With the aim of understanding the molecular regulation of vertebrate adult neural plasticity, this research has led to the identification of several genes in songbirds that encode novel proteins with apparent structural domains and patterns of RNA distribution suggesting fundamental roles in plasticity, especially in the forebrain. The focus of the next phase of this research is on two of these: HAT-3 and HAT-14. They apparently encode proteins not described before. However, the putative proteins have distinctive features which suggest that: 1) they should be conserved more widely in vertebrates, and 2) they may be involved in synaptic processes related to plasticity.
The specific aims of this research are to test those two hypotheses. To accomplish this, homologous genes will be isolated from the rat, and the presence of related sequences in other organisms will be assessed using nucleic acid hybridization techniques. Antibodies which recognize the encoded proteins will be generated and used to determine the distribution of the proteins in rat songbird (zebra finch) brain.
The aim will be determine whether the proteins are associated with synaptic or dendritic regions, or other defined sites of neural plasticity. These sites include (in rats) the cerebral cortex and hippocampus, and (in songbirds) the plastic song control centers and NCM, an associative forebrain region in which this investigator has identified rapid genomic responses to the sound of birdsong. The proteins will also be tested for activity as kinase substrates, as suggested by their sequences. Behavioral and developmental paradigms in both rats and songbirds will then be used to determine whether the proteins change (in amount, distribution, or phosphorylation) with changing levels of plasticity or synapse formation. Analyses in a cell line from human forebrain (HCN-1) may allow further mechanistic tests on function. The identification and characterization of the molecular components involved in regulation of forebrain function and plasticity is a first and essential step towards the ultimate development of therapies designed to promote human brain repair or rekindle plasticity in aging.
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