CHOLINERGIC INFLUENCES ON PREFRONTAL CORTICAL ACTIVITY DURING COGNITIVE FUNCTION

描述(由申请人提供)：注意力、记忆力和学习能力的核心认知功能下降通常在神经退行性疾病中观察到，如阿尔茨海默病。这些缺陷可以被胆碱能药物部分逆转，例如乙酰胆碱激动剂或乙酰胆碱酯酶抑制剂。胆碱能药物也显示出在促进脑损伤或疾病后认知功能恢复方面的希望，例如在创伤性脑损伤的情况下。尽管已知胆碱能药物的有效性，但ACh靶向的调节认知能力的神经机制却知之甚少。已知前额叶皮质对于更高的认知功能是必不可少的，但尚不清楚调节认知功能的前额叶神经元活动如何受到ACh水平的影响。利用最近的技术创新和实验结果，我们建议使用非人类灵长类动物模型来进行神经生理记录，在全身给药期间，在前额叶皮质上长期植入微电极阵列。该项目依赖于监测同一动物在药物干预前后每天从多个皮质部位的神经元放电。这项研究将确定在认知任务执行过程中与行为表现共同变化的神经元活动方面，并将确定其中哪些方面被ACh拮抗剂降解，并被ACh增强剂改善。该项目的成功完成将使我们能够了解前额叶皮质中胆碱能药物与认知能力相关的影响。我们的研究还将为评估新型药物提供灵长类模型，这些药物可能会改善神经退行性疾病和脑创伤后的认知康复。 公共卫生相关性：大脑中乙酰胆碱水平的调节与衰老、痴呆症和精神分裂症相关的认知障碍有关。这项拟议的研究将依靠灵长类动物模型来确定乙酰胆碱水平对大脑中对较高认知功能至关重要的区域--外侧前额叶皮质的影响。该项目的成功完成将为评估不同类型的药物提供一个新颖的灵长类模型，因为它们与认知表现和康复有关。

DESCRIPTION (provided by applicant): A decline in core cognitive functions of attention, memory, and learning ability is commonly observed in neurodegenerative conditions such as Alzheimer's disease. These deficits can be partially reversed by cholinergic agents, for example acetylcholine agonists or acetylcholinesterase inhibitors. Cholinergic agents have also shown promise in enhancing recovery of cognitive functions after brain insult or disease, as in the case of Traumatic Brain Injury. Despite the known effectiveness of cholinergic agents, the neuronal mechanisms mediating cognitive performance that are targeted by ACh are poorly understood. The prefrontal cortex is known to be essential for higher cognitive functions, yet it is unknown how prefrontal neuronal activity mediating cognitive performance is affected by ACh levels. Taking advantage of recent technical innovations and experimental findings, we propose to use a non-human primate model to perform neurophysiological recordings from a chronically implanted array of microelectrodes over the prefrontal cortex during the systemic administration of cholinergic agents. The project relies on monitoring neuronal discharges from multiple cortical sites each day, in the same animals, before and after pharmacological intervention. This research will identify the aspects of neuronal activity that co-vary with behavioral performance during execution of cognitive tasks and will determine which of these are degraded by ACh antagonists and improved by ACh enhancers. Successful completion of the project will allow us to understand the effects of cholinergic agents in the prefrontal cortex associated with cognitive performance. Our research will also provide a primate model for the evaluation of new types of drugs that can potentially improve cognitive rehabilitation after neurodegenerative conditions and brain trauma. PUBLIC HEALTH RELEVANCE: Regulation of acetylcholine levels in the brain has been linked to the cognitive impairments associated with ageing, dementia, and schizophrenia. The proposed research will rely on a primate model to determine the effects of acetylcholine levels in a brain area critical for higher cognitive functions, the lateral prefrontal cortex. Successful completion of the project will provide a novel, primate model for the evaluation of different types of drugs as they relate to cognitive performance and rehabilitation.