O2.6. A TWO-YEAR LONGITUDINAL EVALUATION OF DIFFUSION MEASURES OF EXTRACELLULAR FREE WATER IN A NON-HUMAN PRIMATE MODEL OF MATERNAL IMMUNE ACTIVATION – EXPLORING NEUROIMMUNE MECHANISMS OF PSYCHIATRIC DISORDERS

Abstract Background A key finding in developmental neurobiology is a widespread role for immune molecules in normal brain development and synaptic function and evidence has been accumulating for an immune-based developmental pathophysiology in psychiatric disorders, particularly in schizophrenia. Epidemiological studies have revealed an increased incidence of schizophrenia in offspring of mothers who had an infection during pregnancy while GWAS studies have identified genetic links to the major histocompatibility complex and peripheral changes in immune markers are widely reported in the illness. The murine maternal immune activation model system is widely used to investigate the effects of immune activation during pregnancy on brain development in behavior in offspring. Here we report findings from an ongoing study of a unique cohort on non-human primates (NHP) who underwent MIA (compared to controls) on a promising biomarker of neuroimmune perturbation in vivo--extracellular free water--a diffusion magnetic resonance imaging measure obtained with a multi-shell acquisition, which we have shown in multiple studies to be increased in young people with early psychosis. Methods Fourteen pregnant rhesus monkeys (Macaca mulatta) received polyICLC and 14 control animals have been scanned prospectively from both to their current age of 3.5 years. The offspring from both groups underwent a diffusion MRI scan on a 3 Tesla Siemens Skyra scanner in which multiple b-value shells were acquired to improve estimation of extracellular free water. Data were collected when the offspring were 1, 6, 12, 24 and 36 months to date. Diffusion images were nonlinearly aligned to individual subject MPRAGE scans, which were segmented and parcellated into regions of interest using multi-atlas techniques. For this preliminary analysis, frontal, cingulate, and temporo-limbic regions were selected as a priori ROIs in addition to whole-brain gray and white matter masks. Group differences were assessed using repeated measures ANOVA and independent samples t-tests. Results Results from birth to age 2 years showed a significant main effect of group in both white (p<.05) and gray (p<.001) cingulate cortex free water, with MIA-exposed offspring showing higher free water. Similar trends were also identified in prefrontal white matter free water (p=.07) and whole-brain white (p=.11) and gray matter free water (p=.07). No significant group by time interactions were identified. Data analysis is currently underway including the 3-year time point. Discussion Despite the lack of gross behavioral abnormalities at age 2, extracellular free water values are increased in MIA-exposed offspring, particularly in the cingulate cortex. More global whole-brain free water group differences, however, did not reach statistical significance, which may indicate some regional specificity to these changes early in development. These NHP MIA model complement the human schizophrenia literature in which extracellular free water increases have been repeatedly identified. And show that changes in the brain occur early in life, well before the emergence of atypical behaviors in the NHP model.

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Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation

Brain Behavior and Immunity ◽

10.1016/j.bbi.2016.11.020 ◽

2017 ◽

Vol 63 ◽

pp. 60-70 ◽

Cited By ~ 44

Author(s):

Destanie R. Rose ◽

Milo Careaga ◽

Judy Van de Water ◽

Kim McAllister ◽

Melissa D. Bauman ◽

...

Keyword(s):

Immune Responses ◽

Immune Activation ◽

Primate Model ◽

Maternal Immune Activation ◽

Human Primate

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Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in non-human primates

10.1101/2020.03.31.019190 ◽

2020 ◽

Author(s):

Nicholas F. Page ◽

Michael Gandal ◽

Myka Estes ◽

Scott Cameron ◽

Jessie Buth ◽

...

Keyword(s):

