The goal of the proposed research is to understand the neuromodulatory effects of dopamine on signal integration in basal and apical dendrites of individual pyramidal neurons. A developing neuronal model for the pathophysiology of schizophrenia, based on the nature of electrophysiological actions of dopamine in the prefrontal cortex, suggests that pyramidal basal and apical dendrites are modulated in a qualitatively different way. According to the model dopamine suppresses the excitability of apical, and enhances the excitability of basal dendrites, resulting in a selective """"""""tuning"""""""" of pyramidal neurons to either transcortical-associative, or horizontal-intralaminar input pathways. The model suggests the link between prefrontal cortex pyramidal layer 5 neurons and both, (1) clinical symptoms, and (2) postmortem pathological findings in schizophrenic subjects. Direct simultaneous measurements from apical and basal dendrites of prefrontal cortex pyramidal neurons would facilitate our understanding of (1) dopamine effects on dendritic excitability and information processing, and (2) dopamine's role in the pathogenesis of schizophrenia (dopamine hypothesis). We propose to use recently developed multi-site voltage-sensitive dye imaging, in order to investigate directly the amplitudes and time courses of synaptic and backpropagating action potentials along basal and apical dendrites, and how these potentials are affected by dopamine D1 and D2 receptor activation. Voltage-sensitive dye imaging will also be used to determine whether dopamine induced changes in dendritic excitability can alter the action potential initiation pattern, and whether dopamine differentially modulates basal and apical dendrites within the same neuron. Our efforts are meant to provide the impetus for new therapeutic approaches in schizophrenia.
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