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: 6894247
• 负责人: DIANA S WOODRUFF-PAK
• 金额: $ 29.4万
• 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/6894247
• 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）：在兔子中，在Eykblink经典条件模型中，关于神经生物学和行为方面的庞大知识基础将用于识别作用部位以及认知增强药物的可能机制。泪链接调节揭示了包括人类在内的几种物种中的自然与年龄相关的缺陷，并具有惊人的相似之处。在阿尔茨海默氏病（AD）的患者中，经典条件严重损害，这使得与认知增强药物的临床前研究有关。除了与人类行为和神经生物学的相似之处外，这种学习形式的基本神经回路也位于小脑中，并在海马和新皮层中鉴定出调节电路。拟议的研究具有创新性，因为它专注于新的途径，通过这些途径，认知增强药物可能会影响学习和记忆。除了作用途径外，实验还将评估小脑乙酰胆碱酯酶抑制（ACHE-I）和烟碱乙酰胆碱受体（NACHRS），并在小脑和小脑中对学习的促进。小脑在经典的呼吸链接条件中至关重要，但它在其他一组其他认知功能中也起着证明的作用。小脑体积正常相关的小脑体积下降有充分的文献记载，但是小脑很少被研究作为药物作用的靶标。由于与海马更好地保留在AD中的大脑结构，小脑可能是药物作用的有用靶标。将使用延迟（小脑是必不可少的）和痕迹（海马和小脑至关重要的痕迹）进行延迟评估的年轻兔子。 AIM 1专注于使用全身药物注射，600和750 ms延迟调节的药物的作用部位，可改善年轻兔子和年龄较大的兔子的学习障碍，以及小脑和海马室中的Ache-I和NACHR结合。 AIM 2专注于使用全身药物注射，600和750 ms的痕量调节，已知可改善年轻兔子和年龄较大兔子的障碍的药物的作用部位，以及小脑和海马州的Ache-I和NACHR结合。 AIM 3的靶标是内侧隔膜，小脑皮层和斑点核，其中将注入药物，并在延迟和痕量过程中获取药物。这些研究可能会支持关于学习和记忆中ACH机制的假设，并可能将小脑识别为药物作用的附加部位。