Maternal immune activation alters adult behavior, intestinal integrity, gut microbiota and the gut inflammation

AbstractA body of epidemiological literature has suggested an association between prenatal infection, subsequent maternal immune activation (MIA), and later risk of schizophrenia. These epidemiological studies have inspired preclinical research using rodent and primate models of prenatal infection and MIA. The findings from these preclinical studies indicate that severe infection and immune activation during pregnancy can negatively impact offspring brain development and impair adult behavior. This review aims to summarize the major epidemiological and preclinical findings addressing the connection between prenatal infection and immune activation and later risk of developing schizophrenia, as well as the more limited literature addressing the mechanisms by which this gestational insult might affect offspring neurodevelopment. Finally, directions for future research will be discussed.

Maternal Immune Activation Causes Social Behavior Deficits and Hypomyelination in Male Rat Offspring with an Autism-Like Microbiota Profile

Brain Sciences ◽

10.3390/brainsci11081085 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1085

Author(s):

Gilbert Aaron Lee ◽

Yen-Kuang Lin ◽

Jing-Huei Lai ◽

Yu-Chun Lo ◽

Yu-Chen S. H. Yang ◽

...

Keyword(s):

Social Behavior ◽

Gut Microbiota ◽

Immune Activation ◽

Repetitive Behavior ◽

Fecal Microbiota ◽

Autism Spectrum ◽

Male Rat ◽

Maternal Immune Activation ◽

Rat Offspring ◽

Microbial Dysbiosis

Maternal immune activation (MIA) increases the risk of autism spectrum disorder (ASD) in offspring. Microbial dysbiosis is associated with ASD symptoms. However, the alterations in the brain–gut–microbiota axis in lipopolysaccharide (LPS)-induced MIA offspring remain unclear. Here, we examined the social behavior, anxiety-like and repetitive behavior, microbiota profile, and myelination levels in LPS-induced MIA rat offspring. Compared with control offspring, MIA male rat offspring spent less time in an active social interaction with stranger rats, displayed more anxiety-like and repetitive behavior, and had more hypomyelination in the prefrontal cortex and thalamic nucleus. A fecal microbiota analysis revealed that MIA offspring had a higher abundance of Alistipes, Fusobacterium, and Ruminococcus and a lower abundance of Coprococcus, Erysipelotrichaies, and Actinobacteria than control offspring, which is consistent with that of humans with ASD. The least absolute shrinkage and selection operator (LASSO) method was applied to determine the relative importance of the microbiota, which indicated that the abundance of Alistipes and Actinobacteria was the most relevant for the profile of defective social behavior, whereas Fusobacterium and Coprococcus was associated with anxiety-like and repetitive behavior. In summary, LPS-induced MIA offspring showed an abnormal brain–gut–microbiota axis with social behavior deficits, anxiety-like and repetitive behavior, hypomyelination, and an ASD-like microbiota profile.

Maternal Immune Activation Alters Adult Behavior, Gut Microbiome and Juvenile Brain Oscillations in Ferrets

eNeuro ◽

10.1523/eneuro.0313-18.2018 ◽

2018 ◽

Vol 5 (5) ◽

pp. ENEURO.0313-18.2018 ◽

Cited By ~ 9

Author(s):

Yuhui Li ◽

Supritha R. Dugyala ◽

Travis S. Ptacek ◽

John H. Gilmore ◽

Flavio Frohlich

Keyword(s):

Immune Activation ◽

Gut Microbiome ◽

Brain Oscillations ◽

Adult Behavior ◽

Maternal Immune Activation

Sensitization and Tolerance to Antipsychotics in Rats Using the Maternal Immune Activation Model

PsycEXTRA Dataset ◽

10.1037/e615912013-001 ◽

2013 ◽

Author(s):

Shinnyi Chou ◽

Qing Shu ◽

Ming Li

Keyword(s):

Immune Activation ◽

Activation Model ◽

Maternal Immune Activation

Maternal immune activation in rats attenuates the excitability of monoamine-secreting neurons in adult offspring in a sex-specific way

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2020.12.002 ◽

2020 ◽

Author(s):

Kristina Csatlosova ◽

Eszter Bogi ◽

Barbora Durisova ◽

Daniil Grinchii ◽

Ruslan Paliokha ◽

...

Keyword(s):

Immune Activation ◽

Adult Offspring ◽

Maternal Immune Activation

Viral model of maternal immune activation alters placental AMPK and mTORC1 signaling in rats

Placenta ◽

10.1016/j.placenta.2021.07.002 ◽

2021 ◽

Author(s):

Eliza R. McColl ◽

Micheline Piquette-Miller

Keyword(s):

Immune Activation ◽

Maternal Immune Activation ◽

Mtorc1 Signaling

Rescue of maternal immune activation-induced behavioral abnormalities in adult mouse offspring by pathogen-activated maternal Treg cells

Nature Neuroscience ◽

10.1038/s41593-021-00837-1 ◽

2021 ◽

Author(s):

Zhipeng Xu ◽

Xiaoyun Zhang ◽

Hao Chang ◽

Yue Kong ◽

Yangyue Ni ◽

...

Keyword(s):

Immune Activation ◽

Adult Mouse ◽

Treg Cells ◽

Maternal Immune Activation ◽

Behavioral Abnormalities

The Need for More Basic Research on SARS-Cov2 Infection and Vaccines on Potential Psychoneurological Effects Using Maternal Immune Activation (MIA) Modeling

Brain Behavior and Immunity ◽

10.1016/j.bbi.2021.06.009 ◽

2021 ◽

Author(s):

William J. Murphy

Keyword(s):

Immune Activation ◽

Basic Research ◽

Maternal Immune Activation

Impaired discrimination of a subanesthetic dose of ketamine in a maternal immune activation model of schizophrenia risk

Journal of Psychopharmacology ◽

10.1177/02698811211029739 ◽

2021 ◽

pp. 026988112110297

Author(s):

Wayne Meighan ◽

Thomas W Elston ◽

David Bilkey ◽

Ryan D Ward

Keyword(s):

Animal Models ◽

Drug Discrimination ◽

Immune Activation ◽

Internal State ◽

Nmda Receptor Antagonist ◽

Activation Model ◽

Data Link ◽

Maternal Immune Activation ◽

Internal States ◽

Reliable Methods

Background: Animal models of psychiatric diseases suffer from a lack of reliable methods for accurate assessment of subjective internal states in nonhumans. This gap makes translation of results from animal models to patients particularly challenging. Aims/methods: Here, we used the drug-discrimination paradigm to allow rats that model a risk factor for schizophrenia (maternal immune activation, MIA) to report on the subjective internal state produced by a subanesthetic dose of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. Results/outcomes: The MIA rats’ discrimination of ketamine was impaired relative to controls, both in the total number of rats that acquired and the asymptotic level of discrimination accuracy. This deficit was not due to a general inability to learn to discriminate an internal drug cue or internal state generally, as MIA rats were unimpaired in the learning and acquisition of a morphine drug discrimination and were as sensitive to the internal state of satiety as controls. Furthermore, the deficit was not due to a decreased sensitivity to the physiological effects of ketamine, as MIA rats showed increased ketamine-induced locomotor activity. Finally, impaired discrimination of ketamine was only seen at subanesthetic doses which functionally correspond to psychotomimetic doses in humans. Conclusion: These data link changes in NMDA responses to the MIA model. Furthermore, they confirm the utility of the drug-discrimination paradigm for future inquiries into the subjective internal state produced in models of schizophrenia and other developmental diseases.

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.