科学家发现了大脑的新型海马体神经元[1]
正文翻译
"There are about 86 billion neurons in the human brain, which is close to the number of stars in the Milky Way. From a certain perspective, everyone's brain is like a deep and boundless universe."
For Professor Zhou Ning of ShanghaiTech University, who studies neuroimaging, our brains are both mysterious and romantic.
Recently, she and her team have unearthed a new treasure in this "brain universe": the discovery of a new type of hippocampal neuron type.
"These cells seem to be able to closely connect an organism's external obxtive information and internal subjective intentions. They not only map spatial information, but also simultaneously characterize the animal's exploration intentions." Zhou Ning said.
At the same time, the coding mechanism of these neurons relies on information input from the lateral entorhinal cortex, which provides new ideas for understanding how the brain integrates external environmental information and inner subjective intentions, and also provides new insights into the function of place cells in the hippocampus. perspective.
It is understood that scholars have discovered that hippocampal lesions and hippocampal function are closely related to many brain diseases, including Alzheimer's disease, epilepsy, and schizophrenia.
Understanding the encoding and memory mechanisms of the hippocampus will help develop new diagnostic markers for brain diseases, conduct brain-computer interface research, and develop new drug targets.
“人类大脑里大约有860亿个神经元，这个数量大致相当于银河系中的恒星数量。在某种意义上，每个人的大脑都可以看作是一个广阔的宇宙。”对于研究神经成像的上海科技大学周宁教授而言，大脑不仅充满了神秘，还带有浪漫的色彩。
最近，周教授和她的团队在这个“脑宇宙”中发现了新的瑰宝：一种新型的海马体神经元。
周宁教授解释说：“这些神经元能够将生物的外部客观信息与内部的主观意图紧密联系起来。它们不仅可以映射空间信息，还能表征动物的探索意图。”
同时，这些神经元的编码机制依赖于外侧内嗅皮层的信息输入，这为理解大脑如何整合外界环境信息与内部主观意图提供了新的思路，并且也为理解海马体中位置细胞的功能开辟了新的视角。
据悉，海马体的功能异常与多种脑疾病有着密切的关联，包括阿尔茨海默病、癫痫和精神分裂症等。
对海马体的编码和记忆机制的深入了解，将有助于开发新的脑疾病诊断标记物、推动脑机接口的研究，以及开发新的药物靶点。
A few weeks before the start of the experiment, they implanted a gradient refractive index lens (Grin Lens) into the head of the mouse and labeled the hippocampal neurons with the calcium ion fluorescent indicator GCaMP6f.
In this way, when the mice perform various behaviors, the activity of hippocampal neurons can be recorded in real time through the head-mounted micro-microscope.
Micromicroscope technology is a breakthrough experimental technology that has emerged in the field of neurobiology in recent years. Although it weighs less than 3 grams, it integrates the key functional components of a traditional microscope.
This enables high-speed, subcellular-level imaging of a brain area of approximately 0.4 square millimeters and the ability to simultaneously capture data from more than 200 neurons.
Thanks to its lightweight design, mice can carry this microscope and carry out free activities in a natural state with almost no restrictions, ensuring the naturalness of mouse movements and behavior.
In the behavior box designed by the research team, mice can independently choose whether to explore approaching obxts.
While using a camera to record the mice's behavioral performance, the team used a miniature microscope to record the calcium signaling activity of hippocampal neurons.
Through in-depth analysis of the collected data, very typical place cells were identified, and the characteristics of these cells are highly consistent with those of previously reported traditional place cells.
在实验开始前几周，他们在小鼠的头部植入了一枚梯度变折射率透镜（Grin Lens），并将海马体神经元标记上钙离子荧光指示剂 GCaMP6f。
这样，当小鼠进行各种行为时，就能通过头戴式微型显微镜，实时地记录海马体神经元的活动情况。
微型显微镜技术，是近年来神经生物学领域涌现的一项突破性实验技术。尽管重量不到 3 克，它却集成了传统显微镜的关键功能组件。
这让其能对大约 0.4 平方毫米的大脑区域进行亚细胞级别的高速成像，并能够同步捕获超过 200 个神经元的数据。
得益于其轻盈的设计，小鼠可以在几乎不受限制的自然状态下携带此显微镜开展自由活动，确保了小鼠动作和小鼠行为的自然性。
在课题组设计的行为箱中，小鼠可以自主选择是否探索接近的物体。
在用摄像机拍摄小鼠行为表现的同时，该团队通过微型显微镜，来记录海马体神经元的钙信号活动。
通过对所收集数据进行深入分析，能够识别出非常典型的位置细胞，这些细胞的特性和此前报道的传统位置细胞高度吻合。
"There are about 86 billion neurons in the human brain, which is close to the number of stars in the Milky Way. From a certain perspective, everyone's brain is like a deep and boundless universe."
For Professor Zhou Ning of ShanghaiTech University, who studies neuroimaging, our brains are both mysterious and romantic.
Recently, she and her team have unearthed a new treasure in this "brain universe": the discovery of a new type of hippocampal neuron type.
