Project 5: Systems and circuits in MIA and schizophrenia

PROJECT SUMMARY – PROJECT 5
Evidence from epidemiology implicates gestational maternal immune activation (MIA) in the pathophysiology of
schizophrenia (SZ). These data, together with recent advances in our understanding of the role of immune
molecules in normal brain development, have led to the overarching hypothesis of this Conte Center: that early
activation of the maternal immune system alters brain development in offspring leading to structural
and functional changes in connectivity that are associated with the emergence of psychopathology in
adolescence and young adulthood. Our initial pilot studies of a unique nonhuman primate (NHP) MIA model
found evidence of altered social, repetitive, and self-injurious behaviors that emerged during adolescence and
were associated with increased striatal dopamine (DA). During the previous funding cycle, we found decreases
in frontal cortical volumes and increases in extracellular free water (FW), a putative measure of
neuroinflammation, measured using diffusion weighted MRI (DWI), in cingulate cortex gray matter (GM) in
male MIA NHPs. These changes in the developing NHP brain were present as early as 6 months postnatally,
prior to the emergence of any behavioral abnormalities, and highlight the importance of the postnatal period for
understanding the effects of MIA on brain development. In a parallel study in patients with SZ, we showed
increased GM FW, with maximal differences present in anterior cingulate, supporting the clinical relevance of
the NHP MIA model. In the present project, we propose to focus on the effects of MIA in the postnatal period
and on brain development in female NHPs, scanning both males and females at 6 and 18 months of age. To
obtain an integrated cross-species understanding of the effects of MIA and SZ on the development of cortico-
striatal functional circuitry, we will pursue the following three aims: (i) Longitudinal imaging studies of
phenotypic heterogeneity in MIA NHPs, (ii) Computational model–based analysis of frontal-striatal circuitry
associated with motivation and cognitive control in SZ, and (iii) Mechanisms underlying sex-related phenotypic
heterogeneity in SZ. Interpretation of the results of these imaging studies will be enhanced by tissue analyses
in the NHPs (Project 4) at age 18 months and measurement of the BIR and immunoreactivity of the mothers
(Project 1) of the offspring we plan to image. Finally, in addition to the above study in MIA NHPs, and in line
with our center’s expanded focus on MIA effects and of SZ on cortico-striatal circuitry, we will use a novel
computational model–based fMRI analysis to dissect the neural circuitry underlying motivation and cognitive
control deficits as well as their relationship to cortical FW and midbrain neuromelanin (NM), a novel proxy for
hyperdopaminergic activity in SZ. This computational model will allow cross-species comparisons of the role
for cortico-striatal circuitry in similar behavioral assays in the mouse MIA model and the MIA NHP. Finally, we
will also examine the role of sex in the phenotypic heterogeneity in humans with SZ at the neural systems level
and in relationship to symptoms and clinical outcomes.

Grant Number: 5P50MH106438-10
NIH Institute/Center: NIH
Principal Investigator: Cameron Carter