Project 2: Striatal circuits in MIA phenotypic heterogeneity

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PROJECT SUMMARY- PROJECT 2 Maternal infection increases susceptibility of offspring to psychiatric and neurodevelopmental disorders, including schizophrenia (SZ). Animal models of maternal immune activation (MIA) support this link, because mid-gestational injection of poly(I:C) induces behavioral and neuropathological abnormalities in adult offspring in domains similar to those affected in SZ. In particular, deficits in executive function, reward processing, and dopaminergic (DA) input to striatal circuits are altered in SZ and in MIA offspring. Thus, the poly(I:C) mouse model provides an opportunity to identify molecular targets in specific neural circuits related to SZ that could lead to earlier diagnosis and treatment of brain disease in humans. However, critical gaps in knowledge persist related to two of the most important aspects of this risk factor for human disease: (i) most pregnancies are resilient to maternal infection and (ii) susceptible pregnancies lead to multiple distinct disorders in offspring. We have recently discovered a way to study both of these issues in the MIA mouse model. Results to date have revealed — for the first time — an intrinsic factor, baseline immunoreactivity (BIR) of female mice before pregnancy, that, together with the poly(I:C) dose used to induce MIA, predicts resilience as well as susceptibility to specific combinations of striatal-dependent behaviors and changes in immune proteins in the striatum in offspring. The central goals of this project are to identify the changes in striatal circuits and immune molecules in offspring and the changes in cytokine signaling in the dam that confer resilience or susceptibility to specific combinations of MIA-induced behavioral outcomes. To that end, we will address three specific aims: (i) characterize behavioral changes across multiple domains in male and female MIA offspring from susceptible and resilient groups, defined by BIR of the dam before pregnancy; (ii) determine whether MIA alters striatal DA release and how D1- and D2-specific pathways shape striatal-dependent behaviors in susceptible and resilient male and female offspring; and (iii) determine whether the balance of pro-inflammatory and regulatory maternal cytokines dictate susceptibility and resilience to MIA-induced changes in cortico-striatal-dependent behaviors, DA release, and immune proteins in male and female offspring. Our project directly addresses the main Center hypothesis, and all 3 Center aims, in a mechanistic manner by defining changes in cortico-striatal circuits that underlie susceptibility and resilience to MIA and by comparing phenotypes between male and female offspring. Results from this project will provide a phenotypic read-out for the maternal immune and the neurodevelopmental molecular pathways identified in Projects 1 and 4, as well as circuit-based and behavioral information in the mouse for comparison to nonhuman primate MIA offspring (Project 3), and in humans with SZ, and for the computational framework that will bridge the species (Project 5). Ultimately, this project may identify neural circuit components that can be targeted for interventions to prevent offspring from developing circuit and behavioral abnormalities in regions and domains similar to those affected in humans with SZ.