We propose to bring together two parallel advances that provide an important new opportunity to harness animal research for understanding schizophrenia and its treatment. 1) Contemporary clinical work indicates that cognitive deficits, such as impaired cognitive control, are a core feature of schizophrenia. In fact, cognitive impairment is the clinical feature of schizophrenia that best predicts functional outcome. 2) In parallel, animal models have now been established to elucidate the physiological and molecular bases of cognition. In particular, hippocampal place-cell technology is a three decades-old standard for assessing the neurobiological mechanisms of long-term memory and cognition in rodents. We propose to investigate impaired cognitive control and its neural correlate, neural discoordination, in two established schizophrenia-related animal models, the Phencyclidine (PCP) and neonatal ventral hippocampal lesion (NVHL) models. We will use these animal models to evaluate and extend the discoordination hypothesis of schizophrenia: cognitive discoordination is the core deficit in schizophrenia. We will investigate the discoordination hypothesis in three aims. 1) Relate neural discoordination to impaired cognitive control by recording place cell ensembles as NVHL and PCP animals perform the two-frame place avoidance task. We will test whether neural discoordination is associated with impaired cognitive control in tasks that are analogous to cognitive tasks that are impaired in schizophrenia. 2) Evaluate effects of antipsychotic medications on neural discoordination and impaired cognitive control. We will test whether typical, atypical, and novel metabotropic glutamate receptor group II agonist antipsychotic compounds produce associated effects on cognition and neural coordination. 3) Develop a high-throughput assay for antipsychotic efficacy by measuring neural coordination in hippocampus and medial prefrontal cortex of anesthetized animals. Current assays of antipsychotic efficacy are based on behavioral measures (hyperactivity, prepulse inhibition) that appear more related to positive symptoms than to the cognitive core of the disease, at which the proposed studies are aimed.
The cognitive deficits at the core of schizophrenia can be understood as alterations in the basic physiological mechanisms of temporally coordinated neuronal firing that underlies healthy cognition. We will study associated alterations of neural coordination and impaired cognition in rat models of schizophrenia to learn how firing problems of cognition-related cells could lead to the core deficits of schizophrenia.
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