A Thalamic Orphan Receptor Drives Variability in Short Term Memory

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 ~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 bi-directional 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 a novel 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. Overall design: Examination of short term memory using Diversity Outbred mice and interrigation through QTL and RNAseq analysis.