NEURODEVELOPMENTAL INSULTS AND SCHIZOPHRENIA

描述(摘自申请者的摘要)：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。各种证据表明，精神分裂症有一个原因不明的神经发育部分，在早期发育过程中会对大脑造成损伤。流行病学研究表明，暴露于营养缺乏、病毒感染、产科并发症和应激等发育侮辱的人类后代患精神分裂症的风险更高。脑部病理可能与神经发育损害有关，包括质子(1H)磁共振波谱(MRS)测量的异常生化。这位研究人员建议，通过评估精神分裂症的MRS结果是否可以通过早期的发育侮辱在大鼠身上重现，将这些生化异常与精神分裂症的早期生活压力素质联系起来。该方案的总体设计包括使用体外1HMRS来表征围产期应激对大脑区域N-乙酰天冬氨酸(NAA)和肌醇(MI)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。在30-360日龄的4个发育时间点和8个脑区进行测定。在实验一中，研究人员提出了一种产前应激影响的特征，即对怀孕的水坝进行重复的每日身体约束。来自有压力或无压力的母亲所生的幼崽将在出生时被交叉养育，并由产前有压力或正常的母亲抚养，产生四个试验组。实验二将以母体剥夺的形式描述出生后应激的影响。四个试验组将被用来表征产前应激源与出生后应激的相互作用，这些应激源是由应激与非应激母亲以及母亲剥夺母亲与正常饲养的动物养育而产生的。研究人员提供了初步证据，表明成年男性后代在围产期受到压力时，左侧额叶皮质的NAA减少。该提案将确定在发展过程中这种NAA变化何时出现，以及它是否具有渐进性质。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。建议的研究结果应提供有关精神分裂症患者的神经发育异常与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.