Memory Consolidation: Hippocampus & Gene Expression

描述(申请人提供)：长时记忆(LTM)的形成和表达涉及基因产物、突触、细胞和细胞网络之间的复杂相互作用。为了更好地治疗和诊断影响记忆和认知的心理健康疾病，我们必须了解大脑中这些不同水平发生的复杂相互作用。这项研究计划的长期目标是增加对学习激活的基因表达如何将经验转化为LTM的理解。为此，这项建议中描述的实验的主要目标是更全面地描述大脑系统的相互作用，这些相互作用控制与海马区突触可塑性有关的动态表达基因的表达，以及在生理相关条件下的功能连接结构。这些研究采用了多学科方法，实验结果将影响分子、系统和行为神经科学领域。Aim1的目标是表征两个重要的神经调节系统对Arc和其他即刻早期基因(LEGS)的功能表达以及对海马区神经元的高阶网络功能的作用。目的1a将使用神经化学损伤技术来研究去甲肾上腺素系统在这些过程中的作用；目的1b将使用可逆失活方法来检查内侧隔神经活动对这些过程的影响。基因表达分析将检查对腿部RNA和蛋白质稳定水平的明确影响是否源于合成的变化(例如，转录或翻译是否受到特定影响)或周转的变化。我们将使用一种新型的基于腿部的脑成像方法，提供细胞和时间分辨率，以探索去甲肾上腺素能系统和内侧隔系统对海马网功能的影响。在目标2中，将使用动物内设计，使用可逆性失活的背侧海马体和鲶鱼，以检查在不同认知任务的学习和提取过程中，海马神经活动在确定的皮质和皮质下结构中建立神经活动模式中的作用。在目标3中，我们将使用转录和翻译抑制剂以及反义寡核苷酸来阻断经验依赖性基因的表达，以检查这些基因在最初学习和恢复到后续记忆过程中的作用。来自拟议研究的数据将为经验依赖型腿部表达对涉及海马结构的记忆过程的调节和作用提供新的见解。此外，这些研究将提供更完整的了解，当大鼠对不同的认知挑战做出反应时，发生在海马结构内以及特定皮质和皮质下结构之间的神经元整体相互作用。

DESCRIPTION (provided by applicant): The formation and expression of long-term memory (LTM) involves complex interplay between gene products, synapses, cells, and cellular networks. To better treat and diagnose mental health disorders that affect memory and cognition, we must understand the complex interactions that occur at these different levels in the brain. The long-term objective of this research program is to increase understanding of how gene expression, activated by learning, is involved in transforming experience into LTM. To this end, the main goal of experiments described in this proposal is to characterize more fully the brain systems interactions that control the expression of dynamically expressed genes implicated in synaptic plasticity in hippocampus and functionally connected structures under physiologically relevant conditions. These studies employ a multidisciplinary approach, and the experimental findings will impact the fields of molecular-, systems-, and behavioral neuroscience. The goal of Aim1 is to characterize the role of two important neuromodulatory systems to the functional expression of Arc and other immediate-early genes (lEGs) and on higher-order network functions of neurons in the hippocampal formation. Aim la will employ neurochemical lesion techniques to address the role of the noradrenergic system to these processes; Aim lb will employ reversible inactivation methods to examine the influence of medial septal neural activity on these processes. Gene expression analysis will examine whether defined effects on steady-state levels of lEG RNA and protein are due to changes in the synthesis (e.g., is transcription or translation specifically affected) or changes in turnover. The influence of the noradrenergic and medial septal systems on hippocampal network functions will be explored using catFISH, a novel lEG-based brain imaging method that provides both cellular and temporal resolution. In Aim 2, a within-animal design using reversible inactivations of the dorsal hippocampus and catFISH will be used to examine the role of hippocampal neural activity in instating neural activity patterns in defined cortical and subcortical structures during the learning and retrieval of different cognitive tasks. In Aim 3, we will block experience dependent gene expression using transcriptional and translational inhibitors, as well as antisense oligonucleotides, to examine the role of such gene expression during initial learning and after retrieval to subsequent memory processes. Data from the proposed studies will provide new insights into the regulation and role of experience-dependent lEG expression to memory processes involving the hippocampal formation. Additionally, these studies will provide a more complete understanding of the neuronal ensemble interactions that occur within the hippocampal formation and between specific cortical and subcortical structures as rats respond to different cognitive challenges.