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

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.

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

10.1101/2020.07.02.185363 ◽

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.

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Behavioral Alterations and Decreased Number of Parvalbumin-Positive Interneurons in Wistar Rats after Maternal Immune Activation by Lipopolysaccharide: Sex Matters

International Journal of Molecular Sciences ◽

10.3390/ijms22063274 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3274

Author(s):

Iveta Vojtechova ◽

Kristyna Maleninska ◽

Viera Kutna ◽

Ondrej Klovrza ◽

Klara Tuckova ◽

...

Keyword(s):

Immune Activation ◽

Autism Spectrum ◽

Startle Reaction ◽

Adult Offspring ◽

Behavioral Alterations ◽

Maternal Immune Activation ◽

Brain And Behavior ◽

Communication Impairments ◽

And Behavior ◽

The Brain

Maternal immune activation (MIA) during pregnancy represents an important environmental factor in the etiology of schizophrenia and autism spectrum disorders (ASD). Our goal was to investigate the impacts of MIA on the brain and behavior of adolescent and adult offspring, as a rat model of these neurodevelopmental disorders. We injected bacterial lipopolysaccharide (LPS, 1 mg/kg) to pregnant Wistar dams from gestational day 7, every other day, up to delivery. Behavior of the offspring was examined in a comprehensive battery of tasks at postnatal days P45 and P90. Several brain parameters were analyzed at P28. The results showed that prenatal immune activation caused social and communication impairments in the adult offspring of both sexes; males were affected already in adolescence. MIA also caused prepulse inhibition deficit in females and increased the startle reaction in males. Anxiety and hypolocomotion were apparent in LPS-affected males and females. In the 28-day-old LPS offspring, we found enlargement of the brain and decreased numbers of parvalbumin-positive interneurons in the frontal cortex in both sexes. To conclude, our data indicate that sex of the offspring plays a crucial role in the development of the MIA-induced behavioral alterations, whereas changes in the brain apparent in young animals are sex-independent.

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Transgenerational modification of dopaminergic dysfunctions induced by maternal immune activation

Neuropsychopharmacology ◽

10.1038/s41386-020-00855-w ◽

2020 ◽

Vol 46 (2) ◽

pp. 404-412 ◽

Cited By ~ 1

Author(s):

Ulrike Weber-Stadlbauer ◽

Juliet Richetto ◽

Ramona A. J. Zwamborn ◽

Roderick C. Slieker ◽

Urs Meyer

Keyword(s):

Dna Methylation ◽

Immune Activation ◽

Poly I:C ◽

Mrna Levels ◽

Transgenerational Effects ◽

Ventral Midbrain ◽

Maternal Immune Activation ◽

Brain And Behavior ◽

And Behavior ◽

Generation Offspring

AbstractPrenatal exposure to infectious and/or inflammatory insults is increasingly recognized to contribute to the etiology of psychiatric disorders with neurodevelopmental components. Recent research using animal models suggests that maternal immune activation (MIA) can induce transgenerational effects on brain and behavior, possibly through epigenetic mechanisms. Using a mouse model of MIA that is based on gestational treatment with the viral mimeticpoly(I:C) (= polyriboinosinic-polyribocytidilic acid), the present study explored whether the transgenerational effects of MIA are extendable to dopaminergic dysfunctions. We show that the direct descendants born to poly(I:C)-treated mothers display signs of hyperdopaminergia, as manifested by a potentiated sensitivity to the locomotor-stimulating effects of amphetamine (Amph) and increased expression of tyrosine hydroxylase (Th) in the adult ventral midbrain. In stark contrast, second- and third-generation offspring of MIA-exposed ancestors displayed blunted locomotor responses to Amph and reduced expression of Th. Furthermore, we found increased DNA methylation at the promoter region of the dopamine-specifying factor, nuclear receptor-related 1 protein (Nurr1), in the sperm of first-generation MIA offspring and in the ventral midbrain of second-generation offspring of MIA-exposed ancestors. The latter effect was further accompanied by reduced mRNA levels of Nurr1 in this brain region. Together, our results suggest that MIA has the potential to modify dopaminergic functions across multiple generations with opposite effects in the direct descendants and their progeny. The presence of altered DNA methylation in the sperm of MIA-exposed offspring highlights the possibility that epigenetic processes in the male germline play a role in the transgenerational effects of MIA.

