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资助（IRPG）的项目2。这个IRPG的长期目标是使用巴甫洛夫眨眼条件反射的研究变体，以了解早期暴露于酒精对经典条件反射基础的定义神经系统的结构，功能和发育的发育后果。IRPG侧重于对介导特定形式条件反射的小脑（项目1）和海马（项目2）回路的剂量相关效应。在这两个项目中提出了剂量效应函数和抗氧化剂保护对这些电路的损害的测试的发展分析。项目1已证实，新生大鼠重度酗酒暴露（人类妊娠晚期暴露的模型）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相关。然而，仅在使用最高剂量时观察到条件反应[CR]的获得缺陷。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低剂量酒精诱导的小脑和海马之间的神经相互作用的行为功能的潜在破坏。具体目标1测试的假设，即新生儿酒精暴露将产生剂量相关的缺陷，在微量眨眼条件的青少年和成年大鼠，这些赤字将与剂量相关的变化，在海马CA 1区的神经元细胞计数。目标1还将比较酒精对痕迹条件反射的影响与其他依赖于大脑半球的任务--眨眼的歧视和逆转，空间延迟交替，和上下文恐惧条件反射-发展会聚的证据对大脑半球小脑功能的酒精相关影响的特异性。具体目标2将检查酒精暴露的发育期，其可能优先靶向海马而不是小脑，以确定对两种结构的损伤（目标1）与单独海马（目标2）在酒精诱导的微量条件反射缺陷中的相对作用。 具体目标3测试的假设，即新生儿酒精暴露将产生剂量相关的缺陷，在成年大鼠的痕量条件反射。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条件反射影响的功能和结构相关性。具体目标4测试的假设，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损失和微量眨眼条件反射的缺陷。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程序和神经回路在物种之间是相似的