Project Summary Cognitive dysfunction is a core symptom of schizophrenia that often precedes formal diagnosis and continues throughout disease progression. It is one of the chief factors in determining quality of life for many patients and remains difficult to treat. The underlying basis of cognitive dysfunction is unknown. The prefrontal cortex (PFC) and striatum are involved in cognition and are consistently dysfunctional in schizophrenia. However, their respective roles are incompletely understood. This proposal approaches this knowledge gap with a combination of behavioral, neurophysiological, and optogenetic techniques. We will study in detail how prefrontal and striatal regions interact during elementary cognitive operations. In Aim 1, we will implant multielectrode arrays in both the PFC and striatum in rats. We will record the activity of neuronal ensembles in each region during an interval-timing task, which draws on the same neural substrates as working memory tasks. This approach will give us information about the simultaneous processing in these two structures and will identify patterns of neuronal activity that underlie elementary cognition. In Aim 2, we will elucidate the relationship between the PFC and striatum during elementary cognition. We will employ optogenetics to specifically modulate frontostriatal circuits. First, we will inhibit prefrontal projections to the striatum with ArchT while recording striatal activity during interval timing. Second, we will stimulate frontostriatal projections with ChR2 while recording striatal activity during timing behavior. These experiments will determine the role of frontostriatal circuits in elementary cognitive processing. This information could suggest possible therapeutic targets and strategies for alleviating the currently untreatable cognitive deficits in schizophrenia and other neuropsychiatric diseases.