This aim examines how receptor-specific pharmacological agents alter the neuronal properties of single neurons as well as interactions between multiple neurons in the prefrontal cortex during the actual performance of cognitive tasks. Dopamine, metabatropic and glutamate agonists and antagonists, IP3 and cAMP blockers, and calcium channel blockers are among the agents that will be used to examine dopamine-mediated calcium mechanisms in a nonhuman primate model of cognition. Behavioral and/or correlated neurophysiological measures will be studied both in monkeys subjected to chronic antipsychotic treatments and in untreated animals and will involve systemic and intracortical application of pharmacological agents. This study therefore extrapolates the findings from cell lines, cortical slices and normal and genetically engineered mice in other subprojects, to specified neural operations in the behaving primate and will form a basis for understanding the neurophysiological mechanisms that would be targeted by antipsychotic medications in human patients in Project 9.
Specific Aim 1 will focus on dissecting the component cognitive processes that are sensitive to pharmacological manipulations, particularly maintenance of information (Oculomotor Delayed Response [ODR]); and ability to withhold and I override prepotent responses (an Oculomotor Antisaccade Task [AS]) tasks, which are impaired in animals I with prefrontal lesions and in patients with schizophrenia. Using the same tasks, Specific Aim 2 will combine recording and iontophoretic application of drugs to examine modulatory influences on elemental cortical microcircuits (ECMs) engaged by the above tasks. Finally, Specific Aim 3will examine ECMs and behavioral outcomes in monkeys chronically treated with antipsychotic medications and a D1 agonist to reveal which neural processes may be implicated in behavioral impairments and behavioral recovery produced by this treatment regimen that will model the clinical trial in Project 9. The unique value of these studies is the window they will provide into the component neural circuits and signaling mechanisms that operate in normal monkeys and are vulnerable targets of abnormal signaling and other disease processes.
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