Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA.
Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
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.
工作记忆是一种短期记忆形式，涉及维持和更新与目标导向追求相关的任务相关信息。经典模型假设前额叶皮层（PFC）中的持续活动是主要的神经相关物，但新兴观点表明可能存在其他机制。我们在一项工作记忆任务中对大约 200 只遗传多样性的小鼠进行了筛选，并在 5 号染色体上确定了一个遗传位点，该位点对表型变异的很大一部分（17%）有贡献。在该位点内，我们鉴定出一个编码孤儿 G 蛋白偶联受体 Gpr12 的基因，该基因足以驱动工作记忆的大量双向变化。分子、细胞和成像研究表明，Gpr12 使丘脑 - 前额叶皮层同步性升高，从而支持记忆维持和选择准确性。这些发现确定了一个孤儿受体作为短期记忆的有力调节剂，并以新兴的丘脑中心框架补充了经典的基于 PFC 的模型，用于工作记忆的机制理解。
