The focus of this research proposal is the identification of genes in fruit fly, Drosophila melanogaster; which are transcriptionally induced or post-translationally regulated by neural activity. These genes are likely to be involved in effecting and consolidating important neurological processes such as long-term memory (LTM). LTM is a neuronal process that is dependent on both neural activity and the subsequent synthesis of new proteins. Pharmacological blockade of either process precludes the formation of LTM. The mechanism through which this occurs can be understood as follows: neural activity leads to increased intracellular concentrations of [Ca++] and cAMP. These signals, via molecules such as protein kinase-A (PKA) and calmodulin-kinase (CAMK), lead to activation of transcription factors such as CAMP Responsive Element Binding protein (CREB). Activation of neuronal molecular """"""""switches,"""""""" such as CREB, results in the induction of genes whose products regulate neuronal function and structure, likely at the level of the synapse. The molecules underlying LTM formation are also likely to be involved in other general neuronal processes and in diseases, which affect neuronal growth and survival. Identification of such regulators may be key to improving the diagnosis and treatment of diseases like Alzheimer's and Parkinson's, where neuronal density and efficacy are dramatically and increasingly degraded over time. A great deal is known about the signaling mechanisms involved in LTM, very little is known about the downstream effectors of this process. This proposal hopes to address this significant gap in our available knowledge of long-term neuronal plasticity.
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