scholarly journals Maternal immune activation during pregnancy alters early neurobehavioral development in nonhuman primate offspring

2020 ◽  
Author(s):  
Roza M. Vlasova ◽  
Ana-Maria Iosif ◽  
Amy M. Ryan ◽  
Takeshi Murai ◽  
Tyler A. Lesh ◽  
...  
Keyword(s):  
Immune Response ◽  
Nonhuman Primate ◽  
Immune Activation ◽  
Gray Matter Volume ◽  
Sickness Behavior ◽  
First Trimester ◽  
Strong Immune Response ◽  
Maternal Immune Activation ◽  
Polycytidylic Acid ◽  
Maternal Immune Response

ABSTRACTBackgroundHuman epidemiologic studies have implicated exposure to infectious or inflammatory insults during gestation in the etiology of neurodevelopmental disorders. Rodent models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant brain and behavior development in offspring. The nonhuman primate MIA model provides an opportunity to maximize the translational utility of this model in a species more closely related to humans.MethodsHere we evaluate the effects of MIA on brain and behavioral development in the rhesus monkey (Macaca mulatta). A modified form of the viral mimic, Polyinosinic-polycytidylic acid (PolyIC), was delivered to pregnant rhesus monkeys (n=14) in the late first trimester to stimulate a maternal immune response. Control dams received saline injections at the same gestational time points (n=10) or were untreated (n=4).ResultsMIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature and inflammatory cytokines. MIA-exposed offspring developed species typical milestones and demonstrate subtle changes in early in social development. However, magnetic resonance imaging demonstrated significant gray matter volume reductions in prefrontal and frontal cortices at 6, 12 and 24 months of age.ConclusionsThese findings provide new insights into the emergence of neuropathology in MIA-exposed primates and have implications for the pathophysiology of human psychiatric disorders associated with maternal gestational infection.

scholarly journals M179. ALTERNATED BRAIN AND BEHAVIORAL DEVELOPMENT IN A NONHUMAN PRIMATE MODEL OF MATERNAL IMMUNE ACTIVATION

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S204-S204
Author(s):  
Melissa Bauman ◽  
Amy Ryan ◽  
Ana-Maria Iosif ◽  
Takeshi Murai ◽  
Tyler Lesh ◽  
...  
Keyword(s):  
Immune Response ◽  
Nonhuman Primate ◽  
Immune Activation ◽  
Rhesus Monkeys ◽  
Behavioral Development ◽  
Autism Spectrum ◽  
Maternal Immune Activation ◽  
Maternal Immune Response ◽  
Brain And Behavior ◽  
And Behavior

Abstract Background Children born to women who experience infection during pregnancy have an increased risk of brain disorders with neurodevelopmental origins, including both schizophrenia (SZ) and autism spectrum disorder (ASD). Rodent models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant brain and behavior development in offspring. The nonhuman primate MIA model provides an opportunity to maximize the translational utility of this model in a species more closely related to humans. Our previous pilot study found that rhesus monkeys (Macaca mulatta) born to MIA-treated dams developed behavioral abnormalities and increased striatal dopamine during adolescence. Here we present emerging behavioral outcomes from a larger cohort of MIA-treated nonhuman primates. Methods A modified form of the viral mimic, Polyinosinic-polycytidylic acid (PolyIC), was delivered to a new cohort of pregnant rhesus monkeys (N=14) in the late first trimester (gestational days 43, 44, 46) to stimulate a maternal immune response. Control dams received saline injections at the same gestational time points (N=10) or were untreated (N=4). The offspring are undergoing ongoing comprehensive behavioral evaluations paired with longitudinal neuroimaging to quantify the emergence of brain and behavior pathology associated with prenatal maternal immune challenge. Results MIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature and inflammatory cytokines. Although MIA offspring developed species-typical milestones and showed no overt signs of atypical interactions with mothers or peers early in development, they had significantly smaller gray matter volume in the prefrontal and frontal cortices than control offspring at 6, 12 and 24 months of age (p < 0.05). At 24 months of age, the animals were tested in a reversal learning paradigm that requires a subject to flexibly adjust its behavior when the reward-related contingencies that it has previously learned are reversed. All animals advanced and performed similarly on the training and initial discrimination phases of the test. However, on the first day of the initial reward reversal, the MIA-treated animals more frequently failed to make a choice as compared to controls (Wilcoxon two-sample test p-value = .005). These emerging data suggest that MIA-treated animals exhibit subtle impairments in cognitive processing. Additional assessments social and cognitive development, including non-invasive eye tracking data, will be presented to further explore the impact of MIA on primate behavioral development. Discussion These findings provide new insights into the emergence of brain pathology in MIA-exposed primates and have implications for the developmental pathophysiology of human psychiatric disorders associated with maternal gestational infection.

scholarly journals Hidden Talents: Poly (I:C)-induced maternal immune activation improves mouse visual discrimination performance and reversal learning in a sex-dependent manner.

