Effects of Statins on Juvenile Learning, Memory and Neuroestrogen

 描述（由申请人提供）：美国儿科学会最近建议使用他汀类药物治疗儿童高胆固醇。没有发表的报告检查了他汀类药物在其他健康和典型发育儿童中的潜在认知或神经影响。使用幼年动物模型进行的研究很少，结果好坏参半。为了解决这一知识缺口，我们开发了一种鸣禽模型来测试他汀类药物对学习，记忆和神经雌激素的影响-这需要胆固醇进行局部合成，并在我们正在研究的听觉学习和记忆类型中发挥特定作用。我们专注于青少年和成年男性，并比较临床相关剂量的普伐他汀和辛伐他汀，不同的亲脂性，因此能够通过血脑屏障的影响。将在鸟类听觉前脑的神经元中对长期和短期记忆进行电生理学评估，并将对歌曲学习和歌曲辨别的准确性进行行为量化。我们还将量化这些他汀类药物对雌二醇水平和同一听觉前脑区域雌激素受体表达的影响，以验证初步研究中发现的脑雌激素改变可能导致潜在他汀类药物诱导的认知缺陷的假设。本研究的目的是验证我们的假设：1）辛伐他汀，具有高度的亲脂性，比普伐他汀更能损害学习和记忆，普伐他汀是亲水性的，2）在歌曲学习的关键时期接受他汀类药物治疗的青少年比成人更受他汀类药物的影响，3）认知能力。 损伤与由于脑胆固醇降低引起的潜在神经内分泌功能障碍有关。这是一项基础研究提案，我们正在寻求更好地了解他汀类药物在行为、神经生理和神经内分泌水平上对学习和记忆的影响。

 DESCRIPTION (provided by applicant): The American Academy of Pediatrics has recently recommended the use of statins to treat high cholesterol in children. No published reports have examined the potential cognitive or neural effects of statins in otherwise healthy and typically-developing children. Few studies have been conducted using juvenile animal models, with mixed findings. To address this knowledge gap, we have developed a songbird model to test the effects of statins on learning, memory, and neuroestrogens -- which require cholesterol for local synthesis and play a role specifically in the types of auditory learning and memory we are examining. We focus on juvenile and adult males and compare effects of clinically-relevant doses of pravastatin and simvastatin, which differ in lipophilicity and thus ability to cross the blood-brain barrier. Long- term and short-term memory will be assessed electrophysiologically in neurons of the avian auditory forebrain, and the accuracy of song learning and song discrimination will be quantified behaviorally. We will also quantify the effects of these statins n levels of estradiol and expression of estrogen receptors in the same auditory forebrain region to test the hypothesis that altered brain estrogen may underlie potential statin-induced cognitive deficits identified in preliminary studies. The goals of the proposed research are to test our hypotheses that 1) simvastatin, which has a high degree of lipophilicity, will impair learning and memory more than pravastatin, which is hydrophilic, 2) juveniles treated with statins during the critical period for song learning will be more affected by statin use than adults, and 3) cognitive impairment is associated with underlying neuroendocrine dysfunction due to decreased brain cholesterol. This is a basic research proposal, and we are seeking to better understand the effects of statins on learning and memory at behavioral, neurophysiological, and neuroendocrine levels.