NEURODEVELOPMENTAL INSULTS AND SCHIZOPHRENIA

描述（改编自申请人摘要）：拟议研究计划的总体目标是对精神分裂症的神经发育假说进行测试。多种证据表明，精神分裂症具有病因不明的神经发育成分，其中大脑损伤发生在早期发育期间。流行病学研究表明，暴露于营养缺乏、病毒感染、产科并发症和压力等发育损害的人类后代随后发展为精神分裂症的风险更高。脑病理可能与神经发育损伤有关，包括质子（1H）磁共振波谱（MRS）测量的异常生化。研究者建议通过评估精神分裂症的MRS结果是否可以通过大鼠早期发育损伤重现，将这些生化异常与精神分裂症的早期生活应激素质联系起来。该提案的总体设计包括使用体外1H MRS来表征围产期应激对n -乙酰-天冬氨酸（NAA）和肌醇（MI）脑区域浓度的影响。围产期应激的行为、神经内分泌和神经化学特征也将被定义。测定将在30-360日龄的4个发育时间点和8个大脑区域进行。在实验一中，研究者提出了一种产前压力的影响特征，其形式是对怀孕的水坝进行重复的日常身体约束。由有压力或没有压力的母鼠所生的幼崽将在出生时交叉饲养，并由产前有压力或正常的母鼠饲养，共产生四个实验组。实验二将以母性剥夺的形式描述产后压力的影响。四个实验组将被用来表征产前压力源与产后压力的相互作用，这些压力来自于有压力的母亲与无压力的母亲的饲养，以及母亲被剥夺与正常饲养的动物。研究者提供了初步证据，成年雄性后代在围产期受到压力时表现出左额叶皮层NAA下降。该提案将决定在开发过程中何时出现这种NAA更改，以及它是否具有进步性。NAA浓度与应激反应的行为、神经内分泌和神经化学指标之间的关系也将被确定。拟议的研究结果应提供神经发育异常与精神分裂症1H MRS定义的成人神经化学异常之间潜在联系的基本信息。

DESCRIPTION (adapted from applicant's abstract): The overall objective of the proposed research plan is a test of the neurodevelopmental hypothesis of schizophrenia. Diverse evidence suggests that schizophrenia has a neurodevelopmental component of unknown etiology in which injury to the brain occurs during early development. Epidemiologic studies indicate that human offspring exposed to developmental insults such as nutritional deficiencies, viral infection, obstetric complications, and stress are at higher risk for subsequent development of schizophrenia. Brain pathology which might be linked to the neurodevelopmental insults includes abnormal biochemistry as measured by proton (1H) magnetic resonance spectroscopy (MRS). The investigator proposes to link these biochemical abnormalities with the early life stress diathesis of schizophrenia by assessing whether the MRS findings in schizophrenia can be reproduced by early developmental insults in rats. The general design of the proposal includes the use of in vitro 1H MRS to characterize the effects of perinatal stress on the brain regional concentration of N-acetyl-aspartate (NAA) and myoinositol (MI). Behavioral, neuroendocrine, and neurochemical characteristics of perinatal stress would also be defined. Determinations would be conducted at 4 developmental time-points spanning 30-360 days of age and in 8 brain regions. In experiment I, the investigator proposes a characterization of the effects of prenatal stress in the form of repeated daily physical restraint of pregnant dams. Pups born from stressed or non-stressed moms will be cross-fostered at birth and reared by prenatally stressed or normal moms to yield four experimental groups. Experiment II would characterize the effect of postnatal stress in the form of maternal deprivation. Four experimental groups would be used to characterize the interaction of the prenatal stressor with the postnatal stress resulting from rearing by stressed versus non-stressed moms and maternally deprived versus normally reared animals. The investigator provides preliminary evidence that adult male offspring subjected to stress perinatally demonstrate decreased NAA in the left frontal cortex. The proposal would determine when during development this NAA change appears and if it is progressive in nature. The relationship among NAA concentration, and behavioral, neuroendocrine, and neurochemical measures of stress response would also be determined. The results of the proposed studies should provide basic information on potential links between the neurodevelopmental abnormalities and anomalies in adult neurochemistry defined by 1H MRS in schizophrenia.