The goal of this research program is to help solve the long-standing problem of the neural mechanisms of working memory, at the cellular level. To this end, we will undertake a biophysical model of prefrontal cortical circuits that is based on cortical physiology and that reproduces neural data from the behaving monkey. Modeling projects will be combined with analysis of experimental data, and will be carried out in parallel with ongoing experiments in the laboratories of PI's collaborators. Ultimately, progress in this area will contribute to our understanding of the cellular substrate of cognitive deficits in schizophrenia. The proposal is focused on three major issues: (a) neural mechanisms of persistent activity and its stimulus selectivity; (b) robustness of spatial working memory storage in a recurrent network; (c) the role of working memory in selective attention. Our research projects are designed to test the following hypotheses. (1) Generation of persistent activity. The generation of a stable persistent activity by reverberation, as a network phenomenon, requires not only a high synaptic efficacy of recurrent connections, but also specific temporal dynamics of synaptic transmission. NMDA receptors at the recurrent synapses play a critical role. Synaptically-generated persistent activity depends sensitively on the intrinsic ionic mechanisms of single cells, and can be controlled by their neuromodulations. (2) Robustness of spatial working memory. A continuum of `bump attractors' (spatially localized activity patterns) may not be robust in the presence of heterogeneity. This problem can be solved by adaptive mechanisms, such as homeostatic synaptic scaling, which homogenize a working memory network and thereby endow the network with robust memory of spatial location as an analog quantity. (3) Working memory and selective attention. The prefrontal cortex is capable of a `biased competition' mechanism for selective attention: persistent activity provides a sustained, location- or feature-specific, top- down bias signal to the sensory cortical areas; whereas its intrinsic inhibitory circuit endows the prefrontal cortex with a `winner-take-all' competition for filtering out behaviorally irrelevant stimuli (distractors).