Omega-3 Fatty Acid Deficient Rat Model of Schizophrenia

Omega-3 脂肪酸缺乏型大鼠精神分裂症模型

• 批准号: 7048319
• 负责人: ROBERT K. MCNAMARA
• 金额: $ 20.72万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048319
• 关键词: amphetamines; antipsychotic agents; appetite; aspartate; attention; behavior test; behavioral /social science research tag; diet therapy; dietary carbohydrates; disease /disorder model; disease /disorder proneness /risk; dizocilpine; isolation /deprivation; laboratory rat; magnetic resonance imaging; memory; neuroanatomy; neuropharmacology; neuropsychology; nonhuman therapy evaluation; nutrition disorders; nutrition related tag; omega 3 fatty acid; psychomotor function; psychopathology; schizophrenia; sensory feedback; short term memory

DESCRIPTION (provided by applicant): Schizophrenia negatively impacts the lives of approximately 3 million Americans, and represents a major global health burden. The identification of susceptibility factors relevant to the pathogenesis of schizophrenia in conjunction with animal modelling will likely accelerate the development of novel treatment strategies with improved efficacy, safety, and tolerability. There is a beurgoning body of evidence from epidemiological, clinical, neuroanatomical, neurochemical, and neurodevelopmental studies that implicate omega-3 (n-3) fatty acid deficiency as an important susceptibility factor in schizophrenia pathogenesis. The objective of this application is to test the central hypothesis that n-3 fatty acid deficiency will reproduce in rats the neuroanatomical, behavioral, and neurochemical abnormalities observed in other putative animal models of schizophrenia. The rationale for the proposed studies is that their completion is anticipated to produce proof- of-concept data regarding the face, construct, and predictive validity of a novel animal model of schizophrenia. The model's face and construct validity will be evaluated by determining the effect of n-3 fatty acid deficiency in rat on: (1) neuroanatomical features by magnetic resonance imaging: volume reductions in white matter, gray matter, amygdala-hippocampus complex, thalamus, cerebellar vermis, and corpus callossum volume, volume increases in lateral and third ventricular, and basal ganglia, and postmortem regional reductions in N-acetyl aspartate levels (Specific Aim 1), (2) behavioral/neuropsychological features: latent inhibition (attention), prepulse inhibition (sensorimotor gating), hippocampus- and prefrontal cortex- dependent learning (declarative and working memory), social interaction (social withdrawal), and sucrose preference (anhedonia)(Specific Aim 2), and (3) neurochemical features: increased sensitivity to dopamine- agonist- (amphetamine) and the NMDA receptor antagonist- (MK-801) induced locomotor activity and stereotypy (Specific Aim 3). The model's predictive validity will be evaluated by determining the capacity of prior chronic antipsychotic treatment to attenuate n-3 fatty acid deficiency-induced deficits. These experiments are innovative and the results will be significant because they are anticipated to establish the face, construct, and predictive validity of a novel animal model of schizophrenia created via the manipulation of a candidate non-genomic susceptibility factor, n-3 fatty acid deficiency.

描述（由申请人提供）：精神分裂症对大约 300 万美国人的生活产生负面影响，是全球主要的健康负担。结合动物模型来鉴定与精神分裂症发病机制相关的易感因素可能会加速新型治疗策略的开发，从而提高疗效、安全性和耐受性。来自流行病学、临床、神经解剖学、神经化学和神经发育研究的大量证据表明，omega-3 (n-3) 脂肪酸缺乏是精神分裂症发病机制中的一个重要易感因素。本申请的目的是测试一个中心假设，即 n-3 脂肪酸缺乏会在大鼠中重现在其他假定的精神分裂症动物模型中观察到的神经解剖学、行为和神经化学异常。拟议研究的基本原理是，预计它们的完成将产生有关新型精神分裂症动物模型的外观、构造和预测有效性的概念验证数据。将通过确定大鼠中 n-3 脂肪酸缺乏对以下方面的影响来评估模型的面部和结构有效性：（1）磁共振成像的神经解剖学特征：白质、灰质、杏仁核-海马复合体、丘脑的体积减少，小脑蚓部和胼胝体体积，侧脑室和第三脑室以及基底神经节体积增加，死后区域 N-乙酰天冬氨酸水平降低（具体目标 1)、(2) 行为/神经心理特征：潜在抑制（注意力）、前脉冲抑制（感觉运动门控）、海马和前额叶皮层依赖性学习（陈述性记忆和工作记忆）、社交互动（社交退缩）和蔗糖偏好（快感缺失）（具体目标 2）和 (3) 神经化学特征：对多巴胺激动剂（安非他明）和NMDA 受体拮抗剂 - (MK-801) 诱导运动活动和刻板印象（具体目标 3）。该模型的预测有效性将通过确定先前的慢性抗精神病药物治疗减轻 n-3 脂肪酸缺乏引起的缺陷的能力来评估。这些实验具有创新性，其结果意义重大，因为它们有望建立通过操纵候选非基因组易感因子 n-3 脂肪酸缺乏而创建的新型精神分裂症动物模型的外观、构建和预测有效性。