Memory Consolidation: Hippocampus & Gene Expression

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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.