HIPPOCAMPAL CONTROL OF WORKING MEMORY: INACTIVATION AND PET IN MONKEYS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本研究评估了非人灵长类动物工作记忆过程中，海马体对背外侧前额叶皮质(DlPFC)的动态控制。这项研究将药理学失活技术与行为测试和PET成像相结合，直接评估海马是否通过中脑边缘多巴胺系统(包括伏核、腹侧苍白球和腹侧被盖区的回路)对背外侧PFC功能进行调制 (VTA))。这样的回路已经在啮齿类动物身上得到了证明，然而，这将是第一次直接证明这种回路在灵长类动物中存在并具有类似的功能。在第一组实验中，我们将探索海马体前部或后部失活对工作记忆任务绩效的影响，该任务取决于dlPFC的完整性，即自我排序任务。然后，我们将使用18F-FDG PET成像来评估海马区失活直接影响工作记忆过程中dlPFC的激活。这些实验的结果将直接证明前额叶活动与海马体活动相关的变化。 第二组实验将直接评估中脑边缘多巴胺系统的作用，它是海马体调节dlPFC活性的回路。具体地说，他们将测试腹侧苍白球起作用的假设 强直的VTA神经元，直到被海马诱发的伏隔核释放抑制。在这些实验中，从伏隔核到苍白球的紧张性抑制将被GABA-A拮抗剂荷包牡丹碱降低，导致苍白球的激活。这种增加的激活将抑制VTA的活性，从而减少向dlPFC释放多巴胺，并损害工作记忆。 最后一项研究将使用顺行示踪剂进入前海马区，逆行示踪剂进入腹侧苍白球，以证明示踪剂共同定位于伏隔核。

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 study 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.