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Changes in the proteome and transcriptome occur rapidly across neuronal compartments in response to plasticity-promoting factors. This coupling between neuronal activity and gene expression varies among cell classes and at single-cell level. While transcriptomic and chromatin-state analyses of activated neurons reveal primary and secondary waves of activity-dependent gene expression48, levels of protein products are often inferred. Here, we demonstrate a powerful methodology to directly measure activity-dependent changes in the proteome with cell-type and compartment specificity. We leverage the subcellular localization and speed of the APEX-based strategy to capture a snapshot of the early changes in the nuclear proteome of dSPNs after chemogenetic activation with hM3Dq35,49,50. We measure protein products of multiple IEGs a few hours after neuronal activation in vivo. These include the AP1, Egr transcription factor family and Arc transcriptional regulator. IEGs are the primary response genes that are thought to control the secondary response genes to elicit long lasting functional and structural changes in neurons48. The extent to which various IEGs are utilized across different neuronal types, as well as their downstream gene targets, remain to be explored. While the development of DREADDs has transformed behavioral neuroscience research, we have limited insight on how gene expression programs are shaped by DREADD activation. Time course studies involving proteomic, transcriptomic, and chromatin-state readouts are likely needed to establish the complete picture of activity-dependent gene expression dynamics and regulation in response to specific stimuli. 153554b96e
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