HIPPOCAMPAL CONTROL OF WORKING MEMORY: INACTIVATION AND PET IN MONKEYS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This proposal assesses the dynamic control of dorsolateral prefrontal cortex (dlPFC) by the hippocampus during working memory performance in nonhuman primates. The study combines pharmacological inactivation techniques with behavioral testing and PET imaging to directly assess whether hippocampal modulation of dorsolateral PFC function occurs via the meso-limbic dopamine system (a circuit including the nucleus accumbens, ventral pallidum and ventral tegmental area (VTA)) in nonhuman primates. Such a circuit has been demonstrated in rodents, however, this will be the first direct demonstration that this circuit exists and functions similarly in primates. In the first set of experiments, we will explore the effects of anterior or posterior inactivation of the hippocampus on performance of a working memory task known to depend upon the integrity of the dlPFC, the self-ordered task. We will then use 18F-FDG PET imaging to assess that hippocampal inactivation directly impacted dlPFC activation during working memory. This results of these experiments will directly demonstrate the changes in prefrontal activity associated with hippocampal activity. The second group of experiments will directly assess the role of the meso-limbic dopamine system is the circuit by which hippocampus modulates dlPFC activity. Specifically, they will test the hypothesis that the ventral pallidum functions to tonically VTA neurons until inhibited by hippocampal evoked release from the nucleus accumbens. In these experiments, tonic inhibition from the nucleus accumbens to the pallidum will be lowered using the GABA-A antagonist bicuculline, resulting in activation of the pallidum. This increased activation will inhibit VTA activity, thereby reducing dopamine release into the dlPFC and impairing working memory. The final study will use anterograde tracers into the anterior hippocampus and retrograde tracers into the ventral pallidum to demonstrate that the tracers co-localize in the nucleus accumbens.