

Development of a compact and general-purpose experimental apparatus with a touch-sensitive screen for use in evaluating cognitive functions in common marmosets

Active vision in marmosets: a model system for visual neuroscience

Cognitive control of complex motor behavior in marmoset monkeys

A Hypothesis-Based Approach: The Use of Animals in Mental Health Research. NIMH Director's Message

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

In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders

Maternal influenza infection during pregnancy impacts postnatal brain development in the rhesus monkey

Brain enlargement and increased behavioral and cytokine reactivity in infant monkeys following acute prenatal endotoxemia

Preliminary evidence of neuropathology in nonhuman primates prenatally exposed to maternal immune activation

Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring

Maternal immune activation in nonhuman primates alters social attention in juvenile offspring

Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation

Preliminary evidence of increased striatal dopamine in a nonhuman primate model of maternal immune activation

Alterations in Retrotransposition, Synaptic Connectivity, and Myelination Implicated by Transcriptomic Changes Following Maternal Immune Activation in Nonhuman Primates

under review)): Altered dendritic morphology in dorsolateral prefrontal cortex of nonhuman primates prenatally exposed to maternal immune activation

Striatal presynaptic dopamine in schizophrenia, part II: meta-analysis of [(18)F/(11)C]-DOPA PET studies

Maternal Immune Activation during Pregnancy Alters Postnatal Brain Growth and Cognitive Development in Nonhuman Primate Offspring

Advancing Autism Research From Mice to Marmosets: Behavioral Development of Offspring Following Prenatal Maternal Immune Activation

Aspects of common marmoset basic biology and life history important for biomedical research

Sex and gender bias in the experimental neurosciences: the case of the maternal immune activation model