scholarly journals Investigating the Effect of Reduced Serotonin Transporter Expression in a Maternal Immune Activation Model of Neurodevelopmental Disorders

2021 ◽  
Author(s):  
◽  
Alexandra Lister
Keyword(s):  
Serotonin Transporter ◽  
Immune Activation ◽  
Neurodevelopmental Disorders ◽  
Allelic Variation ◽  
Autism Spectrum ◽  
Poly I:C ◽  
Supporting Evidence ◽  
Maternal Immune Activation ◽  
Behavioural Effects ◽  
The Impact

<p>Maternal Immune Activation (MIA) during early pregnancy is an established risk factor for the occurrence of neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) and schizophrenia (SCZ) in offspring. Serotonin signalling is also implicated in both ASD and SCZ, in conjunction with a known and extensive influence in neural development. Using a Wistar serotonin transporter (SERT) knockout model to mimic allelic variation in the human serotonin transporter promoter (5‐HTTLPR), this research investigates the impact of full or reduced SERT function on the effect of poly I:C-induced MIA in offspring. Experimental design focuses on ultrasonic vocalisation communication in postnatal day (PND) 7 offspring, followed by genetic expression of the Rac1/Kal7/Disc1 signalosome pathway at PND21 previously implicated in SCZ pathology. Results from behavioural analysis of pups indicate a statistically significant increase in calling and call complexity in pups heterozygous for the SERT (SERT HET) compared to wildtype (WT). When separated by sex, this trend remains consistent however only reaches significance in male offspring. Male SERT HET pups also a significant treatment effect in call complexity, and a significant genotype/treatment interaction which suggests an increased susceptibility to MIA-induced behavioural effects. Additionally, poly I:C exposed pups show increased expression of Disc1, supporting evidence that this pathway may be affected in neurodevelopmental disorders. No genotype and sex effects were observed in signalosome expression; however, this study may be too underpowered to detect these effects. These results suggest that differences between sex and SERT genotype in offspring may modulate the behavioural effects of MIA in rodent models of NDD, with more study required to assess these differences in a molecular context. Furthermore, this study aims to address the overall inconsistency and misrepresentation of statistical methods in MIA models by employing MIA validation tests and linear mixed modelling to account for litter variation. In summary, the research presented in this thesis reports initial evidence suggesting SERT genotype may influence the effect of MIA, however further research is necessary to characterise the effect of genotype on MIA challenge during gestation.</p>

scholarly journals Investigating the Effect of Reduced Serotonin Transporter Expression in a Maternal Immune Activation Model of Neurodevelopmental Disorders

2021 ◽  
Author(s):  
◽  
Alexandra Lister
Keyword(s):  
Serotonin Transporter ◽  
Immune Activation ◽  
Neurodevelopmental Disorders ◽  
Allelic Variation ◽  
Autism Spectrum ◽  
Poly I:C ◽  
Supporting Evidence ◽  
Maternal Immune Activation ◽  
Behavioural Effects ◽  
The Impact

<p>Maternal Immune Activation (MIA) during early pregnancy is an established risk factor for the occurrence of neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) and schizophrenia (SCZ) in offspring. Serotonin signalling is also implicated in both ASD and SCZ, in conjunction with a known and extensive influence in neural development. Using a Wistar serotonin transporter (SERT) knockout model to mimic allelic variation in the human serotonin transporter promoter (5‐HTTLPR), this research investigates the impact of full or reduced SERT function on the effect of poly I:C-induced MIA in offspring. Experimental design focuses on ultrasonic vocalisation communication in postnatal day (PND) 7 offspring, followed by genetic expression of the Rac1/Kal7/Disc1 signalosome pathway at PND21 previously implicated in SCZ pathology. Results from behavioural analysis of pups indicate a statistically significant increase in calling and call complexity in pups heterozygous for the SERT (SERT HET) compared to wildtype (WT). When separated by sex, this trend remains consistent however only reaches significance in male offspring. Male SERT HET pups also a significant treatment effect in call complexity, and a significant genotype/treatment interaction which suggests an increased susceptibility to MIA-induced behavioural effects. Additionally, poly I:C exposed pups show increased expression of Disc1, supporting evidence that this pathway may be affected in neurodevelopmental disorders. No genotype and sex effects were observed in signalosome expression; however, this study may be too underpowered to detect these effects. These results suggest that differences between sex and SERT genotype in offspring may modulate the behavioural effects of MIA in rodent models of NDD, with more study required to assess these differences in a molecular context. Furthermore, this study aims to address the overall inconsistency and misrepresentation of statistical methods in MIA models by employing MIA validation tests and linear mixed modelling to account for litter variation. In summary, the research presented in this thesis reports initial evidence suggesting SERT genotype may influence the effect of MIA, however further research is necessary to characterise the effect of genotype on MIA challenge during gestation.</p>

