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检验精神分裂症的神经发育假说。不同的证据表明，精神分裂症有一个神经发育的组成部分，病因不明，其中大脑损伤发生在早期发展。流行病学研究表明，人类后代暴露于发育损伤，如营养不良，病毒感染，产科并发症，和压力是在较高的风险，为精神分裂症的后续发展。可能与神经发育损伤相关的脑病理学包括通过质子（1H）磁共振波谱（MRS）测量的异常生物化学。研究者建议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，通过评估精神分裂症的MRS结果是否可以通过大鼠的早期发育损伤来重现。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。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I中，研究者提出了一个表征的产前压力的影响，在怀孕的母鼠每天重复的身体约束的形式。从压力或非压力的母亲出生的幼崽将在出生时交叉寄养，并由产前压力或正常的母亲抚养，产生四个实验组。实验二将描述产后压力以母亲被剥夺的形式产生的影响。四个实验组将被用来表征的产前压力源与产后压力的相互作用所产生的饲养压力与非压力的妈妈和母亲剥夺与正常饲养的动物。研究者提供的初步证据表明，成年男性后代在围产期受到压力，表现出左额叶皮质NAA减少。该提案将确定在开发过程中何时出现这种NAA变化，以及它是否具有渐进性。还将确定NAA浓度与应激反应的行为、神经内分泌和神经化学措施之间的关系。拟议的研究结果应提供基本信息之间的潜在联系的神经发育异常和异常的成人神经化学定义的1H MRS精神分裂症。

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.