Memory Consolidation: Hippocampus & Gene Expression

描述（由申请人提供）：长期记忆（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障碍，我们必须了解大脑中这些不同层面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参与将经验转化为LTM的理解。为此，在这个建议中描述的实验的主要目标是更充分地表征大脑系统的相互作用，控制动态表达的基因的表达，涉及在海马和功能连接的结构在生理相关的条件下的突触可塑性。这些研究采用多学科方法，实验结果将影响分子，系统和行为神经科学领域。Aim 1的目标是表征两个重要的神经调节系统对Arc和其他立即早期基因（IEGs）的功能表达以及对海马结构中神经元的高阶网络功能的作用。目的1a将采用神经化学损伤技术来解决去甲肾上腺素能系统对这些过程的作用;目的1b将采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IEG RNA和蛋白质的稳态水平的确定影响是否是由于合成的变化（例如，是转录或翻译特别受到影响）或营业额的变化。将使用catFISH来探索去甲肾上腺素能和内侧隔系统对海马网络功能的影响，catFISH是一种新型的基于lEG的脑成像方法，可提供细胞和时间分辨率。在目标2中，使用背侧海马和catFISH的可逆失活的动物内设计将用于检查海马神经活动在不同认知任务的学习和检索期间在确定的皮质和皮质下结构中确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表达，以研究这种基因表达在初始学习过程中以及在检索后到随后的记忆过程中的作用。从拟议的研究数据将提供新的见解经验依赖性的IEG表达的调节和作用，涉及海马结构的记忆过程。此外，这些研究将提供一个更完整的了解神经元合奏的相互作用，发生在海马结构和特定的皮质和皮质下结构之间的大鼠响应不同的认知挑战。

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.