Rigid firing sequences undermine spatial memory codes in a neurodegenerative mouse model.
Rigid firing sequences undermine spatial memory codes in a neurodegenerative mouse model.
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作者：
Cheng J;Ji D
海马神经元通过在特定位置放电来编码空间记忆。当动物穿越一个空间轨迹时，沿着轨迹的各个沿着位置以独特的放电序列激活这些神经元，这产生了代表轨迹的记忆代码。这种类型的记忆代码在痴呆症神经退行性疾病中是如何改变的尚不清楚。在这里，我们表明，在转基因rTg 4510小鼠，包括阿尔茨海默氏病的tau蛋白病模型，海马神经元没有在特定的位置发射，但显示强大的发射序列的动物运行沿着熟悉或新颖的轨迹。轨迹上看到的序列也出现在自由探索开放空间的过程中。空间分离的放电序列表明，转基因小鼠的海马神经元主要不是由外部空间驱动，而是由内部产生的大脑活动驱动。我们认为，tau蛋白的病理和/或神经退行性病变使海马电路被内部信息淹没，从而阻止它们编码空间记忆。DOI：http://dx.doi.org/10.7554/eLife.00647.001阿尔茨海默病患者经常忘记自己去过哪里或刚刚见过谁。这是因为大脑中处理记忆的区域的神经元正在死亡。事实上，当阿尔茨海默病被诊断出来时，这些区域的许多神经元已经死亡。阿尔茨海默病的症状是由剩下的神经元产生的。然而，剩下的神经元不能产生新记忆的原因尚不清楚。在正常小鼠中，海马体中的神经元，大脑中对记忆很重要的一部分，被称为“位置细胞”，因为当小鼠处于特定位置时，它们会被打开。因此，当老鼠四处走动时，不同的神经元一个接一个地被激活，这种激活序列被认为是一种记忆代码，代表了动物所走过的地方。Cheng和Ji在经过基因工程改造的小鼠中探索了这种现象，使它们的神经元含有被认为与神经元死亡有关的称为“tau缠结”的结构。更重要的是，这些转基因小鼠遭受年龄依赖性神经元损失的方式类似于阿尔茨海默病患者。Cheng和Ji在这些小鼠的海马体中植入了微型传感器，并使用这些传感器来监测小鼠在寻找食物时四处移动时剩余海马体神经元的活动。他们发现神经元几乎到处都被激活，这表明转基因小鼠的海马神经元不再作为位置细胞工作。然而，这些神经元仍然以稳健的序列一个接一个地被激活。此外，转基因小鼠产生的序列在许多不同的环境中是相同的，这表明这些序列不是动物当前环境的记忆代码。Cheng和Ji提出，这些序列反映了已经存储在大脑中的现有记忆，这表明阿尔茨海默氏症患者无法形成新的记忆，因为大脑被旧记忆占据，因此无法存储来自外部世界的新信息。DOI：http://dx.doi.org/10.7554/eLife.00647.002
Hippocampal neurons encode spatial memories by firing at specific locations. As the animal traverses a spatial trajectory, individual locations along the trajectory activate these neurons in a unique firing sequence, which yields a memory code representing the trajectory. How this type of memory code is altered in dementia-producing neurodegenerative disorders is unknown. Here we show that in transgenic rTg4510 mice, a model of tauopathies including Alzheimer's disease, hippocampal neurons did not fire at specific locations, yet displayed robust firing sequences as animals run along familiar or novel trajectories. The sequences seen on the trajectories also appeared during free exploration of open spaces. The spatially dissociated firing sequences suggest that hippocampal neurons in the transgenic mice are not primarily driven by external space but by internally generated brain activities. We propose that tau pathology and/or neurodegeneration renders hippocampal circuits overwhelmed by internal information and therefore prevents them from encoding spatial memories. DOI: http://dx.doi.org/10.7554/eLife.00647.001 Patients with Alzheimer's disease often forget where they have been or who they have just met. This happens because the neurons in those areas of the brain where memories are processed are dying. Indeed, by the time Alzheimer's disease has been diagnosed, many of the neurons in these regions have already died. The symptoms of Alzheimer's disease are then produced by the remaining neurons. However, the reasons why the remaining neurons cannot make new memories are unknown. In normal mice the neurons in the hippocampus, a part of the brain that is important for memory, are called ‘place cells’ because they are turned on when the mouse is in a specific place. As a consequence, when the mice moves around, different neurons are turned on one by one, and this sequence of activation is believed to be a memory code that represents the places the animal has travelled. Cheng and Ji have explored this phenomenon in mice that have been genetically engineered so that their neurons contain structures called ‘tau tangles’ that are thought to be involved in the death of neurons. More importantly, these transgenic mice suffer age-dependent neuron loss in a way that is similarly to people with Alzheimer's disease. Cheng and Ji implanted tiny sensors into the hippocampus of these mice, and used these sensors to monitor the activity of the remaining hippocampal neurons as the mice moved around while searching for food. They found that the neurons were activated almost everywhere, which indicates that the hippocampal neurons in transgenic mice are no longer working as place cells. However, these neurons were still activated one by one in robust sequences. Moreover, the sequences generated by the transgenic mice were the same in many different surroundings, which suggests that these sequences are not memory codes of the animal's current surroundings. Cheng and Ji propose that the sequences reflect existing memories already stored in the brain, which would suggest that Alzheimer's patients cannot form new memories because the brain is preoccupied by old memories, and thus fails to store the new information that is coming in from the outside world. DOI: http://dx.doi.org/10.7554/eLife.00647.002