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）：精神分裂症对约300万美国人的生活产生了负面影响，这代表了全球重大的健康负担。与精神分裂症与动物模型结合使用的发病机理相关的易感因素的鉴定可能会加速发展新型治疗策略，并提高功效，安全性和耐受性。从流行病学，临床，神经解剖学，神经化学和神经发育研究中有大量证据，这暗示了omega-3（n-3）脂肪酸缺乏是精神分裂症发病机理中重要的易感因子。该应用的目的是检验中心假设，即在其他假定的精神分裂症动物模型中观察到的N-3脂肪酸缺乏症将在大鼠的神经解剖学，行为和神经化学异常中繁殖。提出的研究的理由是，预计它们的完成将产生有关精神分裂症的新动物模型的面部，构建和预测有效性的证明数据。 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）和（3）神经化学特征：对多巴胺激动剂 - （苯丙胺）和NMDA受体拮抗剂（MK-801）诱导的运动活性和刻板印象的敏感性提高（特定目标3）。该模型的预测有效性将通过确定先前慢性抗精神病药治疗的能力来减轻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，结果将很大，因为它们预计通过操纵候选非基因组易感因子（N-3脂肪酸缺乏症）创造的新型精神分裂症动物模型的面部，构建和预测有效性。