FETAL ALCOHOL EXPOSURE ALTERS NEUROCHEMICAL RESPONSES TO

胎儿酒精暴露会改变神经化学反应

• 批准号: 6085860
• 负责人: Kevin K. Caldwell
• 金额: $ 7.25万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6085860
• 关键词: alcoholic beverage consumption; behavioral /social science research tag; biological signal transduction; conditioning; drug administration rate /duration; embryo /fetus toxicology; enzyme activity; ethanol; fear; frontal lobe /cortex; gestational age; hippocampus; laboratory rat; neurochemistry; pharmacokinetics; phospholipase C

Maternal consumption of moderate levels of ethanol causes subtle cognitive and behavioral aberrations in offspring. In rats, feat alcohol exposure (FAE) has been associated with decrements in various measures of learning, including spatial learning, operant learning and learned fear. We hypothesize that alterations in phosphatidylinositol-specific phospholipase C-beta1a (PLC-beta1a)-dependent signaling may underlie these learning deficits. In support of this hypothesis, we have found that PLC-beta1a enzyme activities and protein levels in rat HPC (HPC) and medial frontal cortex (MFC) are altered one and twenty-four hours following one-trial fear conditioning (OTFC) and that FAE modifies these responses. In order to further characterize the role of PLC-beta1A in OTFC and to assess the effect of FAE on PLC-beta1a-dependent signaling, we propose: AIM 1: To determine the time course of OTFC-induced changes in PLC- beta1a subcellular distribution and catalytic activity in rats exposed or not, to moderate novels levels of ethanol through gestation. Our initial studies demonstrate that FAE alters PLC-beta1a responses measured one and twenty-four following OTFC. These studies do not, however, provide sufficient data to conclude whether FAE simply alters the magnitudes of the responses only at these times following conditioning or whether it alters the temporal patterns of the response. In the present studies we will address this by measuring PLC-beta1a enzyme activities and protein levels at several other times following conditioning. By obtaining a more detailed profile of the effects of OTFC on PLC-beta1 in control and FAE rats, we will be able to determine if FAE alters the temporal patterns or the magnitudes of the responses to OTFC. AIM 2: To determine the effects of OTFC and FAE on the kinetics of PLC-beta1a enzyme activity. Previously, we reported that FAE reduces basal PLC-beta1 enzyme activity in rat HPC and MHC. In preliminary studies, we have found that this decrease may be the result of a change in the kinetics of the enzyme-catalyzed reaction. We do not know, however, whether, the FAE-dependent changes in PLC-beta1a enzyme activity that we measured and twenty-four hours following OTFC are the result of alterations in enzyme kinetics. In the present studies, we will perform detailed analyses of the effects of OTFC and FAE on the kinetics of PLC- beta1 enzyme activity. These determinations will provide significant insight into the mechanism(s) through which OTFC and FAE regulate PLC-beta1 enzyme activity. Identification of the neurochemical abnormalities that underlie the cognitive and behavioral deficits associated with FAE will facilitate the development of rationale treatment strategies.

母亲摄入适量的乙醇会导致后代出现微妙的认知和行为畸变。在大鼠中，酒精暴露（FAE）与各种学习措施的减少有关，包括空间学习，操作学习和学习恐惧。我们推测磷脂酰肌醇特异性磷脂酶C-β 1a（PLC-β 1a）依赖性信号的改变可能是这些学习缺陷的基础。为了支持这一假设，我们发现大鼠HPC（HPC）和内侧额叶皮层（MFC）中的PLC-β 1a酶活性和蛋白质水平在一次试验恐惧条件反射（OTFC）后1小时和24小时发生变化，并且FAE改变了这些反应。为了进一步表征PLC-β 1A在OTFC中的作用并评估FAE对PLC-β 1a依赖性信号传导的影响，我们提出：目的1：确定在妊娠期间暴露于或不暴露于中等新水平乙醇的大鼠中，OTFC诱导的PLC-β 1a亚细胞分布和催化活性变化的时间过程。我们的初步研究表明，FAE改变了在OTFC后1和24天测量的PLC-β 1a反应。然而，这些研究没有提供足够的数据来得出结论，是否FAE只是改变了这些时间后的条件反射的反应的幅度，或者是否它改变了时间模式的反应。在目前的研究中，我们将通过测量PLC-β 1a酶活性和蛋白质水平在其他几个时间后调节解决这个问题。通过获得OTFC对对照和FAE大鼠中PLC-β 1的影响的更详细的概况，我们将能够确定FAE是否改变了对OTFC的反应的时间模式或幅度。目的2：研究OTFC和FAE对PLC-β 1a酶活性动力学的影响。以前，我们报告说，FAE降低基础PLC-β 1酶活性在大鼠HPC和MHC。在初步研究中，我们发现这种降低可能是酶催化反应动力学变化的结果。然而，我们不知道我们测量的和OTFC后24小时的PLC-β 1a酶活性的FAE依赖性变化是否是酶动力学改变的结果。在本研究中，我们将详细分析OTFC和FAE对PLC-β 1酶活性动力学的影响。这些测定将提供对OTFC和FAE调节PLC-β 1酶活性的机制的重要见解。识别与FAE相关的认知和行为缺陷的神经化学异常，将促进合理治疗策略的发展。