Memory engrams: Recalling the past and imagining the future.
Memory engrams: Recalling the past and imagining the future.
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DOI：
10.1126/science.aaw4325
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发表时间：
2020-01-03
期刊：
影响因子：
--
通讯作者：
Tonegawa S
中科院分区：
文献类型：
--
作者：
Josselyn SA;Tonegawa S
记忆以持久的变化形式储存在大脑中的想法至少可以追溯到柏拉图和亚里士多德时代（大约公元前350年），但它的科学表述出现在20世纪，当时理查德·西蒙（Richard Semon）引入了“印痕”（engram）一词来描述存储和回忆记忆的神经基质。从本质上讲，Semon提出，一种经历激活了一群神经元，这些神经元经历了持续的化学和/或物理变化，成为印记。随后，在经历时可用的线索重新激活印痕，诱发记忆检索。在卡尔·拉什利未能在老鼠大脑中找到这种印记之后，试图定位印记的研究基本上被放弃了。唐纳德·o·赫布（Donald O. Hebb）提出的增强突触强度和神经元连通性对记忆形成至关重要的理论，在这一理论的推动下，许多研究人员发现突触强度的增强与记忆有关。然而，突触连通性的这些持久变化与细胞整体水平上特定的、行为可识别的记忆之间的因果关系有待于实验技术的进一步发展。印迹研究的复苏可能与两项互补的研究有关，这两项研究应用干预策略来靶向支持小鼠特定记忆的印迹中的单个神经元。一项研究表明，切除分配给一个假定印痕的外侧杏仁核神经元亚群会破坏随后的记忆检索（功能丧失）。第二项研究表明，在没有外部检索线索（功能获得）的情况下，人工重新激活在恐惧经历中活跃的海马齿状回神经元子集（因此，是假定的印记的一部分）诱导记忆检索。许多实验室随后的研究结果使用了类似的策略来识别支持不同类型记忆的其他大脑区域的印记。最近在印痕研究方面有一些进展。首先，在给定的大脑区域内，符合条件的神经元会竞争分配给一个印痕，而神经元的相对兴奋性决定了这种竞争的结果。基于兴奋性的竞争也指导了大脑中多个印痕的组织，并决定了这些印痕如何相互作用。其次，研究印迹细胞（神经元是印迹的关键组成部分）的离线、持久变化的本质发现，这些神经元的突触强度和脊柱密度增加，以及与其他下游印迹细胞的优先连接。因此，增加的内在兴奋性和突触可塑性携手形成印痕，这些机制也涉及记忆巩固和检索过程。第三，现在有可能人为地操纵记忆编码和检索过程，以产生错误的记忆，甚至在没有任何自然感官经验的老鼠身上创造记忆（为没有发生过的经历植入记忆）。第四，在健忘症小鼠中发现了“沉默”印记；人工重新激活沉默的记忆印迹会诱发记忆检索，而自然线索则不能。内源性印痕沉默可能有助于记忆随时间的变化（例如，系统记忆巩固）或在不同的情况下（例如，恐惧记忆消失）。这些发现表明，印迹一旦形成，根据其可检索性，可能以不同的状态（从沉默到活跃）存在。尽管最初的印迹研究集中在单个大脑区域，但一个新兴的概念是，给定的记忆是由一个印迹复合体支持的，该复合体由分散在多个大脑区域的功能连接的印迹细胞群组成，每个细胞群支持整体记忆的一个组成部分。识别和操作印迹细胞和全脑印迹复合物的能力已经引入了一个令人兴奋的记忆研究的新时代。许多实验室的研究结果开始将印迹定义为记忆的基本单位。然而，许多问题仍然存在。在短期内，表征信息如何存储在印迹中是至关重要的，包括印迹结构如何影响记忆质量、强度和精度；多重印痕如何相互作用；印记是如何随时间变化的；以及印痕沉默在这些过程中的作用。印迹研究的长期目标是利用啮齿动物印迹研究的基本发现来了解信息是如何在人类中获得、存储和使用的，并促进人类记忆或其他信息处理障碍的治疗。低到无创技术的发展可能会使新的人类治疗基于啮齿动物的印痕知识的增长。与非印迹细胞相邻的印迹细胞。在海马内，齿状回细胞充满生物细胞素（白色）以检查形态学。在环境恐惧条件作用中活跃的印迹细胞被改造成表达红色荧光蛋白mCherry，由于与生物细胞素信号重叠而呈现粉红色。穿孔通路的轴突（绿色）表达兴奋性视蛋白通道视紫红质2和荧光标记物（增强的黄色荧光蛋白）。核染色4′，6-二氨基-2-苯基吲哚（DAPI，蓝色）显示齿状回颗粒细胞层的上部叶片。1904年，理查德·西蒙（Richard Semon）引入了“印痕”一词来描述存储记忆的神经基质。Semon提出，一种经历激活了一部分细胞，这些细胞经历了离线的、持续的化学和/或物理变化，成为印记。随后这个印迹的再激活引起记忆的恢复。尽管Semon的贡献在他的一生中基本上被忽视了，但允许研究人员在单个神经元水平上对大脑进行成像和操作的新技术使印迹研究重新焕发了活力。本文综述了近年来脑印痕研究的最新进展，包括对脑印痕存在证据的评价、脑印痕内在兴奋性和突触可塑性的重要性以及脑印痕的寿命。总之，这些发现开始将印迹定义为记忆的基本单位。
The idea that memory is stored as enduring changes in the brain dates back at least to the time of Plato and Aristotle (circa 350 BCE), but its scientific articulation emerged in the 20th century when Richard Semon introduced the term “engram” to describe the neural substrate for storing and recalling memories. Essentially, Semon proposed that an experience activates a population of neurons that undergo persistent chemical and/or physical changes to become an engram. Subsequent reactivation of the engram by cues available at the time of the experience induces memory retrieval. After Karl Lashley failed to find the engram in a rat brain, studies attempting to localize an engram were largely abandoned. Spurred by Donald O. Hebb’s theory that augmented synaptic strength and neuronal connectivity are critical for memory formation, many researchers showed that enhanced synaptic strength was correlated with memory. Nonetheless, the causal relationship between these enduring changes in synaptic connectivity with a specific, behaviorally identifiable memory at the level of the cell ensemble (an engram) awaited further advances in experimental technologies. The resurgence in research examining engrams may be linked to two complementary studies that applied intervention strategies to target individual neurons in an engram supporting a specific memory in mice. One study showed that ablating the subset of lateral amygdala neurons allocated to a putative engram disrupted subsequent memory retrieval (loss of function). The second study showed that artificially reactivating a subset of hippocampal dentate gyrus neurons that were active during a fearful experience (and, therefore, part of a putative engram) induced memory retrieval in the absence of external retrieval cues (gain of function). Subsequent findings from many labs used similar strategies to identify engrams in other brain regions supporting different types of memory. There are several recent advances in engram research. First, eligible neurons within a given brain region were shown to compete for allocation to an engram, and relative neuronal excitability determines the outcome of this competition. Excitability-based competition also guides the organization of multiple engrams in the brain and determines how these engrams interact. Second, research examining the nature of the off-line, enduring changes in engram cells (neurons