Table 1.

Summary of Nonhuman Primate Models of Maternal Infection and Maternal Immune Activation (MIA)

Studies	Species	Infection, Design, and Timing	Assessments	MIA Offspring Behavioral Development	MIA Offspring Brain Development	MIA Offspring Other Biological Outcomes
Short et al. (138)	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. (139)	Rhesus Macaque	Pregnant 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 combined	Behavioral 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. (40)	Rhesus Macaque	Pregnant 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 offspring	Behavioral 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/A	Dendritic 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. (141); Machado et al. (142); Rose et al. (143); Bauman et al. (144); Page et al. (145); Hanson et al. (K.L. Hanson, Ph.D., et al., unpublished data, November 2020)	Rhesus Macaque	Poly(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 trimester	Behavioral Assessments  Bauman et al. (141) (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. (142) •Eye tracking (first-trimester males) Neuroimaging  Bauman et al. (144) •PET (first- and second-trimester males) Other Outcomes  Rose et al. (143) •Immune system development  Page et al. (145) •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. (147)	Rhesus Macaque	Pregnant 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. (148)	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 offspring	Behavioral 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/A	Physical 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.