In Vivo Analysis of Modulatory Influences on Neuronal Interaction & Intracelluar

对神经元相互作用的调节影响的体内分析

• 批准号: 6893034
• 负责人: HARRIET R FRIEDMAN
• 金额: $ 18.69万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-12 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6893034
• 关键词: Macaca mulatta; antipsychotic agents; behavior test; behavioral /social science research tag; brain electrical activity; calcium flux; central neural pathway /tract; cognition; dopamine; dopamine receptor; eye movements; memory; neural information processing; neuropharmacology; neurophysiology; nontherapeutic iontophoresis; prefrontal lobe /cortex; schizophrenia

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.

该目标研究受体特异性药理学药物如何改变单个神经元的神经元特性以及在认知任务的实际执行过程中前额皮质中多个神经元之间的相互作用。多巴胺、偏向性和谷氨酸激动剂和拮抗剂、IP3和cAMP阻滞剂以及钙通道阻滞剂等药物将用于在非人类灵长类认知模型中检查多巴胺介导的钙机制。将在接受长期抗精神病药物治疗的猴子和未经治疗的动物中研究行为和/或相关的神经生理学测量，并将涉及药剂的全身和皮质内应用。因此，本研究将其他子项目中的细胞系、皮质切片以及正常和基因工程小鼠的发现推断为行为中的特定神经操作。 灵长类动物，将为理解神经生理机制奠定基础 项目 9 中人类患者的抗精神病药物将针对这一点。具体目标 1 将侧重于剖析对药理操作敏感的认知过程组成部分，特别是信息的维持（动眼延迟反应 [ODR]）；以及抑制和超越强效反应（动眼神经抗眼跳任务[AS]）任务的能力，这种能力在患有前额叶病变的动物和精神分裂症患者中受到损害。使用相同的任务，特定目标 2 将结合药物的记录和离子电渗应用来检查对基本皮质的调节影响 微电路（ECM）参与上述任务。最后，具体目标 3 将检查长期接受抗精神病药物和 D1 激动剂治疗的猴子的 ECM 和行为结果，以揭示哪些神经过程可能与该治疗方案产生的行为损伤和行为恢复有关，这将为项目 9 中的临床试验建模。这些研究的独特价值在于，它们将为了解在正常猴子中运行的神经回路和信号机制组成部分提供一个窗口，这些神经回路和信号机制是异常信号和其他疾病过程的脆弱目标。