Brain DHA, Dopamine, and Behavior: Roles in ADHD

描述（由申请人提供）：越来越多的证据表明，发育过程中大脑中二十二碳六烯酸（DHA）的掺入不足会影响CNS多巴胺系统，并且当与适当的遗传和/或其他表观遗传因素结合时，会增加患ADHD的风险或疾病的严重程度。这一建议提出了这样一个假设，即在早期发育过程中，大脑DHA水平低会改变多巴胺能功能，产生类似于ADHD症状的多动和注意力缺陷。本研究的目的是评估早期发育过程中大脑DHA含量的临床相关变化对行为和神经化学的影响。特定目标将使用大鼠模型来确定： 1.发育早期大脑DHA含量低对发育中大鼠活动和注意力过程的影响。将使用测力板动作计来同时测量和评估从受孕开始的大鼠的活动和注意力过程，这些大鼠的饮食旨在调节大脑DHA含量。 2.哌醋甲酯对发育早期脑内DHA含量低的幼鼠多动和注意过程的影响。将使用测力板测力计确定用于治疗ADHD的该药物的剂量反应效应。 3.发育早期脑DHA含量低对幼鼠多巴胺能神经化学的影响。将在特定脑区评估多巴胺含量和周转以及多巴胺受体和转运蛋白的密度。 4.关键发育期，此时大脑中足够的DHA含量对多巴胺系统的正常发育至关重要。DHA治疗将在出生和断奶之间的不同时间点开始，以确定何时存在神经可塑性。 这些实验将显示大脑DHA含量与多巴胺能功能以及多动症和注意力过程的行为指数之间的关系。这些发现将为大脑发育和围产期营养机制提供及时和重要的见解，并为人类ADHD的病因学提供见解。这些见解可以确定一种方法，通过这种方法可以减少或消除ADHD的某些风险因素，或者通过适当的产前和产后营养可以降低疾病的严重程度。

DESCRIPTION (provided by applicant): A growing body of evidence suggests that inadequate incorporation of docosahexaenoic acid (DHA) in brain during development affects the CNS dopamine systems and, when combined with appropriate genetic and/or other epigenetic factors, contribute to the risk of developing ADHD or to the severity of the disease. This proposal addresses the HYPOTHESIS that low brain DHA levels during early development alter dopaminergic function producing hyperactivity and attentional deficits similar to the symptoms of ADHD. The OBJECTIVE of this study is to assess the behavioral and neurochemical effects of clinically-relevant variation in brain DHA content during early development. The Specific Aims will use a rat model to determine: 1. The effects of low brain DHA content during early development on activity and attentional processes in the developing rat. A force-plate actometer will be used to measure simultaneously assess activity and attentional processes in rats raised from conception on diets designed to modulate brain DHA content. 2. The effects of methylphenidate on hyperactivity and attentional processes in juvenile rats with low brain DHA content during early development. Dose-response effects of this drug used in the treatment of ADHD will be determined using the force-plate actometer. 3. The effects of low brain DHA content during early development on dopaminergic neurochemistry in juvenile rats. Dopamine content and turnover and the density of dopamine receptors and transporters will be assessed in specific brain regions. 4. The critical developmental period(s) when sufficient brain DHA content is essential for normal development of the dopamine systems. Treatment with DHA will be initiated at various time points between birth and weaning to determine when neuroplasticity is present. These experiments will show the relationship between brain DHA content and dopaminergic functioning and behavioral indices of hyperactivity and attentional processes. These findings will provide timely and important insights into mechanisms of brain development and perinatal nutrition and provide insights into the etiology of ADHD in humans. Such insights may identify a means by which certain risk factors for ADHD may be reduced or eliminated or the severity of the disease may be reduced through appropriate pre- and postnatal nutrition.