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Alcohol, Development/Cerebellar-Hippocampal Interaction

酒精，发育/小脑-海马相互作用

基本信息

批准号：
7430447
负责人：
Mark E. Stanton
金额：
$ 22.37万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-05 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7430447
关键词：
Adolescent Adult Alcohols Animal Model Animals Antioxidants Behavioral Blinking Blood alcohol level measurement Brain Cell Count Cell Nucleus Cerebellum Child Condition Data Development Discrimination Disruption Dose Evaluation Fetal Alcohol Exposure Foundations Future Goals Hippocampus (Brain)Human Impairment Individual Infant Inferior Investigation Learning Light Measures Mediating Memory Modeling Neonatal Neonatal Alcohol Exposure Neuroanatomy Neurons Numbers Olives - dietary Outcome Performance Procedures Process Property Purkinje Cells Range Rattus Regression Analysis Relative (related person)Research Personnel Research Project Grants Resources Role Specificity Structure System Testing Trolox Variant Vitamin E Water alcohol effect alcohol exposure behavior test classical conditioning clinically relevant conditioned fear conditioning day exposed human population functional disability hippocampal cell loss hippocampal pyramidal neuron neural circuit neurophysiology postnatal prevent programs relating to nervous system research study response

项目摘要

DESCRIPTION (provided by applicant): The studies of this proposal comprise Project 2 of an Interactive Research Project Grant (IRPG). The long-term goals of this IRPG are to use well-studied variants of Pavlovian eyeblink conditioning to understand the developmental consequences of early exposure to alcohol on the structure, function, and development of defined neural systems underlying classical conditioning. The IRPG focuses on dose-related effects on cerebellar (Project 1) and hippocampal (Project 2) circuits that mediate specific forms of conditioning. Developmental analyses of the dose-effect functions and tests of antioxidant protection against damage to these circuits are proposed in both projects. Project 1 has confirmed that heavy binge alcohol exposure in neonatal rats, a model of 3rd trimester human exposure, produces severe impairments in eyeblink conditioning that are correlated with deficits in cerebellar neuron numbers and learning-related unit activity. However, deficits in acquisition of conditioned responses [CRs] were observed only with the highest dose used. In Project 2, we propose new studies that will use trace eyeblink conditioning to characterize potential disruption of behavioral functions involving neural interactions between cerebellum and hippocampus induced by lower doses of alcohol. Specific Aim 1 tests the hypothesis that neonatal alcohol exposure will produce dose-related deficits in trace eyeblink conditioning in juvenile and adult rats, and that these deficits will correlate with dose-related changes in neuronal cell counts in CA1 of the hippocampus. Aim 1 will also compare effects of alcohol on trace conditioning with those on other hippocampal-dependent tasks---eyeblink discrimination and reversal, spatial delayed alternation, and contextual-fear conditioning--to develop converging evidence toward the specificity of alcohol-related effects on hippocampal-cerebellar function. Specific Aim 2 will examine a developmental period of alcohol exposure that may target the hippocampus preferentially over the cerebellum, in order to determine the relative role of damage to both structures (Aim 1), vs. the hippocampus alone (Aim 2), in alcohol-induced trace conditioning deficits. Specific Aim 3 tests the hypothesis that neonatal alcohol exposure will produce dose-related deficits in trace conditioning in adult rats. Hippocampal unit activity and quantitative assessment of hippocampal cell loss will provide functional and structural correlates of alcohol effects on trace conditioning. Specific Aim 4 tests the hypothesis that antioxidant supplements during the neonatal binge exposure can protect against alcohol- induced hippocampal cell loss and deficits in trace eyeblink conditioning. These animal studies can inform future studies of effects of prenatal alcohol exposure in infants and children, because the behavioral procedures and neural circuits underlying eyeblink conditioning are similar across species

描述(由申请人提供)：本建议的研究包括互动研究项目补助金(IRPG)的项目2。该IRPG的长期目标是使用研究良好的巴甫洛夫眨眼条件作用的变体来了解早期接触酒精对经典条件作用下特定神经系统的结构、功能和发育的发育后果。IRPG的重点是调节特定形式的条件反射的小脑(项目1)和海马体(项目2)电路上的剂量相关效应。在这两个项目中，都提出了剂量效应功能的发展分析和抗氧化剂保护这些电路免受损害的测试。项目1已经证实，新生大鼠大量酗酒暴露，这是人类暴露于晚期妊娠的一个模型，会导致眨眼条件反射的严重损害，这与小脑神经元数量和学习相关单位活动的缺陷有关。然而，只有在使用最高剂量的情况下，才能观察到条件反应[CRS]获得的缺陷。在项目2中，我们提出了一项新的研究，将使用示踪眨眼条件反射来表征较低剂量酒精引起的涉及小脑和海马区之间神经相互作用的行为功能的潜在干扰。特定目的1测试了一种假设，即新生儿酒精暴露将在幼年和成年大鼠的痕量眨眼条件反射中产生剂量相关的缺陷，并且这些缺陷将与海马区CA1区神经细胞计数的剂量相关变化相关。目的1还将比较酒精对痕迹条件反射和其他海马区依赖任务的影响-眨眼辨别和翻转、空间延迟交替和背景恐惧条件反射--以发展关于酒精相关影响对海马体-小脑功能的特异性的一致证据。特定目标2将研究酒精暴露的一个发育期，它可能优先针对海马体而不是小脑，以确定两个结构(目标1)与单独的海马体(目标2)在酒精诱导的痕迹条件反射缺陷中的相对作用。《特定目的3》测试了新生儿酒精暴露会在成年大鼠的跟踪条件反射中产生剂量相关缺陷的假说。海马区单位活动和海马区细胞损失的定量评估将提供酒精对痕量条件反射影响的功能和结构相关性。特定目标4测试了这样的假设，即在新生儿暴饮暴食期间补充抗氧化剂可以防止酒精诱导的海马细胞丢失和微量眨眼条件反射缺陷。这些动物研究可以为未来有关婴儿和儿童产前酒精暴露影响的研究提供信息，因为不同物种的行为程序和眨眼条件作用下的神经回路是相似的