Dopamine's role in regulating cognitive functions of prefrontal cortex is a pivotal focus of neurobiological and clinical research, motivated by the striking dependence of prefrontal function on dopamine D1 receptor signaling, and its hypothesized disruption in schizophrenia. Thus, studies on D1 modulation of the neural mechanisms of working memory have generated important insights into the impairment of this core cognitive function in schizophrenia. In nonhuman primates, the spatially tuned delay activity, or """"""""memory fields"""""""" of prefrontal neurons engaged by spatial working memory tasks are highly dependent on the prevailing level of D1 receptor stimulation. Computational models predict that recurrent excitation between pyramidal cells is essential for the generation of memory fields, and a strategic site for D1 modulation. Recent studies in vivo have found evidence of functional connections between pyramidal neurons that may form the basis of recurrent excitation, and D1 modulation of the synaptic efficacy of this circuit element has been demonstrated in vitro. D 1 modulation has also been implicated in the feedforward inhibitory mechanisms of prefrontal circuits, which have been incorporated into network models to provide for spatial and temporal constraints on pyramidal cell firing. Therefore, in order to understand the mechanisms by which D1 modulation impinges on working memory, it is necessary to directly examine the selective actions of this receptor on the key components of functional connectivity in prefrontal circuitry. For this purpose, we intend to pioneer the use of a powerful combination of microiontophoresis for analysis of selective dopamine receptor function, with multielectrode recording for analysis of the functional connectivity between prefrontal neurons, in nonhuman primates performing spatial working memory tasks. By these means, we aim (i) to investigate the hypothesis hat D1 signaling selectively regulates recurrent excitation between putative pyramidal cells, dependent on the degree of concordance in their spatiotemporal processing during cognitive performance, (ii) to show that there is a complementary D 1-mediated regulation of feed forward inhibition in these microcircuits via modification of inhibitory connections between putative interneurons and pyramidal cells, and (iii) to show D 1 modulation of feed forward excitation onto putative interneurons that may be essential for driving their circuit functions. Findings from this work will help to elucidate the elements of intrinsic circuitry by which dopamine exerts its role in prefrontal function and pinpoint the probable sites of dopamine dysregulation in schizophrenia. ? ?
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