2021 ◽  
Author(s):  
Xin Zhao ◽  
Hieu Tran ◽  
Holly DeRose ◽  
Ryland C Roderick ◽  
Amanda C Kentner
Keyword(s):  
Reversal Learning ◽  
Immune Activation ◽  
Visual Discrimination ◽  
Early Life ◽  
Discrimination Performance ◽  
Poly I:C ◽  
Dependent Manner ◽  
Negative Consequences ◽  
Maternal Immune Activation ◽  
Polycytidylic Acid

While there is a strong focus on the negative consequences of maternal immune activation (MIA) on the developing brain, very little attention is directed towards potential advantages of early life challenges. In this study we utilized a polyinosine-polycytidylic acid (poly(I:C)) MIA model to test visual discrimination (VD) and reversal learning (RL) in mice using touchscreen technology. Significant sex differences emerged in that MIA improved the latency for males to make a correct choice in the VD task while females reached criterion sooner, made fewer errors and utilized fewer correction trials in RL compared to saline-treated controls. These surprising improvements were accompanied by the sex-specific upregulation of several neural markers critical to cognitive functioning (e.g., Gabrg2, Grin1, Grin2b, Htr2a, Chrm1, Prkca, and Camk2a mRNA in prefrontal cortex (PFC)), indicative of compensatory plasticity in response to the MIA challenge. In contrast, when exposed to a "two-hit" stress model (MIA combined with loss of the social component of environmental enrichment (EE)), mice showed no evidence of anhedonia but required an increased number of PD and RL correction trials. These animals also had significant reductions of CamK2a mRNA in the PFC. Appropriate functioning of synaptic plasticity, via mediators such as this protein kinase and others, are critical for behavioral flexibility. Although EE has been implicated in delaying the appearance of symptoms associated with certain brain disorders, these findings are in line with evidence that it also makes individuals more vulnerable to its loss. Overall, with the right "dose", early life stress exposure can confer at least some functional advantages, which are lost when the number or magnitude of these exposures become too great.

scholarly journals Variability in PolyIC induced immune response: Implications for preclinical maternal immune activation models

2018 ◽  
Vol 323 ◽  
pp. 87-93 ◽  
Author(s):  
Milo Careaga ◽  
Sandra L. Taylor ◽  
Carolyn Chang ◽  
Alex Chiang ◽  
Katherine M. Ku ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Activation ◽  
Maternal Immune Activation

scholarly journals Poly (I:C)-induced maternal immune activation modifies ventral hippocampal regulation of stress reactivity: prevention by environmental enrichment

2021 ◽  
Author(s):  
Xin Zhao ◽  
Ruqayah Mohammed ◽  
Hieu Tran ◽  
Mary Erickson ◽  
Amanda C. Kentner
Keyword(s):  
Animal Models ◽  
Dentate Gyrus ◽  
Immune Activation ◽  
Maternal Care ◽  
Environmental Enrichment ◽  
Poly I:C ◽  
Receptor Protein ◽  
List Type ◽  
Maternal Immune Activation ◽  
Polycytidylic Acid

AbstractEnvironmental enrichment (EE) has been successfully implemented in human rehabilitation settings, including demonstrated benefits for children with autism. However, the mechanisms underlying its success are not understood. Incorporating components of EE protocols into our animal models allows for the exploration of these mechanisms and their role in mitigation. Using a mouse model of maternal immune activation (MIA), the present study explored disruptions in social behavior and associated hypothalamic pituitary adrenal (HPA) axis functioning, and whether a supportive environment could prevent these effects. We show that prenatal immune activation of toll-like receptor 3, by the viral mimetic polyinosinic-polycytidylic acid (poly(I:C)), led to disrupted maternal care in that dams built nests of poorer quality, an effect corrected by EE housing. Standard housed male and female MIA mice engaged in higher rates of repetitive rearing and had lower levels of social interaction, alongside sex-specific expression of several ventral hippocampal neural stress markers (e.g., corticotropin releasing hormone (Crh) and Crh receptor 1, glucocorticoid receptor, oxytocin receptor, protein kinase C and Camk2a mRNA). Moreover, MIA males had delayed recovery of plasma corticosterone in response to a novel social encounter. Enrichment housing, likely mediated by improved maternal care, protected against these MIA-induced effects. We also evaluated c-Fos immunoreactivity associated with the novel social experience and found MIA to decrease neural activation in the dentate gyrus. Activation in the hypothalamus, including the suprammamillary nucleus (an important region for social novelty) was blunted in EE housed animals, suggesting that the putative circuits modulating social behaviors may be different between standard and complex housing environments. Gestational poly (I:C) and EE also altered gene expression of stress and synaptic plasticity markers in the prefrontal cortex and hypothalamus. These data demonstrate that augmentation of the environment supports parental care and offspring safety/security, which can offset effects of early health adversity by buffering HPA dysregulation.Highlights- Environmental enrichment (EE) protocols are used clinically to promote rehabilitation- Use of EE in animal models may identify mechanisms underlying clinical successes- Maternal immune activation (MIA) decreased social engagement; this effect was blocked by EE- MIA reduced c-Fos activation in the dentate gyrus, while EE reduced activation in the hypothalamus, in response to social stimuli- EE inhibited MIA-induced HPA dysregulation in ventral hippocampus

