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

Ryan, Amy; Bauman, Melissa D.

doi:10.1016/j.bpsc.2022.02.012

Cited by 7 publications

(3 citation statements)

References 145 publications

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“…In fact, many female-biased, ASD-upregulated genes in both species were also microglial markers, and among genes identified as female-biased in either species (N = 249), genes that were also upregulated in ASD (N = 66) were enriched for numerous cytokine- and immune-related pathways (p < 0.05) (Supplementary Table 14). This bolsters previous work on rhesus macaque models of maternal immune activation-associated neurodevelopmental disorders (which include ASD) (58, 59).…”

Section: Resultssupporting

confidence: 74%

Evolutionary and biomedical implications of sex differences in the primate brain transcriptome

DeCasien

Chiou

Testard

et al. 2022

Preprint

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Humans exhibit sex differences in the prevalence of many neurodevelopmental and neurodegenerative conditions. To better understand the translatability of a critical nonhuman primate model, the rhesus macaque, we generated one of the largest multi-brain region bulk transcriptional datasets for this species and characterized sex-biased gene expression patterns. We demonstrate that these patterns are similar to those in humans and are associated with overlapping regulatory mechanisms, biological processes, and genes implicated in sex-biased human disorders, including autism. We also show that sex-biased genes exhibit greater genetic variance for expression and more tissue-specific expression patterns, which may facilitate the rapid evolution of sex-biased genes. Our findings provide insights into the biological mechanisms underlying sex-biased disease and validate the rhesus macaque model for the study of these conditions.

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Section: Resultssupporting

confidence: 74%

Evolutionary and biomedical implications of sex differences in the primate brain transcriptome

DeCasien

Chiou

Testard

et al. 2022

Preprint

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“…An important recent development in the investigation of neuroimmune mechanisms of altered neurodevelopment is the emergence of a nonhuman primate (NHP) MIA model. This model offers unique advantages due to the increased similarity to human brain structure and function, cognition and social behavior 30 . Initial studies using the NHP MIA model revealed changes in species-typical behavioral development 31,32 and long-term alterations in the immune responses of offspring born to MIA-exposed dams 33 .…”

Section: Introductionmentioning

confidence: 99%

Extracellular free water elevations are associated with brain volume and maternal cytokine response in a longitudinal nonhuman primate maternal immune activation model

et al. 2023

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Maternal infection has emerged as an important environmental risk factor for neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Animal model systems of maternal immune activation (MIA) suggest that the maternal immune response plays a signi cant role in the neurodevelopment and behavioral outcomes of offspring. Extracellular free water is a measure of freely diffusing water in the brain that may be associated with neuroin ammation and impacted by MIA. The present study evaluates the brain diffusion characteristics of male rhesus monkeys (Macaca mulatta) born to MIA-exposed dams (n = 14) treated with a modi ed form of the viral mimic polyinosinic:polycytidylic acid at the end of the rst trimester. Control dams received saline injections at the end of the rst trimester (n = 10) or were untreated (n = 4). Offspring underwent diffusion MRI scans at 6, 12, 24, 36, and 45 months of age. Offspring born to MIA-exposed dams showed signi cantly increased extracellular free water in cingulate cortex gray matter starting as early as 6 months of age and persisting through 45 months. Additionally, offspring gray matter free water in this region was signi cantly correlated with the magnitude of the maternal IL-6 response in the MIA-exposed dams. These ndings provide strong evidence for the construct validity of the NHP MIA model as a system of relevance for investigations of the pathophysiology of human neurodevelopmental psychiatric disorders. Elevated free water in individuals exposed to immune activation in utero could represent an early marker of a perturbed or vulnerable neurodevelopmental trajectory.

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“…Research on rodents and nonhuman primates has provided key insights into the downstream effects of MIA in the exposed offspring [43]. While this review focuses on studies performed in rodents, there is also a very strong nonhuman primate evidence in this field (refer to these reviews for more information [44][45][46]). Studies in rodents generally induce MIA with various inflammatory agents, including poly I:C, the bacterial endotoxin lipopolysaccharide (LPS), human influenza virus, and others [43,47,48].…”

Section: Mia With Poly I:c: Insights From Rodent Modelsmentioning

confidence: 99%

The Outcomes of Maternal Immune Activation Induced with the Viral Mimetic Poly I:C on Microglia in Exposed Rodent Offspring

Loewen¹,

Chavesa²,

Murray³

et al. 2023

Dev Neurosci

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Maternal immune activation (MIA) can result from a variety of maternal inflammatory factors, including metabolic disorders, nutritional deficits, infections, and psychosocial stress. MIA has been consistently recognized as a major risk factor for neurodevelopmental disorders, and this association seems to be especially important for viral infections, as viral exposure during pregnancy was associated with a higher risk of developing neurodevelopmental disorders, such as schizophrenia. In MIA, the gestational parent’s inflammatory response to an immune stimulus alters or interrupts fetal development, triggering neurodevelopmental consequences. As MIA can occur in any pregnancy it is important to understand the many factors at play that contribute to altered brain development in the offspring, especially considering recent global events such as the COVID-19 pandemic. The underlying mechanisms by which MIA results in deleterious outcomes are not yet clear, but due to the inflammatory response it initiates, it is becoming apparent that microglia are critically involved. Through investigation of MIA animal models, the role of microglia in this field is becoming more evident. Compelling evidence from animal models indicates that MIA can disrupt synaptic pruning, neuronal progenitor cell proliferation /differentiation, oligodendrogenesis and more. Microglia appear as an active player, assisting these neural-related functions during healthy development, but also mediating MIA-induced disturbances in these critical processes when neurodevelopment is challenged. The present review illustrates this complex web by reviewing recent literature, focusing on the outcomes of MIA resulting from viral mimetic poly I:C in rodents, to provide a clear description of how MIA impacts microglial functions and what this means for the offspring’s neurodevelopment. Moreover, we discuss the possible implications of the COVID-19 pandemic on the neurodevelopment of the current and next generations in the frame of MIA models and propose some putative pharmacological and non-pharmacological approaches to prevent or attenuate MIA consequences.

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

Cited by 7 publications

References 145 publications

Evolutionary and biomedical implications of sex differences in the primate brain transcriptome

Evolutionary and biomedical implications of sex differences in the primate brain transcriptome

Extracellular free water elevations are associated with brain volume and maternal cytokine response in a longitudinal nonhuman primate maternal immune activation model

The Outcomes of Maternal Immune Activation Induced with the Viral Mimetic Poly I:C on Microglia in Exposed Rodent Offspring

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