The amygdala has been implicated in nearly every neurodevelopmental and neuropsychiatric disorder, from autism to depression to schizophrenia, and likely contributes to socioemotional deficits that characterize these disorders. Although the causal mechanisms of these disorders remain unknown, a growing body of evidence suggests that maternal factors in utero may influence disease susceptibility. Indeed, children who were prenatally exposed to maternal infection have an increased risk for developing autism, schizophrenia or other neurodevelopmental disorders. Because the genetic, ecological, and behavioral diversity of humans is so remarkably heterogeneous, animal models are essential for testing causality, identifying molecular mechanisms, and developing new diagnostic tools and therapeutics. Maternal immune activation (MIA) models in rodents have demonstrated a causal relationship between maternal response to infection and neuropathological and behavioral abnormalities consistent with a range of neurodevelopmental and psychiatric disorders. However, it was not known if prenatal immune challenge in primates would lead to similar outcomes. To address this major gap, we created a nonhuman primate MIA model of rhesus macaques prenatally exposed to immune challenge. This unprecedented nonhuman primate cohort has undergone extensive behavioral, immune, and neuroimaging studies, and is now being used to evaluate genomic and cellular alterations. We have found that MIA-exposed nonhuman primate offspring show biological and behavioral changes that mimic human psychiatric disease, including amygdala-relevant alterations in socioemotional development. In this proposal, we will utilize the archived brain tissue from this cohort and to evaluate, for the first time, how cellular and molecular mechanisms are altered in the amygdala following prenatal immune challenge. The first step in this pilot proposal is to ask: Is the molecular signature of the amygdala altered in nonhuman primate offspring prenatally exposed to a maternal immune system challenge? To address this question, we will utilize next generation sequencing methods (RNA-seq) to measure genome-wide transcriptome changes as well as weighted-genome co-expression network analysis (WGCNA), a powerful unsupervised systems-biology framework, to identify co-expression modules within and across amygdala nuclei in MIA-exposed animals relative to controls. These modules will be integrated with behavioral, immunologic, and neuroimaging results from the same cohort to identity putative molecular drivers of observed phenotypic alterations following MIA exposure.

Public Health Relevance

The amygdala has been implicated in nearly every neurodevelopmental and psychiatric disorder, from autism to depression to schizophrenia. Although the causal mechanisms of these disorders remain unknown, maternal factors in utero may influence disease susceptibility. The overarching objective of this research program is to determine how cellular and molecular mechanisms are altered in the amygdala as a result of prenatal exposure to maternal infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH119650-01A1
Application #
9830517
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Tonelli, Leonardo H
Project Start
2019-06-01
Project End
2021-04-30
Budget Start
2019-06-01
Budget End
2020-04-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Davis
Department
Psychiatry
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618