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

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.

scholarly journals Neurodevelopmental Disorders Induced by Maternal Immune Activation: Toward a Prevention Strategy in the Era of the COVID-19 Pandemic

2020 ◽  
Vol 1 (1) ◽  
pp. 24-26
Author(s):  
Kazuhiro Sakurada ◽  
Yoshihiro Noda
Keyword(s):  
Immune Activation ◽  
Neurodevelopmental Disorders ◽  
Data Science ◽  
Biological Effects ◽  
Global Scale ◽  
Maternal Infection ◽  
Public Health Perspective ◽  
Daily Lives ◽  
Maternal Immune Activation ◽  
The Impact

As of summer 2020, the COVID-19 pandemic is having a major impact on our daily lives on a global scale, forcing us to change to the new normal. However, the effects are not only detrimental to our present socioeconomic conditions but also have the risk of having negative biological effects on our descendants. Of concern is the effect of maternal immune activation following maternal infection with COVID-19 on the fetus’ cerebral nervous system. While we are currently occupied with countering the imminent threats in front of us, we also need to take steps from a public health perspective to reduce the impact of maternal infection on the fetus, especially the risk of neurodevelopmental disorders. However, such a risk can be prevented and managed through the digital transformation of the nation’s health data and the strategic application of sophisticated data science approaches to those big data.

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

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.

scholarly journals Preliminary evidence that maternal immune activation specifically increases diagonal domain volume in the rat brain during early postnatal development

2018 ◽  
Author(s):  
Tobias C. Wood ◽  
Michelle E. Edye ◽  
Michael K. Harte ◽  
Joanna C. Neill ◽  
Eric P. Prinssen ◽  
...  
Keyword(s):  
Rat Brain ◽  
Immune Activation ◽  
Diffusion Tensor ◽  
Ex Vivo ◽  
Morphological Changes ◽  
Female Offspring ◽  
Preliminary Evidence ◽  
Poly I:C ◽  
Maternal Immune Activation ◽  
The Impact

AbstractMaternal immune activation (MIA) is consistently associated with elevated risk for multiple psychiatric disorders in the affected offspring. Related to this, an important goal of our work is to explore the impact of MIA effects across the lifespan. In this context, we recently reported the effects of poly (I:C)-induced MIA at gestational day (GD)15, immediately prior to birth, at GD21 and again at post-natal day (PD)21, providing a systematic assessment of plasma IL-6, body temperature and weight alterations in pregnant rats following poly (I:C) exposure and preliminary evidence for gross morphological changes and microglial neuropathology in both male and female offspring at GD21 and PD21. Here, we sought to complement and extend these data by characterising in more detail the meso-scale impact of gestational poly (I:C) exposure at GD15 on the neuroanatomy of the juvenile (PD21) rat brain using high-resolution, ex vivo anatomical magnetic resonance imaging (MRI) in combination with atlas-based segmentation. Our preliminary data suggest subtle neuroanatomical effects of gestational poly (I:C) exposure (n=10) relative to saline controls (n=10) at this time-point. Specifically, we report here preliminary evidence for a significant increase in the relative volume of the diagonal domain in poly (I:C) offspring (p<0.01; q<0.1), particularly in female offspring. This occurred in the absence of any microstructural alterations as detectable using diffusion tensor imaging (DTI). Longitudinal in vivo studies, informed by the effect sizes from this dataset are now required to establish both the functional relevance and cellular mechanisms of the apparent DD volume increase.

