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在健康儿童或青少年动物模型中的潜在认知或神经效应。 为了解决这一知识差距，研究人员将开发鸣禽作为模型系统，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。 他们专注于鸣禽发声学习的关键时期发生的认知过程，这是人类语音习得的既定模型系统。 他们将量化和比较他汀类药物在青少年发育和成年期使用临床相关剂量的口服他汀类药物对认知和神经的影响。 长期和短期记忆将在鸟类听觉前脑的神经元中进行电生理学评估，并且将从行为上量化歌曲学习的准确性。 研究人员将描述神经元的产生率和整个生命周期的存活率如何有助于正常青少年和成年人大脑的声音学习和记忆。 将通过比较亲水性和亲脂性他汀类药物的作用来检测作用的位点和特异性，这两种药物在穿过血脑屏障方面存在差异。 他们将提供一种敏感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。 项目叙述：研究人员将评估口服他汀类药物对整个生命周期的学习和记忆的纵向影响。 对认知过程的负面影响可能与评估长期他汀类药物暴露的安全性有关，特别是在儿童中。 此外，他们还将探索神经元的产生率和整个生命周期的存活率如何有助于正常大脑的学习和记忆。 关于神经发生和存活的数据，以及功能后果，将导致关于胆固醇合成途径在神经发育和可塑性的关键方面的作用的新假设。

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.