Alcohol, Development/Cerebellar-Hippocampal Interaction

酒精，发育/小脑-海马相互作用

• 批准号: 6900345
• 负责人: Mark E. Stanton
• 金额: $ 23.59万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-05 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6900345
• 关键词: animal developmental psychology; antioxidants; association learning; behavioral /social science research tag; brain stem; cognition disorders; conditioning; developmental neurobiology; disease /disorder model; embryo /fetus drug adverse effect; embryo /fetus toxicology; ethanol; eye movements; fetal alcohol syndrome; gestational age; hippocampus; juvenile animal; laboratory rat; learning disorders; mature animal; neural plasticity; neurons; neurotoxicology; newborn animals; tocopherols

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）：本提案的研究包括互动研究项目补助金（IRRPG）的项目 2。该 IRPG 的长期目标是使用经过充分研究的巴甫洛夫眨眼条件反射变体来了解早期接触酒精对经典条件反射基础神经系统的结构、功能和发育的发育影响。 IRPG 重点关注介导特定形式调节的小脑（项目 1）和海马（项目 2）回路的剂量相关效应。这两个项目都提出了剂量效应函数的发展分析和针对这些电路的抗氧化保护的测试。项目 1 已证实，新生大鼠（人类妊娠第三个月的模型）大量酗酒会导致眨眼条件反射严重受损，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，仅在使用最高剂量时观察到获得条件反应[CR]的缺陷。在项目 2 中，我们提出了新的研究，将使用微量眨眼条件反射来表征行为功能的潜在破坏，这些行为功能涉及低剂量酒精引起的小脑和海马体之间的神经相互作用。具体目标 1 测试了这样的假设：新生儿酒精暴露会在幼年和成年大鼠的微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 CA1 中神经元细胞计数的剂量相关变化相关。目标 1 还将比较酒精对微量条件反射与其他海马依赖性任务（眨眼辨别和逆转、空间延迟交替和情境恐惧条件反射）的影响，以开发与酒精相关的海马-小脑功能影响特异性的证据。具体目标 2 将检查酒精暴露的发育阶段，该阶段可能优先针对海马体而非小脑，以确定两种结构损伤（目标 1）与单独海马体损伤（目标 2）在酒精引起的微量调节缺陷中的相对作用。 具体目标 3 测试了这样的假设：新生儿酒精暴露会在成年大鼠的微量条件反射中产生剂量相关的缺陷。海马单位活动和海马细胞损失的定量评估将提供酒精对微量调理影响的功能和结构相关性。具体目标 4 测试了这样的假设：新生儿暴食期间补充抗氧化剂可以防止酒精引起的海马细胞损失和微量眨眼调节能力的缺陷。这些动物研究可以为未来研究婴儿和儿童产前酒精暴露的影响提供信息，因为眨眼条件反射的行为过程和神经回路在不同物种之间是相似的