PROJECT 3 Common psychiatric disorders such as schizophrenia (SZ), in which symptoms manifest in late adolescence or early adulthood, are increasingly considered neurodevelopmental disorders. There is substantial evidence, for example, that maternal viral disease with resulting immune activation (maternal immune activation, or MIA) significantly increases the risk of having a child who is ultimately diagnosed with SZ. Yet, very little is known about the consequences of MIA on the developmental trajectory of the brain. This knowledge might offer enhanced opportunities for prevention or early treatment. Over the last 8 years, the Center team has developed a nonhuman primate (NHP) model of MIA: a modified form of a viral mimic adapted for use in primates (poly IC/LC) is recognized as foreign by the primate immune system and induces a transient innate inflammatory response. Offspring from this NHP MIA model display abnormal behaviors from early postnatal development that increase in severity up to adulthood. This is the first use of poly IC/LC-induced MIA in the rhesus monkey, which directly parallels the much larger literature on the rodent poly IC model. In addition to behavioral disturbances, members of this Center recently discovered several other phenotypes that are expected in a model for SZ. At 3-4 years of age, offspring exhibit enhanced striatal dopamine uptake, a hallmark of psychosis, as well as neural inflammation. The working hypothesis is that there will be MIA-induced prodromal modifications of the trajectory of brain development that presage the emergence of behavioral abnormalities. Project 3 will carry out longitudinal structural and resting state functional MRI studies of a cohort of 24 rhesus monkeys, half of which will be exposed to MIA; the entire cohort will be behaviorally tested by the NHP Core. The objectives are to establish MIA-induced abnormal brain organization signature in the NHP and compare it to that of MIA-exposed mice and human patients undergoing their first episode of SZ. To test this working hypothesis, the project will pursue the following aims: 1) determine normal and abnormal trajectories of structural brain development for NHP controls and individuals exposed to MIA during gestation; 2) Identify atypical functional connectivity in NHP controls and individuals exposed to MIA during gestation; 3) Compare the MIA-induced abnormal brain organization signature established in NHP to brain abnormalities observed in MIA-exposed mice and human patients undergoing their first episode of SZ. These studies will reveal hitherto unknown information on the alterations in brain development caused by MIA that may precede psychosis. Moreover, establishing a common developmental neuropathology across mice, monkeys and humans will lead to clinically useful biomarkers for detecting individuals at high risk for SZ and will promote earlier prevention and more effective treatment.
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