scholarly journals Early or late gestational exposure to maternal immune activation alters neurodevelopmental trajectories in mice: an integrated neuroimaging, behavioural, and transcriptional study

2020 ◽  
Author(s):  
Elisa Guma ◽  
Pedro Bordignon ◽  
Gabriel Allan Devenyi ◽  
Daniel Gallino ◽  
Chloe Anastassiadis ◽  
...  
Keyword(s):  
Immune Activation ◽  
Neurodevelopmental Disorders ◽  
Dorsal Hippocampus ◽  
Early Adulthood ◽  
Sensorimotor Gating ◽  
Cingulate Cortex ◽  
Late Gestation ◽  
Anterior Cingulate ◽  
Poly I:C ◽  
Maternal Immune Activation

Prenatal maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders. How gestational timing of MIA-exposure differentially impacts downstream development remains unclear. Here, we characterize neurodevelopmental trajectories of mice exposed to MIA induced by poly I:C either early (gestational day [GD]9) or late (GD17) in gestation using longitudinal structural magnetic resonance imaging from weaning to adulthood. Early MIA-exposure associated with accelerated brain volume increases in adolescence/early-adulthood that normalized in later adulthood, in regions including the striatum, hippocampus, and cingulate cortex. Similarly, alterations in anxiety, stereotypic, and sensorimotor gating behaviours observed in adolescence normalized in adulthood. In contrast, MIA-exposure in late gestation had less impact on anatomical and behavioural profiles. Using a multivariate technique to relate imaging and behavioural variables for the time of greatest alteration, i.e. adolescence/early adulthood, we demonstrate that variation in anxiety, social, and sensorimotor gating associates significantly with volume of regions including the dorsal and ventral hippocampus, and anterior cingulate cortex. Using RNA sequencing to explore the molecular underpinnings of region-specific alterations in early MIA-exposed mice in adolescence, we observed the most transcriptional changes in the dorsal hippocampus, with regulated genes enriched for fibroblast growth factor regulation, autistic behaviours, inflammatory pathways, and microRNA regulation. This indicates that MIA in early gestation perturbs brain development mechanisms implicated in neurodevelopmental disorders. Our findings demonstrate the power of an integrated hypothesis- and data-driven approach in linking brain-behavioural alterations to the transcriptome to understand how MIA confers risk for major mental illness.

scholarly journals Possible risk of fetal development of autism in pregnant women infected by SARS-CoV-2

2021 ◽  
Vol 29 ◽  
pp. 1-24
Author(s):  
Sayd Douglas Rolim Carneiro Oliveira ◽  
José Eduardo Ribeiro Honório Júnior ◽  
Gislei Aragao
Keyword(s):  
Pregnant Women ◽  
Immune Activation ◽  
Neurodevelopmental Disorders ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
World Health ◽  
Rapid Progression ◽  
Maternal Immune Activation ◽  
Gestational Period ◽  
Health Organization

Introduction. In March 2020, the World Health Organization (WHO) announced the emergence of a global pandemic, COVID-19. A disease triggered by the new coronavirus infection (SARS-CoV-2).  More recent findings indicate that the gestational period makes the mother and her offspring more susceptible to the new coronavirus and the rapid progression to the critical stage of the disease. The maternal organism presents a certain degree of immunological and cardiorespiratory deficiency due to physiological adaptations to the gestational period and, consequently, if affected by prenatal infections caused by viruses, they lead to an exacerbated Maternal Immune Activation (MIA), thus contributing to alterations in maternal-fetal neurogenesis, fetal myelinization, and is directly involved in the pathogenesis of neurodevelopmental disorders in the offspring, especially autism. Objective. This study hypothesizes that maternal COVID-19 infections during pregnancy are a potential risk for the offspring to develop Autism Spectrum Disorder. Conclusion. The exposure to viral infectious agents during the gestational period leads to exacerbated maternal immune activation. It contributes to alterations in maternal-fetal neurogenesis and is directly involved in the pathogenesis of neurodevelopmental disorders, being correlated to the predisposition to affective and psychiatric disorders in the offspring. Therefore, greater attention should be given to the offspring of pregnant women infected by COVID-19, since prenatal infectious processes have a strong correlation with the prevalence of Autistic Spectrum Disorder in the offspring.

