Malnutrition and Mental Health: A Rat Model

描述(申请人提供)：使用啮齿动物模型，我们先前的研究已经确定冲动是产前蛋白质营养不良的主要行为后果。在人类中，越来越多的证据表明，冲动在许多精神病理疾病中发挥着核心作用，包括注意力缺陷多动障碍(ADHD)、反社会和其他人格障碍，以及药物成瘾。重要的是，冲动可能是与儿童早期营养不良相关的精神健康障碍的一个共同因素。在我们在巴巴多斯对有营养不良史的个人进行的35年跟踪研究中，我们记录了ADHD患病率增加了四倍。我们目前正在评估与儿童营养不良有关的成年人的心理健康结果，包括注意力缺陷和冲动。拟议的动物研究将验证我们产前营养不良的大鼠模型，并将利用创新的多学科方法来研究冲动和注意力不集中的神经基础。以下目的是基于这样一个总体假设，即前额叶皮质(RFC)神经元的多巴胺(DA)、去甲肾上腺素(NE)和5-羟色胺(5-HT)调制发生显著变化，导致冲动增加和注意力下降。两个高度整合的具体目标将检验这一假设。在目标1中，将评估患有和不患有出生前蛋白质营养不良的成年大鼠在以下方面的表现：a)冲动、反应准确性和坚持性的5种选择系列反应时测试；b)冲动延迟奖赏操作测试；以及c)注意力集中转移测试。在目标2中，目标1中测量的相关行为的神经底物将通过在相同动物中的活体研究来进一步检验。Aim 2的所有研究都将在产前蛋白质营养不良和营养良好的受试者身上进行，包括：a)PFC和大脑其他区域代谢活动的2-脱氧葡萄糖检查，以及b)体内微透析评估PFC中DA、NE和5-HT的释放。由于产前营养不良是发展中国家和西方人口的一个主要公共卫生问题，我们的模型的验证可能会导致具有广泛临床意义的研究。如上所述，拟议的项目与我们正在巴巴多斯进行的人体研究平行，为最大限度地发挥我们翻译研究的影响提供了巨大和独特的优势。

DESCRIPTION (provided by applicant): Using a rodent model, our previous studies have established that impulsivity is a major behavioral consequence of prenatal protein malnutrition. In humans, evidence is mounting that impulsivity plays a central role in many psychopathological conditions, including attention deficit hyperactivity disorder (ADHD), antisocial and other personality disorders, and also in drug addiction. Importantly, impulsivity may be a common factor in those mental health disorders associated with early childhood malnutrition. In our 35 year follow-up study in Barbados of individuals with a history of malnutrition, we have documented a four-fold increase in the prevalence of ADHD. We are currently assessing in the adults, now 33-38 years of age, mental health outcomes, including attention deficits and impulsivity, associated with childhood malnutrition. The proposed animal research will validate our rat model of prenatal malnutrition and will make use of an innovative multidisciplinary approach to study the neural substrates of impulsivity and inattention. The following aims are based on the overall hypothesis that significant alterations in dopaminergic (DA), noradrenergic (NE) and serotonergic (5-HT) modulation of neurons from the prefrontal cortex (RFC) underlie increased impulsivity and decreased attention. Two highly integrated Specific Aims will test this hypothesis. In Aim 1, adult rats with and without prenatal protein malnutrition will be assessed with regard to performance on: a) the 5-choice serial reaction time test of impulsivity, response accuracy and perseveration; b) the delayed reward operant test of impulsivity, and; c) the attentional set-shifting test of attention. In Aim 2 the neural substrates of relevant behaviors measured in Aim 1 will be further examined using in vivo studies in the same animals. All studies of Aim 2 will be performed on behaviorally tested prenatally protein malnourished and well-nourished subjects, and include: a) 2-deoxyglucose examination of metabolic activity in the PFC and other regions of brain and b) in vivo microdialysis assessment of DA, NE and 5-HT release in the PFC. Since prenatal malnutrition is a major public health problem in developing countries and also in Western populations, the validation of our model is likely to lead to research with widespread clinical relevance. As indicated, the proposed project parallels our ongoing human study in Barbados, affording a tremendous and unique advantage to maximize the impact of our translational research.