The Worley laboratory examines the role of dynamic gene expression in long-term synaptic plasticity. His laboratory has made important advances in describing the functional contribution of IEG proteins such as Homer, Narp and Arc, which are rapidly upregulated by cocaine and target to excitatory synapses. Experiments in Aim 1 will continue this approach and examine the function of the IEG termed Rheb (Ras Homolog Enriched in Brain). Rheb is a unique member of the Ras family of small GTP binding proteins that is epressed at high levels in developing and adult forebrain, and is rapidly induced following cocaine administration. Biochemical studies indicate that Rheb couples to Raf under conditions of concomitant activation of protein kinase A (PKA). Rheb is unique in this regard as coupling of H-Ras to Raf is typically blocked by PKA. PKA is persistently up regulated with the induction long-term potentiation and during responses to dopamine receptor activation. A conditional deletion mutant for Rheb will be generated and used to examine the hypothesis that Rheb plays a special role in models of synaptic and behavioral plasticity.
Aim 2 will develop a new line of investigation that is based on the recent demonstration that Arc mRNA induction permits histochemical detection of stable neural networks in mammalian brain. A novel mouse model will be generated that fuses a green fluorescent protein (GFP) to Arc such that the natural Arc promoter will express the fusion gene. Neurons that naturally activate Arc will also activate Arc-GFP. Initial studies will confirm that the Arc-GFP transgene is expressed with the same dynamics and cellular specificity as native Arc. Once validated, we will identify and study properties of living neurons that express Arc-GFP using slice electrophysiology in combination with 2-photon microscopy. Important uses of the model will be to identify and study neural networks that underlie behavior and the neural-network substrate of addiction.
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