Dopaminergic Modulation of Persistent Activity in Prefrontal Cortical Circuits

Yale University, New Haven CT

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Abstract

One of the hallmarks of schizophrenia is the inability to perform tasks that require a continual and logical flow of thought processes. A key component of this process is the operation of working memory in the prefrontal cortex, and the ability of ascending dopaminergic systems to modulate this. The leading model of working memory is that it is generated as recurrent activity by the continual flow of excitation between pyramidal cells, controlled by a precise balance with local, recurrent inhibition. We have recently described an in vitro slice preparation of the ferret prefrontal cortex that naturally generates this type of activity. Networks of cortical pyramidal and local circuit interneurons generate periods of recurrent activity that can last for several seconds or longer. Here we will use this in vitro slice preparation to examine the mechanisms by which dopamine may modulate the ability of the prefrontal cortex to generate self-sustained periods of recurrent network activity. In Specific Aim 1 we will examine how stimulation of D1 and D2 dopamine receptor subtypes modulate the ability of prefrontal cortical circuits to generate periods of persistent activity. In Specific Aim 2 we will examine the cellular mechanisms by which these effects occur, specifically testing the hypothesis that modulation of dopaminergic modulation of the h-current, intracellular Ca2+ levels, and cAMP are important variables. Finally, in Specific Aim 3, we will examine, through intracellular recordings in vivo, the cellular mechanisms of generation of delay period activity during working memory tasks. Through these investigations, we will obtain a cellular level understanding of how persistent activity may be generated in prefrontal cortical circuits and how this activity may be modulated by the stimulation of dopaminergic receptors. A better understanding of dopaminergic modulation of persistent activity in the prefrontal cortex will help us understand the physiological basis of schizophrenia and its treatment.