A Thalamic Orphan Receptor Drives Variability in Short-Term Memory

Cell. 2020 Oct 15;183(2):522-536.e19. doi: 10.1016/j.cell.2020.09.011. Epub 2020 Sep 29.


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.

Keywords: GPCR; RNA; genetic Variation/genetics; genome/genetics; memory/physiology; messenger/analysis; mice; neural pathways/physiology; outbred; prefrontal cortex/physiology; quantitative trait loci/genetics; thalamus/cytology; thalamus/physiology; transcriptome/genetics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Male
  • Memory, Short-Term / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Neural Pathways / physiology
  • Neurons / metabolism
  • Neurons / physiology
  • Prefrontal Cortex / physiology
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism
  • Thalamus / metabolism*


  • Gpr12 protein, mouse
  • Receptors, G-Protein-Coupled