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复杂的相互作用。为了更好地治疗和诊断影响记忆和认知的精神健康障碍，我们必须了解大脑中这些不同层次上发生的复杂相互作用。这个研究项目的长期目标是增加对由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，本文所述实验的主要目的是更全面地描述在生理相关条件下，控制海马突触可塑性和功能连接结构中动态表达基因表达的脑系统相互作用。这些研究采用多学科方法，实验结果将影响分子神经科学、系统神经科学和行为神经科学领域。Aim1的目的是表征两个重要的神经调节系统对Arc和其他即时早期基因（lEGs）的功能表达和海马形成神经元的高阶网络功能的作用。Aim la将采用神经化学损伤技术来解决去肾上腺素能系统在这些过程中的作用；目的：采用可逆失活方法研究中间隔神经活动对这些过程的影响。基因表达分析将检查对lEG RNA和蛋白质稳态水平的确定影响是由于合成的变化（例如，转录或翻译是否受到特别影响）还是由于周转的变化。去甲肾上腺素能和内侧间隔系统对海马网络功能的影响将使用catFISH，一种新的基于腿的脑成像方法，提供细胞和时间分辨率。在第二项研究中，研究人员将采用动物体内设计，对海马背侧和鲶鱼进行可逆失活，以检验海马神经活动在不同认知任务的学习和检索过程中，在确定的皮层和皮层下结构中启动神经活动模式的作用。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阻断经验依赖的基因表达，以检查此类基因表达在初始学习和检索后的后续记忆过程中的作用。这些研究的数据将为经验依赖的lEG表达对海马形成记忆过程的调节和作用提供新的见解。此外，这些研究将提供一个更完整的理解神经元集合的相互作用，发生在海马结构和特定皮层和皮层下结构之间，当大鼠对不同的认知挑战作出反应。

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.