Non-human primate investigations into hippocampal and prefrontal contributions to the cognitive dysfunction apparent in schizophrenia

Schizophrenia is a devastating psychiatric disorder for which there is no cure. Clinically, it is associated with three types of symptoms: psychotic symptoms that are fairly well treated with antipsychotic drugs, and alterations in emotional and cognitive processes that are harder to treat, and profoundly impact quality of life. Brain imaging studies in patients with schizophrenia and rodent models of the disorder have identified problems in the connectivity between regions of the brain called the anterior hippocampus (aHipp), orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (dlPFC) that contribute to these symptoms. Unfortunately, differences in the structure and complexity of rodent and human brains mean that we lack a fundamental understanding of how these alterations in brain connectivity contribute to these cognitive impairments. This limits our insight into the brain mechanisms underlying these important symptoms and restricts our ability to target existing treatments appropriately, refine treatment strategies, and develop novel, more effective treatments. To address this challenge, we have developed and validated a primate-based approach for the study of schizophrenia symptoms - marmoset aHipp perineuronal net degradation. Crucially, the use of a marmoset, a small New World monkey with a brain structure closer to humans, permits the study of aHipp-OFC/dlPFC connectivity and its role in schizophrenia symptoms. We now aim to capitalize on this approach to identify the neurochemical and anatomical basis of defined cognitive abilities known to be disrupted in schizophrenia. We will apply a repertoire of techniques that are rare in primates and include direct pharmacological manipulations of the brain, magnetic resonance and positron emission tomographic brain imaging (MRI and PET), and sophisticated, unrestrained behavioural testing using both well-validated and novel tasks. Specifically, we will: Characterize the functional impact of aHipp degradation on different aspects of OFC- and dlPFC-dependent schizophrenia-relevant cognition (goal-directed learning processes, working memory and aberrant salience). Utilize the changes in brain chemicals that we previously identified in the OFC and dlPFC to target these cognitive abilities pharmacologically, and ameliorate any cognitive impairments with both receptor specific and putative antipsychotic compounds. Extend this approach into adolescent marmosets to characterize the impact of compromised aHipp-OFC/dlPFC connectivity during development on their cognitive abilities in adulthood. Consequently, this proposal will enhance our understanding of the brain mechanisms underlying these debilitating symptoms, and reveal how abnormal development of these brain connections contribute to cognitive dysfunction. In doing so, this proposal also aims to provide insight into strategies for the prevention and symptom-specific (rather than disorder-specific) targeting of potential treatments for use by researchers, and ultimately to benefit patients.