Mechanisms of Context Conditioning in the Developing Rat

描述（申请人提供）：近年来，情境恐惧条件反射已成为研究啮齿动物连接/空间信息加工正常与异常发展的重要范式。然而，关于在个体发生过程中引起环境条件反射的神经机制，我们知之甚少。为此，我们建议使用情境暴露前促进效应（CPFE）。CPFE是情境恐惧条件反射的一种变体，其中情境记忆的学习、情境记忆的巩固和检索、情境记忆与休克的关联以及情境-休克关联的检索发生在该过程的不同阶段，这使得它们特别适合实验操作，可以揭示潜在的机制。最近的CPFE模型表明，这些过程依赖于颞皮质区域、海马体和杏仁核之间的相互作用[65]。我们实验室的新数据表明，前额皮质也参与CPFE。此外，我们最近的研究表明，CPFE出现在大鼠的产后（PD） 17和PD24之间，并且在环境预暴露期间海马NMDA受体的拮抗消除了对PD24的影响[74]。目前的建议将通过研究即时早期基因（IEG）激活和前额叶皮层-海马-杏仁核相互作用在CPFE个体发生中的作用来扩展这项工作。我们发现，在幼年大鼠CPFE的不同阶段，这些脑区中直接早期基因Egr1的表达模式不同（见意义）。目的1将确定这些Egr-1表达模式的变化是否与CPFE的早期个体发生有关。目的2将使用Egr1的反义来测试这些eeg在CPFE个体发生中激活的因果作用。目的3将扩展目的1和目的2的发现，探索胎儿酒精谱系障碍（FASD）动物模型中认知发育受损的机制。我们最近发现，在我们建立的FASD啮齿动物模型中，CPFE对不同剂量的酒精暴露和发育窗口异常敏感[49,50]。目的3将检验前额叶皮质、海马体和/或杏仁核中IEG表达受损导致发育性酒精暴露导致CPFE严重中断的假设。总的来说，本提案的工作将促进对大鼠认知发展机制的理解，并促进这种理解在FASD中发现的人类发展性学习障碍的转化应用。

DESCRIPTION (provided by applicant): In recent years, contextual fear conditioning has become a prominent paradigm for studying normal and abnormal development of conjunctive/spatial information processing in rodent models. However, very little is known concerning the neural mechanisms that cause context conditioning to emerge during ontogeny. We propose to use the context pre-exposure facilitation effect (CPFE) for this purpose. The CPFE is a variant of contextual fear conditioning in which learning about the context, consolidation and retrieval of the context memory, associating the context memory with shock, and retrieval of the context-shock association occur during separate phases of the procedure, making them especially amenable to experimental manipulations that can reveal underlying mechanisms. A recent model of the CPFE suggests that these processes depend on interactions between temporal cortical regions, the hippocampus, and the amygdala [65].. New data from our lab demonstrates the prefrontal cortex is also involved in the CPFE. Furthermore, we have recently shown that the CPFE emerges between Postnatal Day (PD) 17 and PD 24 in the rat and that antagonism of hippocampal NMDA receptors during context preexposure eliminates the effect on PD24 [74]. The present proposal will extend this work by examining the role of immediate early gene (IEG) activation and prefrontal cortex-hippocampus-amygdala interactions in the ontogeny of the CPFE. We have found distinct patterns of expression of the immediate early gene, Egr1, in these brain regions during different phases of the CPFE in juvenile rats (see Significance). Aim 1 will determine whether changes in these patterns of Egr-1 expression are associated with the early ontogeny of the CPFE. Aim 2 will use antisense to Egr1 to test a causal role for activation of these IEGs in the ontogeny of the CPFE. Aim 3 will extend the findings from Aims 1 and 2 to explore mechanisms of impaired cognitive development in an animal model of Fetal Alcohol Spectrum Disorder (FASD). We have recently shown that the CPFE is unusually sensitive to various doses and developmental windows of alcohol exposure in our established rodent model of FASD [49, 50]. Aim 3 will test the hypothesis that impaired IEG expression in the prefrontal cortex, hippocampus and/or amygdala contributes to the severe disruptions of the CPFE produced by developmental alcohol exposure. Taken as a whole, the work in this proposal will advance understanding of the mechanisms of cognitive development in the rat and promote translational applications of this understanding to human developmental learning disorders found in FASD.