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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 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. • Genetic mapping in outbred mice identifies a locus (Smart1) for short-term memory • Thalamic transcriptome stratifies Smart1 haplotypes into high and low performers • Within the Smart1 locus, an orphan GPCR is a potent modifier of short-term memory • Brain recordings reveal Gpr12-driven thalamocortical functions in short-term memory A modifier of short-term memory, the orphan receptor Gpr12 is identified using genetic mapping in outbred mice and characterized to reveal that it enables thalamus-PFC synchrony to support memory maintenance and choice accuracy. [ABSTRACT FROM AUTHOR]