scholarly journals GABAergic malfunction underlying maternal immune activation-induced social deficits

2018 ◽  
Author(s):  
Kazuki Okamoto ◽  
Natsuko Hitora-Imamura ◽  
Hiroyuki Hioki ◽  
Yuji Ikegaya
Keyword(s):  
Immune Activation ◽  
Pyramidal Cells ◽  
Social Behaviors ◽  
Underlying Mechanism ◽  
Autism Spectrum ◽  
Anterior Cingulate ◽  
Poly I:C ◽  
Social Deficits ◽  
Social Ability ◽  
Maternal Immune Activation

AbstractSocial deficits are one of the major symptoms of psychiatric disorders, including autism spectrum disorders (ASDs) and schizophrenia. However, the underlying mechanism remains ill-defined. Here, we focused on the anterior cingulate cortex (ACC), a brain region that is related to social behaviors, of mice that received poly(I:C)-induced maternal immune activation. Using whole-cell patch clamp recordings, we found that layer 2/3 pyramidal cells were hyperactive in acute ACC slices prepared from poly(I:C)-treated mice compared to those from saline-treated mice. The hyperexcitation was associated with a reduction in inhibitory synapse activity. Local injection of the GABAA receptor enhancer clonazepam into the ACC of poly(I:C)-treated mice restored the social behaviors of the mice. These results suggest that the balanced excitability of ACC neurons is essential for social ability.

scholarly journals Long-Lasting Impact of Maternal Immune Activation and Interaction With a Second Immune Challenge on Pig Behavior

2020 ◽  
Vol 7 ◽  
Author(s):  
Haley E. Rymut ◽  
Courtni R. Bolt ◽  
Megan P. Caputo ◽  
Alexandra K. Houser ◽  
Adrienne M. Antonson ◽  
...  
Keyword(s):  
Immune Activation ◽  
Social Behaviors ◽  
Combined Effect ◽  
Poly I:C ◽  
Immune Challenge ◽  
Mixed Effect ◽  
Maternal Immune Activation ◽  
Polycytidylic Acid ◽  
Behavioral Disruptions ◽  
The Impact

The combined effects on pig behavior of maternal immune challenge during gestation followed by a second immune challenge later in life have not been studied. Porcine reproductive and respiratory syndrome virus (PRRSV) infection during gestation can elicit maternal immune activation (MIA) yet the interactions with the offspring response to a second immune challenge after birth remains unexplored. Knowledge on the response to viral challenges in rodents has been gained through the use of the viral mimetic polyinosinic-polycytidylic acid (Poly(I:C)), yet the effects of this immune stimulant on pig behavior have not been assessed. This study advances the understanding of the combined effect of MIA and a second immune challenge later in life on female and male pig behavior. Three complementary experiments enabled the development of an effective Poly(I:C) challenge in pigs, and testing the interaction between PRRSV-elicited MIA, Poly(I:C) challenge at 60 days of age, and sex on behaviors. Individual-level observations on sickness, locomotor, and social behaviors were measured 1–3 h after Poly(I:C) challenge. Vomiting, panting, lethargy, walking, laying, playing, and touching behaviors were analyzed using generalized linear mixed effect models. Results indicated that a Poly(I:C) dose of 1 mg/kg within 1 h after injection increased the incidence of laying and sickness behavior. The Poly(I:C) challenge decreased the incidence of locomotor behaviors and activity levels. Pigs exposed to MIA had lower rates of social behaviors such as playing. The combined effect of PRRSV-elicited MIA and Poly(I:C) immune challenge further sensitized the pigs to behavior disruption across sexes including changes in sternal and lateral laying, walking, lethargy, and touching incidence. Notably, the effects of Poly(I:C) immune challenge alone on behaviors tended to be more extreme in males, whereas the effects of Poly(I:C) following MIA tended to be more extreme in females. Our findings demonstrate that MIA and Poly(I:C) affected behaviors, and the viral mimetic effects shortly after injection can offer insights into the prolonged effect of postnatal viral infections on feeding, social interactions and health status. Management practices that reduce the likelihood of gestational diseases and accommodate for behavioral disruptions in the offspring can minimize the impact of MIA.

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