that are critical components of an engram) found increased synaptic strength and spine density in these neurons as well as preferential connectivity to other downstream engram cells. Therefore, both increased intrinsic excitability and synaptic plasticity work hand in hand to form engrams, and these mechanisms are also implicated in memory consolidation and retrieval processes. Third, it is now possible to artificially manipulate memory encoding and retrieval processes to generate false memories, or even create a memory in mice without any natural sensory experience (implantation of a memory for an experience that did not occur). Fourth, “silent” engrams were discovered in amnesic mice; artificial reactivation of silent engrams induces memory retrieval, whereas natural cues cannot. Endogenous engram silencing may contribute to the change in memory over time (e.g., systems memory consolidation) or in different circumstances (e.g., fear memory extinction). These findings suggest that once formed, an engram may exist in different states (from silent to active) on the basis of their retrievability. Although initial engram studies focused on single brain regions, an emerging concept is that a given memory is supported by an engram complex, composed of functionally connected engram cell ensembles dispersed across multiple brain regions, with each ensemble supporting a component of the overall memory. The ability to identify and manipulate engram cells and brainwide engram complexes has introduced an exciting new era of memory research. The findings from many labs are beginning to define an engram as the basic unit of memory. However, many questions remain. In the short term, it is critical to characterize how information is stored in an engram, including how engram architecture affects memory quality, strength, and precision; how multiple engrams interact; how engrams change over time; and the role of engram silencing in these processes. The long-term goal of engram research is to leverage the fundamental findings from rodent engram studies to understand how information is acquired, stored, and used in humans and facilitate the treatment of human memory, or other information-processing, disorders. The development of low- to noninvasive technology may enable new human therapies based on the growing knowledge of engrams in rodents. An engram cell alongside a nonengram cell. Within the hippocampus, dentate gyrus cells were filled with biocytin (white) to examine morphology. Engram cells active during context fear conditioning were engineered to express the red fluorescent protein mCherry, which appears pink owing to overlap with biocytin signals. Axons of the perforant path (green) express the excitatory opsin channelrhodopsin 2 and a fluorescent marker (enhanced yellow fluorescent protein). The upper blade of the dentate gyrus granule cell layer is revealed by the nuclear stain 4′,6-diamidino-2-phenylindole (DAPI, blue). In 1904, Richard Semon introduced the term “engram” to describe the neural substrate for storing memories. An experience, Semon proposed, activates a subset of cells that undergo off-line, persistent chemical and/or physical changes to become an engram. Subsequent reactivation of this engram induces memory retrieval. Although Semon’s contributions were largely ignored in his lifetime, new technologies that allow researchers to image and manipulate the brain at the level of individual neurons has reinvigorated engram research. We review recent progress in studying engrams, including an evaluation of evidence for the existence of engrams, the importance of intrinsic excitability and synaptic plasticity in engrams, and the lifetime of an engram. Together, these findings are beginning to define an engram as the basic unit of memory.
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DOI：
10.1073/pnas.0700293104
发表时间：
2007-03-20
影响因子：
11.1
作者：
Armbruster, Blaine N.;Li, Xiang;Roth, Bryan L.
通讯作者：
Roth, Bryan L.
DOI：
10.1037/0278-7393.20.5.1063
发表时间：
1994-09-01
影响因子：
2.6
作者：
ANDERSON, MC;BJORK, RA;BJORK, EL
通讯作者：
BJORK, EL
影响因子：
25
作者：
Boyden, ES;Zhang, F;Deisseroth, K
通讯作者：
Deisseroth, K
影响因子：
25
作者：
Carr, Margaret F.;Jadhav, Shantanu P.;Frank, Loren M.
通讯作者：
Frank, Loren M.
影响因子：
64.8
作者：
Cai, Denise J.;Aharoni, Daniel;Shuman, Tristan;Shobe, Justin;Biane, Jeremy;Song, Weilin;Wei, Brandon;Veshkini, Michael;La-Vu, Mimi;Lou, Jerry;Flores, Sergio E.;Kim, Isaac;Sano, Yoshitake;Zhou, Miou;Baumgaertel, Karsten;Lavi, Ayal;Kamata, Masakazu;Tuszynski, Mark;Mayford, Mark;Golshani, Peyman;Silva, Alcino J.
通讯作者：
Silva, Alcino J.