Effects of Statins on the Neurobiology of Learning and Memory Across the Lifespan

描述（由申请人提供）：美国儿科学会最近推荐使用他汀类药物治疗儿童高胆固醇。目前，还没有研究检查他汀类药物对健康儿童或幼年动物模型的潜在认知或神经影响。为了解决这一知识差距，研究人员将开发鸣禽作为一个模型系统，以测试他汀类药物对整个生命周期的学习、记忆和成人神经发生的影响。他们关注的是在鸣禽声乐学习的关键时期发生的认知过程，鸣禽声乐学习是人类语言习得的一个既定模型系统。他们将量化和比较他汀类药物在青少年发育和成年期间使用临床相关剂量的口服他汀类药物的认知和神经效应。对鸟类听觉前脑神经元的长期和短期记忆进行电生理评估，并对鸣叫学习的准确性进行行为量化。研究人员将描述在整个生命周期中，神经元的产生和存活率如何影响正常青少年和成人大脑的声音学习和记忆。通过比较亲水性和亲脂性他汀类药物在穿过血脑屏障方面的不同作用，将检验其作用位点和特异性。他们将提供一种灵敏的新方法来测试他汀类药物对发育和成人大脑的功能和结构影响。

DESCRIPTION (Provided by Applicant): The American Academy of Pediatrics has recently recommended the use of statins to treat high cholesterol in children. Currently, no studies have examined potential cognitive or neural effects of statins in healthy children or in juvenile animal models. To address this knowledge gap, the investigators will develop the songbird as a model system to test the influence of statins on learning, memory, and adult neurogenesis across the lifespan. They focus on cognitive processes occurring during the critical period for songbird vocal learning, an established model system for human speech acquisition. They will quantify and compare the cognitive and neural effects of statins using clinically-relevant doses of oral statins across juvenile development and in adulthood. Long-term and short-term memory will be assessed electrophysiologically in neurons of the avian auditory forebrain, and the accuracy of song learning will be quantified behaviorally. The investigators will delineate how rates of neuron production and survival across the lifespan contribute to vocal learning and memory in normal juvenile and adult brains. The locus and specificity of effects will be tested by comparing effects of hydrophilic and lipophilic statins, which differ in crossing the blood-brain barrier. They will provide a sensitive new methodology to test functional and structural effects of statins on the developing and adult brain. PROJECT NARRATIVE: The investigators will assess the longitudinal effects of oral statins on learning and memory across the lifespan. Negative effects on cognitive processes might be relevant to assessing the safety of long-term statin exposure, especially in children. Additionally, they will explore how rates of neuron production and survival across the lifespan contribute to learning and memory in normal brains. Data on neurogenesis and survival, in conjunction with functional consequences, will lead to new hypotheses about the role of the cholesterol synthesis pathway in critical aspects of neural development and plasticity.