Maternal immune activation induced by lipopolysaccharide triggers immune response in pregnant mother and fetus, and induces behavioral impairment in adult rats

2018 ◽  
Vol 100 ◽  
pp. 71-83 ◽  
Author(s):  
Lutiana Roque Simões ◽  
Gustavo Sangiogo ◽  
Michael Hikaru Tashiro ◽  
Jaqueline S. Generoso ◽  
Cristiano Julio Faller ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Activation ◽  
Pregnant Mother ◽  
Behavioral Impairment ◽  
Adult Rats ◽  
Maternal Immune Activation

Alternated Neurodevelopment and Immune Function a Nonhuman Primate Model of Maternal Immune Activation

2020 ◽  
Vol 87 (9) ◽  
pp. S251
Author(s):  
Melissa Bauman ◽  
Ana-Maria Iosif ◽  
Cameron Carter ◽  
A. Kimberley McAllister ◽  
Judy Van de Water ◽  
...  
Keyword(s):  
Immune Function ◽  
Nonhuman Primate ◽  
Immune Activation ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Maternal Immune Activation

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

2021 ◽  
Vol 12 ◽  
Author(s):  
Danielle Santana-Coelho ◽  
Donna Layne-Colon ◽  
Roslyn Valdespino ◽  
Corinna C. Ross ◽  
Suzette D. Tardif ◽  
...  
Keyword(s):  
Social Behavior ◽  
Immune Activation ◽  
Large Body ◽  
Autism Spectrum ◽  
Rodent Models ◽  
Primate Model ◽  
Maternal Immune Activation ◽  
Polycytidylic Acid ◽  
Experimental Treatments ◽  
Development Assessment

Understanding the mechanism(s) by which maternal immune activation (MIA) during gestation may disrupt neurodevelopment and increase the susceptibility for disorders such as autism spectrum disorder (ASD) or schizophrenia is a critical step in the development of better treatments and preventive measures. A large body of literature has investigated the pathophysiology of MIA in rodents. However, a translatability gap plagues pre-clinical research of complex behavioral/developmental diseases and those diseases requiring clinical diagnosis, such as ASD. While ideal for their genetic flexibility, vast reagent toolkit, and practicality, rodent models often lack important elements of ethological validity. Hence, our study aimed to develop and characterize the prenatal MIA model in marmosets. Here, we adapted the well-characterized murine maternal immune activation model. Pregnant dams were administered 5 mg/kg poly-L-lysine stabilized polyinosinic-polycytidylic acid (Poly ICLC) subcutaneously three times during gestation (gestational day 63, 65, and 67). Dams were allowed to deliver naturally with no further experimental treatments. After parturition, offspring were screened for general health and vigor, and individual assessment of communication development and social behavior was measured during neonatal or adolescent periods. Similar to rodent models, offspring subjected to MIA exhibited a disruption in patterns of communication during early development. Assessment of social behavior in a marmoset-modified 3-chamber test at 3 and 9 months of age revealed alterations in social behavior that, in some instances, was sex-dependent. Together, our data indicate that marmosets are an excellent non-human primate model for investigating the neurodevelopmental and behavioral consequences of exposure to prenatal challenges, like MIA. Additional studies are necessary to more completely characterize the effect of prenatal inflammation on marmoset development and explore therapeutic intervention strategies that may be applicable in a clinical setting.

scholarly journals Adolescent THC Treatment Does Not Potentiate the Behavioral Effects in Adulthood of Maternal Immune Activation

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3503
Author(s):  
Todd M. Stollenwerk ◽  
Cecilia J. Hillard
Keyword(s):  
Immune Activation ◽  
Synergistic Effects ◽  
Acoustic Startle ◽  
Acoustic Startle Reflex ◽  
Behavioral Effects ◽  
Poly I:C ◽  
Adult Males ◽  
Maternal Immune Activation ◽  
Polycytidylic Acid ◽  
Increased Risk

Both in utero exposure to maternal immune activation and cannabis use during adolescence have been associated with increased risk for the development of schizophrenia; however, whether these exposures exert synergistic effects on brain function is not known. In the present study, mild maternal immune activation (MIA) was elicited in mice with prenatal exposure to polyinosinic-polycytidylic acid (poly(I:C)), and ∆9-tetrahydrocannabinol (THC) was provided throughout adolescence in cereal (3 mg/kg/day for 5 days). Neither THC nor MIA pretreatments altered activity in assays used to characterize hyperdopaminergic states in adulthood: amphetamine hyperlocomotion and prepulse inhibition of the acoustic startle reflex. Adolescent THC treatment elicited deficits in spatial memory and enhanced spatial reversal learning in adult female mice in the Morris water maze, while exposure to MIA elicited female-specific deficits in fear extinction learning in adulthood. There were no effects in these assays in adult males, nor were there interactions between THC and MIA in adult females. While doses of poly(I:C) and THC were sufficient to elicit behavioral effects, particularly relating to cognitive performance in females, there was no evidence that adolescent THC exposure synergized with the risk imposed by MIA to worsen behavioral outcomes in adult mice of either sex.

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