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.
We will assess the effects of oral statins on learning and memory across the lifespan. Negative effects of statins on cognitive processes may be relevant to the safety and side effects of long- term statin exposure, especially in children. We will also explore the effects of statins on neuroestrogen levels and estrogen receptor expression, which, in conjunction with cognitive correlates, may lead to new hypotheses about the role of the cholesterol synthesis pathway in these critical components of neural development and plasticity.