Immune Activation ◽

Molecular Mechanisms ◽

Brain Regions ◽

Repetitive Behaviors ◽

Anterior Cingulate ◽

Psychiatric Disease ◽

Primate Model ◽

Maternal Immune Activation ◽

Transcriptomic Changes ◽

And Control

AbstractBackgroundMaternal immune activation (MIA) is a proposed risk factor for multiple neurodevelopmental and psychiatric disorders, including schizophrenia. However, the molecular and neurobiological mechanisms through which MIA imparts risk for these disorders remain poorly understood. A recently developed nonhuman primate model of exposure to the viral mimic poly:ICLC during pregnancy shows abnormal social and repetitive behaviors and elevated striatal dopamine, a molecular hallmark of human psychosis, providing an unprecedented opportunity for mechanistic dissection.MethodsWe performed RNA-sequencing across four psychiatrically-relevant brain regions (prefrontal cortex, anterior cingulate, hippocampus, and primary visual cortex) from 3.5-4-year old male MIA-exposed and control offspring—an age comparable to mid adolescence in humans.ResultsWe identify 266 unique genes differentially expressed (DE) in at least one brain region with the greatest number observed in hippocampus. Co-expression networks identified region-specific alterations in synaptic signaling and oligodendrocytes. Across regions, we observed temporal and regional differences, but transcriptomic changes were largely similar across 1st or 2nd trimester MIA exposures, including for the top DE genes—PIWIL2 and MGARP. In addition to PIWIL2, several other known regulators of retrotransposition, as well as endogenous transposable elements were dysregulated in MIA offspring.ConclusionsTogether, these results begin to elucidate the brain-level molecular mechanisms through which MIA may impart risk for psychiatric disease.

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Behavioral alterations in rat offspring following maternal immune activation and ELR-CXC chemokine receptor antagonism during pregnancy: Implications for neurodevelopmental psychiatric disorders

Progress in Neuro-Psychopharmacology and Biological Psychiatry ◽

10.1016/j.pnpbp.2014.11.002 ◽

2015 ◽

Vol 57 ◽

pp. 155-165 ◽

Cited By ~ 33

Author(s):

Stephanie A. Ballendine ◽

Quentin Greba ◽

Wojciech Dawicki ◽

Xiaobei Zhang ◽

John R. Gordon ◽

...

Keyword(s):

Psychiatric Disorders ◽

Chemokine Receptor ◽

Immune Activation ◽

Behavioral Alterations ◽

Receptor Antagonism ◽

Maternal Immune Activation ◽

Rat Offspring ◽

Cxc Chemokine

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Alternated Neurodevelopment and Immune Function a Nonhuman Primate Model of Maternal Immune Activation

Biological Psychiatry ◽

10.1016/j.biopsych.2020.02.649 ◽

2020 ◽

Vol 87 (9) ◽

pp. S251

Author(s):

Melissa Bauman ◽

Ana-Maria Iosif ◽

Cameron Carter ◽

A. Kimberley McAllister ◽

Judy Van de Water ◽

...

Keyword(s):

Immune Function ◽

Nonhuman Primate ◽

Immune Activation ◽

Nonhuman Primate Model ◽

Primate Model ◽

Maternal Immune Activation

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Advancing Autism Research From Mice to Marmosets: Behavioral Development of Offspring Following Prenatal Maternal Immune Activation

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.705554 ◽

2021 ◽

Vol 12 ◽

Author(s):

Danielle Santana-Coelho ◽

Donna Layne-Colon ◽

Roslyn Valdespino ◽

Corinna C. Ross ◽

Suzette D. Tardif ◽

...

Keyword(s):

Social Behavior ◽

Immune Activation ◽

Large Body ◽

Autism Spectrum ◽

Rodent Models ◽

Primate Model ◽

Maternal Immune Activation ◽

Polycytidylic Acid ◽

Experimental Treatments ◽

Development Assessment

Understanding the mechanism(s) by which maternal immune activation (MIA) during gestation may disrupt neurodevelopment and increase the susceptibility for disorders such as autism spectrum disorder (ASD) or schizophrenia is a critical step in the development of better treatments and preventive measures. A large body of literature has investigated the pathophysiology of MIA in rodents. However, a translatability gap plagues pre-clinical research of complex behavioral/developmental diseases and those diseases requiring clinical diagnosis, such as ASD. While ideal for their genetic flexibility, vast reagent toolkit, and practicality, rodent models often lack important elements of ethological validity. Hence, our study aimed to develop and characterize the prenatal MIA model in marmosets. Here, we adapted the well-characterized murine maternal immune activation model. Pregnant dams were administered 5 mg/kg poly-L-lysine stabilized polyinosinic-polycytidylic acid (Poly ICLC) subcutaneously three times during gestation (gestational day 63, 65, and 67). Dams were allowed to deliver naturally with no further experimental treatments. After parturition, offspring were screened for general health and vigor, and individual assessment of communication development and social behavior was measured during neonatal or adolescent periods. Similar to rodent models, offspring subjected to MIA exhibited a disruption in patterns of communication during early development. Assessment of social behavior in a marmoset-modified 3-chamber test at 3 and 9 months of age revealed alterations in social behavior that, in some instances, was sex-dependent. Together, our data indicate that marmosets are an excellent non-human primate model for investigating the neurodevelopmental and behavioral consequences of exposure to prenatal challenges, like MIA. Additional studies are necessary to more completely characterize the effect of prenatal inflammation on marmoset development and explore therapeutic intervention strategies that may be applicable in a clinical setting.

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