Aging and Sties of Action of Cognition-Enhancing Drugs

衰老和认知增强药物的作用方式

• 批准号: 7065168
• 负责人: DIANA S WOODRUFF-PAK
• 金额: $ 28.7万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7065168
• 关键词: acetylcholine; acetylcholinesterase; age difference; aging; behavioral /social science research tag; cerebellum; cholinesterase inhibitors; cognition; hippocampus; histology; injection /infusion; laboratory rabbit; learning; neural transmission; neuroanatomy; neuropharmacology; neuroprotectants; neuropsychology; neurotransmitter receptor; psychopharmacology; receptor binding; reflex

DESCRIPTION (provided by applicant): The large knowledge base on neurobiological and behavioral aspects of associative learning in the eyeblink classical conditioning model in rabbits will be used to identify sites of action and possible mechanisms for cognition enhancing drugs. Eyeblink conditioning reveals natural age-related deficits with striking parallels in several species including humans. In patients with Alzheimer's disease (AD) eyeblink classical conditioning is profoundly impaired, making the procedure relevant for preclinical studies of cognition-enhancing drugs. In addition to parallels with human behavior and neurobiology, the essential neural circuitry for this form of learning has been localized in the cerebellum, with modulatory circuits identified in hippocampus and neocortex. The proposed research is innovative because it has a focus on novel pathways through which cognition-enhancing drugs may affect learning and memory. In addition to septohippocampal acetylcholine (ACh) routes of action, experiments will assess acetylcholinesterase inhibition (AChE-I) and nicotinic acetylcholine receptors (nAChRs) in cerebellum and cerebellar contributions to the facilitation of learning. The cerebellum is essential in classical eyeblink conditioning, but it also plays a demonstrated role in a diverse group of other cognitive functions. Normal age-related decline in cerebellar volume is well documented, yet the cerebellum is seldom studied as a target for drug action. As a brain structure preserved in AD better than the hippocampus, the cerebellum may be a useful target for drug action. Young and older rabbits will be assessed using delay (for which the cerebellum is essential) and trace (for which the hippocampus and the cerebellum are essential) eyeblink conditioning procedures. Aim 1 focuses on site(s) of action of drugs known to ameliorate learning impairment in young and older rabbits using systemic drug injection, 600 and 750 ms delay conditioning, and AChE-I and nAChR binding in cerebellum and hippocampus. Aim 2 focuses on site(s) of action of drugs known to ameliorate learning impairment in young and older rabbits using systemic drug injection, 600 and 750 ms trace conditioning, and AChE-I and nAChR binding in cerebellum and hippocampus. The targets of Aim 3 are the medial septum, cerebellar cortex, and interpositus nucleus where drugs will be infused and acquisition in the delay and trace procedures will be assessed. These studies will likely support hypotheses about ACh mechanisms in learning and memory and may identify the cerebellum as an additional site of drug action.

描述（由申请人提供）：兔子眨眼经典条件反射模型中联想学习的神经生物学和行为方面的大型知识库将用于识别认知增强药物的作用位点和可能的机制。眨眼条件反射揭示了与年龄相关的自然缺陷，这在包括人类在内的多个物种中具有惊人的相似之处。在阿尔茨海默病（AD）患者中，眨眼经典条件反射受到严重损害，使得该程序与认知增强药物的临床前研究相关。除了与人类行为和神经生物学相似之外，这种学习形式的基本神经回路位于小脑，在海马体和新皮质中发现了调节回路。拟议的研究具有创新性，因为它重点关注认知增强药物可能影响学习和记忆的新途径。除了隔海马乙酰胆碱（ACh）的作用途径外，实验还将评估小脑中乙酰胆碱酯酶抑制（AChE-I）和烟碱乙酰胆碱受体（nAChR）对促进学习的贡献。小脑在经典的眨眼条件反射中至关重要，但它也在多种其他认知功能中发挥着重要作用。正常情况下，与年龄相关的小脑体积下降已有充分记录，但很少将小脑作为药物作用的靶点进行研究。由于 AD 中比海马体保存得更好的大脑结构，小脑可能是药物作用的有用目标。将使用延迟（小脑对此至关重要）和跟踪（海马和小脑对此至关重要）眨眼调节程序来评估年轻和年长的兔子。目标 1 重点关注已知通过全身药物注射、600 和 750 ms 延迟调节以及小脑和海马中 AChE-I 和 nAChR 结合来改善年轻和年长兔子学习障碍的药物的作用位点。目标 2 重点关注已知可通过全身药物注射、600 和 750 ms 微量调节以及小脑和海马中的 AChE-I 和 nAChR 结合来改善年轻和年长兔子学习障碍的药物的作用位点。目标 3 的目标是内侧隔、小脑皮质和间核，将在此处输注药物并评估延迟和追踪程序中的获取情况。这些研究可能会支持关于学习和记忆中乙酰胆碱机制的假设，并可能将小脑确定为药物作用的另一个部位。