Malnutrition and Mental Health: A Rat Model

描述（由申请人提供）：使用啮齿动物模型，我们之前的研究已经确定冲动性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状况中起着核心作用，包括注意缺陷多动障碍（ADHD）、反社会和其他人格障碍，以及吸毒成瘾。重要的是，冲动可能是与儿童早期营养不良相关的心理健康障碍的一个共同因素。我们在巴巴多斯对有营养不良史的个体进行了35年的随访研究，发现ADHD的患病率增加了4倍。我们目前正在评估33-38岁的成年人的心理健康状况，包括与儿童营养不良相关的注意力缺陷和冲动。动物研究将验证我们的大鼠产前营养不良模型，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质。以下目标是基于前额皮质（RFC）神经元多巴胺能（DA）、去甲肾上腺素能（NE）和血清素能（5-HT）调节的显著改变是冲动增加和注意力下降的基础。两个高度整合的具体目标将检验这一假设。在第1项研究中，研究人员将对患有和未患有产前蛋白质营养不良的成年大鼠进行以下方面的评估：a)冲动性、反应准确性和持久性的5项连续反应时间测试；B)冲动性延迟奖励操作性测试；C)注意力集中转移测试。在Aim 2中，Aim 1中测量的相关行为的神经基质将在同一动物的体内研究中进一步研究。目标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中进行行为测试，包括：a) PFC和大脑其他区域代谢活性的2-去氧葡萄糖检查和b) PFC中DA、NE和5-羟光胺释放的体内微透析评估。由于产前营养不良是发展中国家和西方人群的一个主要公共卫生问题，我们模型的验证可能会导致具有广泛临床相关性的研究。如上所述，拟议的项目与我们正在巴巴多斯进行的人类研究相吻合，为我们的转化研究提供了巨大而独特的优势，以最大限度地发挥其影响。

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.