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A thalamic orphan receptor drives variability in short-term memory
Hsiao, K., Noble, C., Pitman, W., Yadav, N., Kumar, S., Keele, G. R., Terceros, A., Kanke, M., Conniff, T., Cheleuitte-Nieves, C., Tolwani, R., Sethupathy, P., & Rajasethupathy, P. (2020). A thalamic orphan receptor drives variability in short-term memory. Cell, 183(2), 522-536.e19. https://doi.org/10.1016/j.cell.2020.09.011
Working memory is a form of short-term memory that involves maintaining and updating task-relevant information toward goal-directed pursuits. Classical models posit persistent activity in prefrontal cortex (PFC) as a primary neural correlate, but emerging views suggest additional mechanisms may exist. We screened similar to 200 genetically diverse mice on a working memory task and identified a genetic locus on chromosome 5 that contributes to a substantial proportion (17%) of the phenotypic variance. Within the locus, we identified a gene encoding an orphan G-protein-coupled receptor. Gpr12, which is sufficient to drive substantial and bidirectional changes in working memory. Molecular, cellular, and imaging studies revealed that Gpr12 enables high thalamus-PFC synchrony to support memory maintenance and choice accuracy. These findings identify an orphan receptor as a potent modifier of short-term memory and supplement classical PFC-based models with an emerging thalamus-centric framework for the mechanistic understanding of working memory.