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The Effect of Maternal Immune Activation on Social Play-Induced Ultrasonic Vocalization in Rats

Brain Sciences ◽

10.3390/brainsci11030344 ◽

2021 ◽

Vol 11 (3) ◽

pp. 344

Author(s):

Kinga Gzielo ◽

Agnieszka Potasiewicz ◽

Ewa Litwa ◽

Diana Piotrowska ◽

Piotr Popik ◽

...

Keyword(s):

Immune Activation ◽

Social Play ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Male Rats ◽

Poly I:C ◽

Maternal Immune Activation ◽

Increased Risk ◽

Adolescent Rats ◽

The Impact

Prenatal maternal infection is associated with an increased risk of various neurodevelopmental disorders, including autism spectrum disorders (ASD). Maternal immune activation (MIA) can be experimentally induced by prenatal administration of polyinosinic:polycytidylic acid (poly I:C), a synthetic viral-like double-stranded RNA. Although this MIA model is adopted in many studies, social and communicative deficits, included in the first diagnostic criterion of ASD, are poorly described in the offspring of poly(I:C)-exposed dams. This study aimed to characterize the impact of prenatal poly(I:C) exposure on socio-communicative behaviors in adolescent rats. For this purpose, social play behavior was assessed in both males and females. We also analyzed quantitative and structural changes in ultrasonic vocalizations (USVs) emitted by rats during the play test. Deficits of social play behaviors were evident only in male rats. Males also emitted a significantly decreased number of USVs during social encounters. Prenatal poly(I:C) exposure also affected acoustic call parameters, as reflected by the increased peak frequencies. Additionally, repetitive behaviors were demonstrated in autistic-like animals regardless of sex. This study demonstrates that prenatal poly(I:C) exposure impairs socio-communicative functioning in adolescent rats. USVs may be a useful tool for identifying early autistic-like abnormalities.

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Prospective Analysis of the Effects of Maternal Immune Activation on Rat Cytokines during Pregnancy and Behavior of the Male Offspring Relevant to Schizophrenia

eNeuro ◽

10.1523/eneuro.0249-18.2018 ◽

2018 ◽

Vol 5 (4) ◽

pp. ENEURO.0249-18.2018 ◽

Cited By ~ 12

Author(s):

Brittney R. Lins ◽

Jessica L. Hurtubise ◽

Andrew J. Roebuck ◽

Wendie N. Marks ◽

Nadine K. Zabder ◽

...

Keyword(s):

Immune Activation ◽

Male Offspring ◽

Prospective Analysis ◽

Maternal Immune Activation ◽

And Behavior

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Ketogenic diet improves behaviors in a maternal immune activation model of autism spectrum disorder

PLoS ONE ◽

10.1371/journal.pone.0171643 ◽

2017 ◽

Vol 12 (2) ◽

pp. e0171643 ◽

Cited By ~ 34

Author(s):

David N. Ruskin ◽

Michelle I. Murphy ◽

Sierra L. Slade ◽

Susan A. Masino

Keyword(s):

Autism Spectrum Disorder ◽

Ketogenic Diet ◽

Immune Activation ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Activation Model ◽

Maternal Immune Activation

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Oxytocin and Vasopressin: Mechanisms for Potential Sex Differences Observed in Autism Spectrum Disorders

10.1093/med/9780199744312.003.0018 ◽

2013 ◽

Author(s):

C. Sue Carter ◽

Suma Jacob

Keyword(s):

