【脑·未来】 让老年痴呆患者重新找回丢失的记忆

BCBDI在本公众号平台定期推出e-JournalClub系列，分享脑科学与脑技术领域的最新研究进展，欢迎关注。...

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中科院深圳先进技术研究院－MIT麦戈文联合脑认知与脑疾病研究所

The Brain Cognition & Brain Disease Institute for Collaboration Research of SIAT at CAS and the McGovern Institute at MITBCBDI在本公众号平台定期推出e-Journal Club系列，分享脑科学脑技术领域的最新研究进展，欢迎关注。



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第37期：让老年痴呆患者重新找回丢失的记忆

阿尔兹海默症，又名老年性痴呆症，在老年群体中发病率非常的高。在我国发病率约为5%，多发于65岁以上人群，近年来发病人数呈现逐步增长的趋势。而该病的显著病理特征，患者通常会出现近期的记忆障碍，经常性忘记刚刚经历的事情。然而，近期麻省理工学院（MIT）的神经生物学教授利根川进（Tonegawa Susumu）团队利用光遗传学的方法直接激活老年痴呆症的小鼠的脑细胞，找回其因疾病造成丢失的记忆。这项研究结果表明：在阿尔兹海默氏症早期阶段，所谓丢失的记忆依然存在于大脑中，只是记忆“提取”出现问题。

记忆缺失

在记忆研究中的经典范式，将动物放入新环境中并给予恶性的足部电击，让其对新环境和恶性刺激进行关联性学习。几天之后，当动物再次进入该环境时，会回忆起先前的电击经历出现恐惧反应。然而，相比较正常动物的恐惧反应，阿尔兹海默症的小鼠却忘记之前的不恐惧经历。该结果表明，阿尔兹海默症的小鼠出现记忆的丢失现象。

记忆提取问题

研究者发现，阿尔兹海默症的小鼠的记忆是存在的，只是其无法记起这些事情。

为了证明这点，研究人员首先使用光遗传学工具标记恐惧记忆痕迹的细胞。随后用光激活这些被标记的记忆细胞，并唤起这些细胞中编码恐惧的记忆。同正常的动物一样，患有阿尔兹海默症的小鼠被置入一个它们从来没有进入过的环境，并且用光照射记忆痕迹细胞时，这些小鼠也会立刻表现出害怕。这一结果说明，疾病模型动物的记忆并没有丢失，而是读取异常，造成记忆障碍。

记忆的重新唤起

正常情况，新记忆产生时，与此记忆相关的记忆痕迹细胞会生成新的树突棘。然而研究者发现，患有阿尔兹海默症的小鼠缺乏这个能力，记忆痕迹细胞不能收到内嗅皮层的信号输入，最终造成记忆提取障碍。Tonegawa表示：存储记忆的细胞的激活是唤起记忆的必要条件。如果树突棘密度在学习过程中没有增加，那么在之后唤起记忆的过程中便无法激活记忆的细胞。

研究者在后续实验中，用光照射去诱发神经元会重新长出树突棘，并与内嗅皮质形成紧密连结。阿尔兹海默症的小鼠记忆提取功能渐渐恢复，当它们重新进入被电击环境时，出现恐惧反应。

该项研究还处于比较初级的阶段，但它开启了一个充满希望的方向，帮助我们理解阿尔兹海默症的发病机理，并可能启发出新的方法治疗这种疾病，并促进记忆的提取。

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论文标题：Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease

原文摘要：Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions1. Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role2. However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent3, 4, 5, which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD.

全文链接：

http://www.nature.com/nature/journal/v531/n7595/abs/nature17172.html

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论文标题：Engram cells retain memory under retrograde amnesia

原文摘要：Memory consolidation is the process by which a newly formed and unstable memory transforms into a stable long-term memory. It is unknown whether the process of memory consolidation occurs exclusively through the stabilization of memory engrams. By using learning-dependent cell labeling, we identified an increase of synaptic strength and dendritic spine density specifically in consolidated memory engram cells. Although these properties are lacking in engram cells under protein synthesis inhibitor–induced amnesia, direct optogenetic activation of these cells results in memory retrieval, and this correlates with retained engram cell–specific connectivity. We propose that a specific pattern of connectivity of engram cells may be crucial for memory information storage and that strengthened synapses in these cells critically contribute to the memory retrieval process.

全文链接：

http://science.sciencemag.org/content/348/6238/1007

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论文标题：Bidirectional switch of the valence associated with a hippocampal contextual memory engram

原文摘要：The valence of memories is malleable because of their intrinsic reconstructive property1. This property of memory has been used clinically to treat maladaptive behaviours2. However, the neuronal mechanisms and brain circuits that enable the switching of the valence of memories remain largely unknown. Here we investigated these mechanisms by applying the recently developed memory engram cell- manipulation technique3, 4. We labelled with channelrhodopsin-2 (ChR2) a population of cells in either the dorsal dentate gyrus (DG) of the hippocampus or the basolateral complex of the amygdala (BLA) that were specifically activated during contextual fear or reward conditioning. Both groups of fear-conditioned mice displayed aversive light-dependent responses in an optogenetic place avoidance test, whereas both DG- and BLA-labelled mice that underwent reward conditioning exhibited an appetitive response in an optogenetic place preference test. Next, in an attempt to reverse the valence of memory within a subject, mice whose DG or BLA engram had initially been labelled by contextual fear or reward conditioning were subjected to a second conditioning of the opposite valence while their original DG or BLA engram was reactivated by blue light. Subsequent optogenetic place avoidance and preference tests revealed that although the DG-engram group displayed a response indicating a switch of the memory valence, the BLA-engram group did not. This switch was also evident at the cellular level by a change in functional connectivity between DG engram-bearing cells and BLA engram-bearing cells. Thus, we found that in the DG, the neurons carrying the memory engram of a given neutral context have plasticity such that the valence of a conditioned response evoked by their reactivation can be reversed by re-associating this contextual memory engram with a new unconditioned stimulus of an opposite valence. Our present work provides new insight into the functional neural circuits underlying the malleability of emotional memory.

全文链接：http://www.nature.com/nature/journal/v513/n7518/full/nature13725.html





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