That osteocalcin (OCN) is necessary for hippocampal-dependent memory and to prevent anxiety-like behaviors raises novel questions. One question is to determine whether OCN is also sufficient to improve these behaviors in wild-type mice, when circulating levels of OCN decline as they do with age. Here we show that the presence of OCN is necessary for the beneficial influence of plasma from young mice when injected into older mice on memory and that peripheral delivery of OCN is sufficient to improve memory and decrease anxiety-like behaviors in 16-mo-old mice. A second question is to identify a receptor transducing OCN signal in neurons. Genetic, electrophysiological, molecular, and behavioral assays identify Gpr158, an orphan G protein–coupled receptor expressed in neurons of the CA3 region of the hippocampus, as transducing OCN’s regulation of hippocampal-dependent memory in part through inositol 1,4,5-trisphosphate and brain-derived neurotrophic factor. These results indicate that exogenous OCN can improve hippocampal-dependent memory in mice and identify molecular tools to harness this pathway for therapeutic purposes.

骨钙素（OCN）对于海马依赖性记忆和预防焦虑样行为是必需的，这提出了新的问题。一个问题是确定当OCN的循环水平随着年龄的增长而下降时，OCN是否也足以改善野生型小鼠的这些行为。在这里，我们表明，OCN的存在对于从年轻小鼠血浆中注入到老年小鼠中对记忆产生有益影响是必要的，而OCN的周边递送足以改善记忆力并减少16个月大小鼠的焦虑样行为。第二个问题是鉴定在神经元中转导OCN信号的受体。遗传，电生理，分子和行为分析可鉴定Gpr158，一种孤立的G蛋白偶联受体，在海马CA3区的神经元中表达，部分通过肌醇1,4,5-三磷酸酯和脑源性神经营养因子转导OCN对海马依赖性记忆的调节。这些结果表明，外源性OCN可以改善小鼠海马依赖性记忆，并确定分子工具来利用该途径进行治疗。