Autism Spectrum Disorders ◽

Arginine Vasopressin ◽

Protective Factor ◽

Brain Regions ◽

Autism Spectrum ◽

Sexually Dimorphic ◽

Unique Role ◽

Spectrum Disorders ◽

Brain And Behavior ◽

And Behavior

The effects of oxytocin and vasopressin on the brain and behavior can be sexually dimorphic, especially during the course of development (Bales, Kim, et al., 2004; Bales, Pfeifer, et al., 2004; Bales, Plotsky, et al., 2007; Bielsky et al., 2005a; Carter, 2003; Thompson et al., 2006; Yamamoto et al., 2005; Yamamoto et al., 2004). Given the sexual discrepancy observed in autism spectrum disorders (ASDs), these two neuropeptides, oxytocin (OT) and arginine vasopressin (AVP), have received attention for their potential role in ASDs (Green and Hollander, 2010; Insel et al., 1999; Leckman & Herman, 2002; Welch et al., 2005; Winslow, 2005; Young et al., 2002). Changes in either OT or AVP and their receptors could be capable of influencing symptom domains or behaviors associated with ASDs. Arginine vasopressin is androgen dependent in some brain regions (De Vries & Panzica, 2006), and males are more sensitive to AVP, especially during development. We hypothesize here that AVP, which has a unique role in males, must be present in optimal levels to be protective against ASDs. Either excess AVP or disruptions in the AVP system could play a role in development of the traits found in ASDs. In contrast, OT may possibly be secreted in response to adversity, especially in females, serving as a protective factor.

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NEUROBIOLOGICAL UNDERPINNINGS OF LANGUAGE IN AUTISM SPECTRUM DISORDERS

Annual Review of Applied Linguistics ◽

10.1017/s0267190508080021 ◽

2008 ◽

Vol 28 ◽

pp. 128-149 ◽

Cited By ~ 2

Author(s):

Inge-Marie Eigsti ◽

Jillian M. Schuh

Keyword(s):

Cognitive Task ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Behavioral Differences ◽

Brain Organization ◽

Communicative Skills ◽

Complex Cognitive Task ◽

Brain And Behavior ◽

And Behavior ◽

The Brain

As a neurodevelopmental disorder, autism is characterized by impairments and differences at the levels of both brain and behavior. Communicative impairments in autism are a core feature of the disorder, and a rapidly expanding literature is exploring language in autism using the tools of cognitive neuroscience, particularly electroencephalography and brain imaging. Recent research indicates consistent differences in the degree to which language-specific processes are lateralized in the brain, and it also suggests that language impairments are linked to differences in brain structure that may lead to inefficient coordination of activity between different neural assemblies to achieve a complex cognitive task, defined as functional connectivity. We review findings from current work and suggest that neurobiological data are critical in our ability to understand the mechanisms underlying behavioral differences in communicative skills. Going beyond simple dichotomies between delayed versus deviant development, we can use such data to ask whether behavior reflects processes that are merely inefficient or, instead, whether impairments at the behavioral level reflect fundamental differences in brain organization and the networks involved in various tasks.

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Integration of behavioral and biological variables using penalized regression: an application to the maternal immune activation model of autism

10.1101/2020.03.31.018333 ◽

2020 ◽

Author(s):

Cristina Paraschivescu ◽

Susana Barbosa ◽

Thomas Lorivel ◽

Nicolas Glaichenhaus ◽

Laetitia Davidovic

Keyword(s):

Immune Activation ◽

Animal Studies ◽

Penalized Regression ◽

Autism Spectrum ◽

Individual Variability ◽

Poly I:C ◽

Maternal Immune Activation ◽

Biological Variables ◽

Underlying Mechanisms ◽

New Variables

AbstractMaternal immune activation (MIA) during pregnancy increases the odds of developing neuropsychiatric disorders such as autism spectrum disorder (ASD) later in life. In pregnant mice, MIA can be induced by injecting the viral mimic polyinosinic:polycytidylic acid (poly(I:C) to pregnant dams resulting in altered fetal neurodevelopmental and behavioral changes in their progeny. Although the murine MIA model has been extensively studied worldwide, the underlying mechanisms have only been partially elucidated. Furthermore, the murine MIA model suffers from lack of reproducibility, at least in part because it is highly influenced by subtle changes in environmental conditions. In human studies, multivariable (MV) statistical analysis is widely used to control for covariates including sex, age, exposure to environmental factors and many others. We reasoned that animal studies in general, and studies on the MIA model in particular, could therefore benefit from MV analyzes to account for complex phenotype interactions and high inter-individual variability. Here, we used a dataset consisting of 26 variables collected on 67 male pups during the course of several independent experiments on the MIA model. We then analyzed this dataset using penalized regression to identify variables associated with in utero exposure to MIA. In addition to confirming the association between some previously described biological variables and MIA, we identified new variables that could play a role in neurodevelopment alterations. Aside from providing new insights into variable interactions in the MIA model, this study highlights the importance of extending the use of MV statistics to animal studies.

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