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

eNeuro ◽  
2018 ◽  
Vol 5 (4) ◽  
pp. ENEURO.0249-18.2018 ◽  
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

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 VEGF Treatment Ameliorates Depression-Like Behavior in Adult Offspring after Maternal Immune Activation

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1048
Author(s):  
Spyridon Sideromenos ◽  
Claudia Lindtner ◽  
Alice Zambon ◽  
Orsolya Horvath ◽  
Angelika Berger ◽  
...  
Keyword(s):  
Immune Activation ◽  
Therapeutic Potential ◽  
Preference Test ◽  
Tail Suspension Test ◽  
Vegf Receptor ◽  
Maternal Immune Activation ◽  
Extracellular Signal ◽  
Sucrose Preference Test ◽  
And Behavior ◽  
Endothelial Growth Factor

Maternal immune activation (MIA) during pregnancy impacts offspring neurodevelopmental trajectories and induces lifelong consequences, including emotional and cognitive alterations. Using the polyinosinic:polycytidilic acid (PIC) MIA model we have previously demonstrated enhanced depression-like behavior in adult MIA offspring, which was associated with reduced expression of the vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) in the hippocampus. Since VEGF mediates the effects of various antidepressant agents, we here set out to explore whether VEGF administration could rescue the depression-like behavioral deficits in MIA offspring. To test our hypothesis, control and MIA offspring were intracerebroventricularly (i.c.v.) infused with either VEGF or vehicle solution and depression-related behavior was assessed in the sucrose preference test (SPT) and the tail suspension test (TST). As a surrogate of VEGF activity, the phosphorylation of the extracellular signal-regulated kinase (ERK) in hippocampus was quantified. We found that VEGF treatment reduced depression-related behavioral despair in the TST in MIA offspring but had no effect on anhedonia-like behavior in the SPT. While VEGF administration induced the phosphorylation of ERK in the hippocampus of control offspring, this effect was blunted in the MIA offspring. We conclude that VEGF administration, at the dosage tested, beneficially affects some aspects of the depression-like phenotype in the adult MIA offspring, inviting further studies using different dosage regimes to further explore the therapeutic potential of VEGF treatment in MIA-related changes in brain function and behavior.

scholarly journals Transgenerational modification of dopaminergic dysfunctions induced by maternal immune activation

2020 ◽  
Vol 46 (2) ◽  
pp. 404-412 ◽  
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.

scholarly journals Maternal Immune Activation Sensitizes Male Offspring Rats to Lipopolysaccharide-Induced Microglial Deficits Involving the Dysfunction of CD200–CD200R and CX3CL1–CX3CR1 Systems

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1676
Author(s):  
Katarzyna Chamera ◽  
Magdalena Szuster-Głuszczak ◽  
Ewa Trojan ◽  
Agnieszka Basta-Kaim
Keyword(s):  
Adult Male ◽  
Immune Activation ◽  
Sensorimotor Gating ◽  
Male Offspring ◽  
Sprague Dawley ◽  
Second Hit ◽  
Maternal Immune Activation ◽  
Lps Challenge ◽  
Life Challenges ◽  
Sprague Dawley Rats

Early life challenges resulting from maternal immune activation (MIA) may exert persistent effects on the offspring, including the development of psychiatric disorders, such as schizophrenia. Recent evidence has suggested that the adverse effects of MIA may be mediated by neuron–microglia crosstalk, particularly CX3CL1–CX3CR1 and CD200–CD200R dyads. Therefore, the present study assessed the behavioural parameters resembling schizophrenia-like symptoms in the adult male offspring of Sprague-Dawley rats that were exposed to MIA and to an additional acute lipopolysaccharide (LPS) challenge in adulthood, according to the “two-hit” hypothesis of schizophrenia. Simultaneously, we aimed to clarify the role of the CX3CL1–CX3CR1 and CD200–CD200R axes and microglial reactivity in the brains of adult offspring subjected to MIA and the “second hit” wit LPS. In the present study, MIA generated a range of behavioural changes in the adult male offspring, including increased exploratory activity and anxiety-like behaviours. The most intriguing finding was observed in the prepulse inhibition (PPI) test, where the deficit in the sensorimotor gating was age-dependent and present only in part of the rats. We were able to distinguish the occurrence of two groups: responsive and non-responsive (without the deficit). Concurrently, based on the results of the biochemical studies, MIA disrupted mainly the CD200–CD200R system, while the changes of the CX3CL1–CX3CR1 axis were less evident in the frontal cortex of adult non-responsive offspring. MIA markedly affected the immune regulators of the CD200–CD200R pathway as we observed an increase in cortical IL-6 release in the responsive group and IL-4 in the non-responsive offspring. Importantly, the “second hit” generated disturbances at the behavioural and biochemical levels mostly in the non-responsive adult animals. Those offspring were characterized both by disturbed PPI and “priming” microglia. Altogether, the exposure to MIA altered the immunomodulatory mechanisms, including the CD200–CD200R axis, in the brain and sensitized animals to subsequent immunological challenges, leading to the manifestation of schizophrenia-like alterations.

