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 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 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 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.

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 Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder

2016 ◽  
Author(s):  
Michael V. Lombardo ◽  
Hyang Mi Moon ◽  
Jennifer Su ◽  
Theo D. Palmer ◽  
Eric Courchesne ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Autism Spectrum Disorder ◽  
Translation Initiation ◽  
Immune Activation ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Brain Gene Expression ◽  
Maternal Immune Activation ◽  
Increased Risk

AbstractMaternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates fetal brain gene expression near the end of the first trimester of human gestation in ways relevant to ASD-associated pathophysiology. MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations. MIA also downregulates expression of many genes also known to be persistently downregulated in ASD cortex later in life and which are canonically known for roles in affecting prenatally-late developmental processes at the synapse. Transcriptional and translational programs that are downstream targets of highly ASD-penetrant FMR1 and CHD8 genes are also heavily affected by MIA. MIA strongly upregulates expression of a large number of genes involved in translation initiation, cell cycle, DNA damage, and proteolysis processes that affect multiple key neural developmental functions. Upregulation of translation initiation is common to and preserved in gene network structure with the ASD cortical transcriptome throughout life and has downstream impact on cell cycle processes. The cap-dependent translation initiation gene, EIF4E, is one of the most MIA-dysregulated of all ASD-associated genes and targeted network analyses demonstrate prominent MIA-induced transcriptional dysregulation of mTOR and EIF4E-dependent signaling. This dysregulation of translation initiation via alteration of the Tsc2-mTor-Eif4e-axis was further validated across MIA rodent models. MIA may confer increased risk for ASD by dysregulating key aspects of fetal brain gene expression that are highly relevant to pathophysiology affecting ASD.

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.

scholarly journals Maternal and early postnatal immune activation produce sex-specific effects on autism-like behaviors and neuroimmune function in mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
William A. Carlezon ◽  
Woori Kim ◽  
Galen Missig ◽  
Beate C. Finger ◽  
Samantha M. Landino ◽  
...  
Keyword(s):  
Immune Activation ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Poly I:C ◽  
Inflammatory Factors ◽  
Specific Effects ◽  
Immune System Activation ◽  
Pregnant Mice ◽  
The Brain

AbstractIncreasing evidence suggests a role for inflammation in neuropsychiatric conditions including autism spectrum disorder (ASD), a neurodevelopmental syndrome with higher prevalence in males than females. Here we examined the effects of early-life immune system activation (EIA)—comprising regimens of prenatal, early postnatal, or combined (“two-hit”) immune activation—on the core behavioral features of ASD (decreased social interaction, increased repetitive behavior, and aberrant communication) in C57BL/6J mice. We treated timed-pregnant mice with polyinosinic:polycytidylic acid (Poly I:C) on gestational day 12.5 to produce maternal immune activation (MIA). Some offspring also received lipopolysaccharide (LPS) on postnatal day 9 to produce postnatal immune activation (PIA). EIA produced disruptions in social behavior and increases in repetitive behaviors that were larger in males than in females. Ultrasonic vocalizations (USVs) were altered in both sexes. Molecular studies revealed that EIA also produced prominent sex-specific changes in inflammation-related gene expression in the brain. Whereas both sexes showed increases in pro-inflammatory factors, as reflected by levels of mRNA and protein, expression of anti-inflammatory factors was decreased in males but increased in females. Our findings demonstrate that EIA can produce sex-specific behavioral effects and immune responses in the brain, and identify molecular processes that may contribute to resilience in females.

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