Our long range goal is to improve our understanding of working memory at the level of individual neurons, and to use this information to develop a model of non-human primate model of disrupted working memory that will shed light on the neural basis of the cognitive deficits in schizophrenia. Schizophrenia patients show structural abnormalities in the dorsolateral prefrontal cortex and the thalamus that may be related to their deficits in working memory. We propose to use both established and novel techniques to investigate normal and disrupted working memory function in these and other areas. In particular, we will use whole-brain functional magnetic resonance imaging in the non-human primate to identify neural circuits involved in working memory and to provide a basis for comparison with analogous human data; we will use single neuron recording in the pulvinar nucleus of the thalamus to characterize its role in working memory; and we will use a novel electrical microstimulation paradigm to disrupt function in prefrontal cortex and thalamus during a context-specific working memory task in order to probe the structure of working memory at a single neuron level. By comparing the animal' s performance with that of schizophrenia patients, we will further our understanding of the role that the targeted areas play in mediating the working memory deficits of the patients. Our choice of target areas is guided by the anatomical data of which explores structural deficits in human schizophrenia patients. Our experimental design is and will continue to be informed by findings , which uses behavioral and imaging techniques to study working memory deficits in patients. Once our model is established, we will directly compare patient behavior with that of our model under identical task conditions. In summary, we believe that our strategy of combining neurophysiological, neuroimaging and behavioral techniques with cross-species comparisons will significantly advance our understanding of the neural bases of both working memory and schizophrenia.
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