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: 6362197
• 负责人: Kevin K. Caldwell
• 金额: $ 7.35万
• 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/6362197
• 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.

母亲摄入适量的酒精会导致后代出现微妙的认知和行为异常。在大鼠中，酒精暴露(FAE)与各种学习指标的减少有关，包括空间学习、操作性学习和获得性恐惧。我们推测，依赖于磷脂酰肌醇的磷脂酶C-β1a(PLC-β1a)信号的改变可能是这些学习缺陷的基础。为了支持这一假说，我们发现，在一次恐惧条件反射(OTFC)后1小时和24小时，大鼠HPC(HPC)和内侧额叶皮质(MFC)中PLC-β1a酶的活性和蛋白水平发生了变化，而FAE改变了这些反应。为了进一步研究PLC-β1a在OTFC中的作用，并评估FAE对PLC-β1a依赖的信号转导的影响，我们提出：目的1：确定OTFC诱导的PLC-β1a亚细胞分布和催化活性变化的时程，以达到妊娠期间适度酒精水平。我们的初步研究表明，FAE改变了PLC-Beta1a的反应，在OTFC之后测量了24次。然而，这些研究没有提供足够的数据来得出结论，FAE是否仅仅在条件反射之后的这些时间改变了反应的大小，或者它是否改变了反应的时间模式。在目前的研究中，我们将通过在条件化后的其他几个时间段测量PLC-Beta1a酶的活性和蛋白质水平来解决这个问题。通过更详细地了解OTFC对对照组和FAE大鼠PLC-β1的影响，我们将能够确定FAE是否改变了OTFC的时间模式或反应的幅度。目的：研究OTFC和FAE对PLC-Beta1a酶活性的影响。此前，我们曾报道过FAE可降低大鼠HPC和MHC的基础PLC-β1酶活性。在初步研究中，我们发现这种下降可能是酶催化反应动力学改变的结果。然而，我们不知道我们测量的依赖FAE的PLC-β1a酶活性的变化以及OTFC后24小时是否是酶动力学变化的结果。在本研究中，我们将详细分析OTFC和FAE对PLC-β1酶活性动力学的影响。这些测定将为深入了解OTFC和FAE调节PLC-β1酶活性的机制(S)提供重要的见解。识别与FAE相关的认知和行为缺陷背后的神经化学异常将有助于制定合理的治疗策略。