The prefrontal cortex (PFC) plays an important role in governing a number of behaviors, including motivation, emotion learning and memory. The PFC receives a dopaminergic projection from the ventral tegmental area (VTA) which has been specifically implicated in cognitive and neuropsychiatric processes. Dopamine (DA) is believed to be an endogenous neuromodulator in the cerebral cortex and to be important for normal brain function. Clinical and experimental studies have also implicated DA in the pathogenesis of a number of neurological and psychiatric disorders, including epilepsy and schizophrenia. The overall goal of this research is to understand the role of DA in the modulation of activity in local neocortical circuits. The cerebral cortex, particularly the prefrontal cortex (PFC), is heavily innervated by dopaminergic afferents, suggesting this system plays a prominent role in regulating neuronal excitability. Despite the wealth of evidence supporting a role for DA in cognition, neuropsychiatric processes and neurological disorders, our knowledge of the function of DA receptors at the circuit and single cell level is incomplete. It is hypothesized that the net effort of DA will be determined by the interaction of changes in excitatory and inhibitory synaptic activity and alterations in intrinsic neuronal excitability. Specifically, it is planned: (1) to determine if DA receptors positively modulate excitatory inputs to layer II/III PFC pyramidal neurons via a mechanism involving Dl receptors, (2) to ascertain if evoked inhibitory postsynaptic currents (IPSCs) are negatively modulated by DA. Studies will determine if this is a presynaptic effect of Dl receptors mediated by activation of PKA and (3) to characterize and compare the postsynaptic effects of DA in pyramidal cells and fast spiking interneurons. The proposed experiments will provide important new information regarding the role of specific DA receptors in the regulation of local cortical circuits. These data will be important not only in understanding normal cortical functioning, but also in understanding the mechanisms underlying abnormal processes such as schizophrenia, epilepsy and Parkinson's disease, relatedto inappropriate DA signaling.
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