scholarly journals Got Milk? Maternal immune activation during the mid-lactational period affects nutritional milk quality and adolescent offspring sensory processing in male and female rats

2022 ◽  
Author(s):  
Holly DeRosa ◽  
Hieu Tran ◽  
Amanda C Kentner
Keyword(s):  
Animal Models ◽  
Immune Activation ◽  
Maternal Care ◽  
Life Stress ◽  
Early Life ◽  
Early Life Stress ◽  
Female Rats ◽  
Maternal Immune Activation ◽  
Adolescent Offspring ◽  
And Behavior

The neonatal environment requires a high level of maternal demand in terms of both breastfeeding and other forms of maternal care. Previous studies have underscored the importance of these maternal factors on offspring development and behavior. However, their contribution as dynamic variables in animal models of early life stress are often overlooked. In the present study, we show that lipopolysaccharide (LPS)-induced maternal immune activation (MIA) on postnatal day (P)10 immediately elevated milk corticosterone concentrations, which recovered by P11. In contrast, both milk triglyceride and percent creamatocrit values demonstrated a prolonged decrease following inflammatory challenge. Sustained inflammatory-induced changes to the nutritional quality of milk were also evidenced by its composition of microbial communities associated with inefficient energy and lipid metabolism. Nutritional deficits in early development have been associated with metabolic dysfunction later in life. Indeed, MIA-associated changes in the nutritional profile of milk were reflected by increased adolescent offspring bodyweights. While MIA did not decrease maternal care quality, there was a significant compensatory increase in maternal licking and grooming the day that followed the inflammatory challenge. However, this did not protect against disrupted neonatal huddling or later-life alterations in sensorimotor gating and mechanical allodynia in MIA offspring. Animal models of early life stress can impact both parents and their offspring. One mechanism that can mediate the effects of such stressors is changes to maternal lactation quality which our data show can confer multifaceted and compounding effects on offspring physiology and behavior.

scholarly journals Impact of Weaning and Maternal Immune Activation on the Metabolism of Pigs

2021 ◽  
Vol 8 ◽  
Author(s):  
Bruce R. Southey ◽  
Courtni R. Bolt ◽  
Haley E. Rymut ◽  
Marissa R. Keever ◽  
Alexander V. Ulanov ◽  
...  
Keyword(s):  
Amino Acid ◽  
Immune Activation ◽  
Behavior Disorders ◽  
Pentose Phosphate ◽  
Mass Spectrometry Analysis ◽  
Gas Chromatography Mass Spectrometry ◽  
Maternal Immune Activation ◽  
And Behavior ◽  
The Impact

Weaning wields environmental, social, and nutritional stresses that are detectable in the blood metabolite levels of the offspring. Prenatal stress in the form of maternal immune activation (MIA) in response to infection, which is associated with health and behavior disorders, also elicits prolonged changes in blood and brain cytokine and metabolite levels of the offspring. The goal of this study was to investigate the effects of weaning and MIA on the offspring’s liver function to advance the understanding of the impact of stressors on peripheral and central nervous systems, physiology, and health. Gas chromatography–mass spectrometry analysis was used to compare the level of hepatic metabolites from 22-day-old pigs (n = 48) evenly distributed among weaning (nursed or weaned), viral MIA exposure (yes or no), and sexes. Weaning effects were detected on 38 metabolites at p-value < 0.05 (28 metabolites at FDR p-value < 0.05), and sex-dependent MIA effects were detected on 11 metabolites. Multiple intermediate and final products of the enriched (FDR p-value < 0.05) glycolysis and gluconeogenesis and pentose phosphate pathways were over-abundant in nursed relative to weaned pigs. The enriched pathways confirm the impact of weaning on hepatic metabolic shift, oxidative stress, and inflammation. Higher levels of the glucogenic amino acid histidine are observed in pigs exposed to MIA relative to controls, suggesting that the role of this metabolite in modulating inflammation may supersede the role of this amino acid as an energy source. The lower levels of cholesterol detected in MIA pigs are consistent with hypocholesterolemia profiles detected in individuals with MIA-related behavior disorders. Our findings underline the impact of weaning and MIA stressors on hepatic metabolites that can influence peripheral and central nervous system metabolic products associated with health and behavior disorders.

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

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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