Alcohol, Development/Cerebellar-Hippocampal Interaction

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。该IRPG的长期目标是利用巴甫洛夫眨眼条件反射的变体来了解早期暴露于酒精对经典条件反射基础的特定神经系统的结构、功能和发育的发育后果。IRPG的重点是剂量对小脑（项目1）和海马（项目2）回路的影响，这些回路介导特定形式的条件反射。在这两个项目中提出了剂量效应功能的发展分析和抗氧化保护这些电路的试验。项目1已经证实，在新生大鼠（妊娠晚期人类暴露的模型）中，大量酗酒会导致眨眼条件反射的严重损伤，这与小脑神经元数量和学习相关单元活动的缺陷有关。然而，只有在使用最高剂量时才观察到条件反应（CRs）的习得缺陷。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涉及小脑和海马体之间神经相互作用的行为功能的潜在破坏。特异性目的1验证了一种假设，即新生儿酒精暴露将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神经元细胞计数的剂量相关变化相关。目的1还将比较酒精对微量条件反射的影响与对其他海马体依赖任务的影响——眨眼辨别和逆转、空间延迟交替和情境恐惧条件反射——以发展酒精对海马体-小脑功能特异性影响的趋同证据。专项目的2将检查酒精暴露的发育时期，该时期可能优先针对海马而不是小脑，以确定在酒精诱导的微量条件反射缺陷中，对这两个结构的损伤（目的1）与单独的海马（目的2）的相对作用。

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