Detailed modeling in the Computational Core will address hypotheses concerning the specific projects in this[unreadable] grant, linking the cellular, systems, and behavioral levels. Our central analytical tool will be the[unreadable] hippocampus-entorhinal cortex model that was developed in the last funding period. We will increase its[unreadable] degree of biological realism in order to accommodate new research findings generated by the individual[unreadable] projects. Its purpose is to shed light on the hippocampal etiology of schizophrenia at an intermediate or[unreadable] "endophenotype" level. Because it is important that our model manifest behaviors that are clinically verifiable[unreadable] and that capture important symptomatic features of schizophrenia, a number of psychological tests will be[unreadable] used as assays of schizophrenia vs. normal functioning, including The California Verbal Learning Task[unreadable] (CVLT), modified free recall tasks with semantic cueing, the paired associate (PA) task, and the crossing[unreadable] sequences (CS) task. The computational work related to this grant we have done to date has indicated that[unreadable] a failure to appropriately utilize context is a core cognitive abnormality in schizophrenia; the category[unreadable] clustering indices that are part of the CVLT tap this cognitive function. The PA task is thought to index[unreadable] declarative memory function generally, and schizophrenic patients have consistently shown difficulties with it.[unreadable] It is thought that inability to recall and process sequential information, as revealed by deficienies in the CS[unreadable] task, may underlay the tangentiality and looseness characteristic of schizophrenic thought. After training the[unreadable] network on these tasks, we will subject it to the the many neurophysiologic or neuroanatomic abormalities[unreadable] thought to cause or contribute to schizophrenia (e.g., interneuron deficiencies and related connectivity[unreadable] disturbances, decreased NMDA activity as a result of abnormal levels of NAAG, excessive dopamine levels).[unreadable] We predict that schizophrenogenic changes will produce decreased performance of the model on the[unreadable] aforementioned psychological tasks. We then will examine model behaviors to test hypotheses, as[unreadable] described in the individual projects of the grant, concerning the mechanisms by which the cellular level[unreadable] abnormalities interact to produce clinical symptoms. Even if particular hypothesized mechanisms do not[unreadable] appear to be operative, this is instructive also--as biologically realistic in silico modeling is completely[unreadable] transparent, its behaviors can generate new hypotheses which can then be tested experimentally.