McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Molecular and Cellular Neuroscience Graduate Program, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Cell. 2020 Apr 16;181(2):410-423.e17. doi: 10.1016/j.cell.2020.02.055. Epub 2020 Mar 17.
Memories are believed to be encoded by sparse ensembles of neurons in the brain. However, it remains unclear whether there is functional heterogeneity within individual memory engrams, i.e., if separate neuronal subpopulations encode distinct aspects of the memory and drive memory expression differently. Here, we show that contextual fear memory engrams in the mouse dentate gyrus contain functionally distinct neuronal ensembles, genetically defined by the Fos- or Npas4-dependent transcriptional pathways. The Fos-dependent ensemble promotes memory generalization and receives enhanced excitatory synaptic inputs from the medial entorhinal cortex, which we find itself also mediates generalization. The Npas4-dependent ensemble promotes memory discrimination and receives enhanced inhibitory drive from local cholecystokinin-expressing interneurons, the activity of which is required for discrimination. Our study provides causal evidence for functional heterogeneity within the memory engram and reveals synaptic and circuit mechanisms used by each ensemble to regulate the memory discrimination-generalization balance.
记忆被认为是由大脑中稀疏的神经元集合编码的。然而，目前尚不清楚个体记忆印迹内是否存在功能异质性，即是否存在分离的神经元亚群来编码记忆的不同方面，并以不同的方式驱动记忆表达。在这里，我们表明，小鼠齿状回中的情景性恐惧记忆印迹包含功能上不同的神经元集合，这些集合通过 Fos 或 Npas4 依赖性转录途径在基因上定义。Fos 依赖性集合促进记忆泛化，并从内侧缰核接收增强的兴奋性突触输入，我们发现内侧缰核本身也介导泛化。Npas4 依赖性集合促进记忆辨别，并从表达胆囊收缩素的局部中间神经元接收增强的抑制性驱动，其活动对于辨别是必需的。我们的研究为记忆印迹内的功能异质性提供了因果证据，并揭示了每个集合用于调节记忆辨别-泛化平衡的突触和电路机制。
