TRANSCRIPTION FACTOR/REGULATION IN LEARNING AND MEMORY

University Of Puerto Rico Rio Piedras, San Juan PR

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Abstract

Description (Adapted from Application): The overall goal of this research is to examine the role of transcriptional gene regulation in acquisition and retention of spatial memory. Spatial memory is associative in nature and relates to the orientation and movement of an individual in space in relation to the location of objects in the surrounding environment. A basic understanding of how spatial memories are formed will enable the design of appropriate and effective treatment and prevention strategies for the various neurologic and neuropsychiatric conditions that display alterations in memory processing, such as Alzheimer's disease (AD) and stroke. Regulation of gene expression is considered essential for the establishment of long-lasting cellular changes that underlie the formation of long-term memory. The hzf-3/nurr1 gene is a member of the family of inducible orphan nuclear receptors (ONRs), comprised by immediate-early transcription factors thought to be involved in synaptic plasticity. Recent studies by the PI have shown that the mRNA levels of hzf-3 increase in the rat hippocampus following induction of long-term potentiation at the hippocampal mossy fiber-CA3 synapse and during acquisition of the hole board food search task for spatial memory. Results suggest that the expression of the hzf-3 gene in the hippocampus is closely associated with acquisition and retention of spatial learning. The investigators hypothesize that the hzf-3 protein product is required for normal learning acquisition and that it regulates the transcription of genes whose control is important for appropriate spatial memory formation. This proposal will examine the role of the hzf-3/nurr1 protein product in the formation of long-term spatial memory and will identify genes expressed during acquisition and retention of spatial memory including those that require the hzf-3 product for transcriptional activation. Specific aim 1 will examine the effects of sequence specific antisense oligodeoxynucleotides, designed to block translation of the hzf-3 protein product, on the acquisition of the hole board food search task for spatial memory. Oligodeoxynucleotides are microinfused intrahippocampally prior to training in the hole board food search task and the effects on acquisition and retention are determined. The effectiveness of translational disruption of the hzf-3/nurr1 gene will be determined with Western blots and immunohistochemistry and compared with the behavioral effects of the hzf-3 antisense oligodeoxynucleotides. In specific aim 2, cDNA microarrays are used to define a transcripts expression profile of spatial learning in the Hole Board Food Search Task. Commercially available cDNA microarrays used initially to select candidate learning and memory transcripts will be used to prepare macroarrays on glass slides that will be used for further analysis and validation. The arrays are hybridized with rat hippocampal cDNA probes prepared from rats trained in the food search maze. Finally, studies in specific aim 3 will define an hzf-3 dependent transcriptional profile of spatial learning by combining antisense treatments with cDNA microarray analysis. DNA arrays will be hybridized with cDNA probes prepared from animals trained in the maze after hippocampal injection of either saline, hzf-3 antisense or control oligodeoxynucleotides. The proposed set of experiments will provide new and fundamental knowledge which concerns the molecular mechanisms subserving information storage in the brain and which is necessary for the development of proper management strategies of neural conditions that display problems in memory processing.