"These cells seem to be able to closely connect an organism's external obxtive information and internal subjective intentions. They not only map spatial information, but also simultaneously characterize the animal's exploration intentions." Zhou Ning said.
At the same time, the coding mechanism of these neurons relies on information input from the lateral entorhinal cortex, which provides new ideas for understanding how the brain integrates external environmental information and inner subjective intentions, and also provides new insights into the function of place cells in the hippocampus. perspective.
It is understood that scholars have discovered that hippocampal lesions and hippocampal function are closely related to many brain diseases, including Alzheimer's disease, epilepsy, and schizophrenia.
Understanding the encoding and memory mechanisms of the hippocampus will help develop new diagnostic markers for brain diseases, conduct brain-computer interface research, and develop new drug targets.
“人类大脑里大约有860亿个神经元，这个数量大致相当于银河系中的恒星数量。在某种意义上，每个人的大脑都可以看作是一个广阔的宇宙。”对于研究神经成像的上海科技大学周宁教授而言，大脑不仅充满了神秘，还带有浪漫的色彩。
最近，周教授和她的团队在这个“脑宇宙”中发现了新的瑰宝：一种新型的海马体神经元。
周宁教授解释说：“这些神经元能够将生物的外部客观信息与内部的主观意图紧密联系起来。它们不仅可以映射空间信息，还能表征动物的探索意图。”
同时，这些神经元的编码机制依赖于外侧内嗅皮层的信息输入，这为理解大脑如何整合外界环境信息与内部主观意图提供了新的思路，并且也为理解海马体中位置细胞的功能开辟了新的视角。
据悉，海马体的功能异常与多种脑疾病有着密切的关联，包括阿尔茨海默病、癫痫和精神分裂症等。
对海马体的编码和记忆机制的深入了解，将有助于开发新的脑疾病诊断标记物、推动脑机接口的研究，以及开发新的药物靶点。
In the field of neuroscience, people have been puzzled by such an interesting question: How does the brain determine the position of an organism in space and use this information to navigate?
With their remarkable achievements in this field, British scientist Professor John O'Keefe and Norwegian scientists Edvard Moser and May-Britt Moser (now divorced), shared the 2014 Nobel Prize in Physiology or Medicine.
As early as 1971, Professor John O'Keefe discovered a special type of neuron in the hippocampus while studying rats and named it "place cell."
When recording electrodes were implanted into the hippocampus of rats to track the activity of neurons, each place cell was observed to fire only when the rat passed through a specific area.
In other words, each place cell corresponds to a specific area in space, and they constitute an indexing mechanism for the animal brain to map external spatial information.
Interestingly, there are similar positioning cells in the human brain, and these cells together constitute the human brain's "cognitive map" of the external world.
Over the years, scientists have never stopped exploring the formation and function of place cells.
For example, are hippocampal neurons restricted to representing spatial locations? Do they also indicate time, or even more abstract concepts?
Do these neurons simply exist as a map of the external world in the brain? Or are they also influenced and modulated by the psychological state of the organism?
Furthermore, do hippocampal neurons have the ability to simultaneously encode obxtive information from the outside world and subjective intentions of the brain?
It is these questions that continue to inspire people to continue to explore. The answers to these questions may help us further uncover the deep mysteries of brain cognition.
在神经科学领域，人们一直被这样一个有趣的问题所困扰：大脑如何确定生物体在空间中的位置，并利用这一信息进行导航？
凭借在这一领域的显著成就，英国科学家约翰·奥基夫（John O'Keefe）教授、与挪威科学家爱德华·莫泽（Edvard Moser）和迈-布里特·莫泽（May-Britt Moser）夫妇（现已离婚），于 2014 年共同获得诺贝尔生理学或医学奖。
早在 1971 年，约翰·奥基夫教授就在研究大鼠时发现了海马体（hippocampus）内一种特殊的神经元，并将其命名为“位置细胞”。
当人们将记录电极植入大鼠的海马体来追踪神经元的活动时，可以观察到每个位置细胞仅在大鼠穿过某个特定区域时激活。
换句话说，每一个位置细胞对应着空间中的一个特定区域，它们构成了动物大脑映射外部空间信息的一种索引机制。
有趣的是，人脑中也存在着类似的定位细胞，这些细胞共同构成了人脑对于外部世界的“认知地图”。
多年来，科学家从未停止对于位置细胞形成机制和功能的探索。
比如，海马神经元是否只局限于表征空间位置？它们是否同样指示时间、甚至是更为抽象的概念？
这些神经元是否仅仅作为外部世界在大脑中的映射存在？或者它们也会受到生物体心理状态的影响和调节？
更进一步，海马神经元是否有能力同时编码外界客观信息和大脑主观意向？
正是这些问题不断激发着人们不断地探索。而对这些疑问的解答，可能会帮助我们更进一步地揭开大脑认知的深层奥秘。
With their remarkable achievements in this field, British scientist Professor John O'Keefe and Norwegian scientists Edvard Moser and May-Britt Moser (now divorced), shared the 2014 Nobel Prize in Physiology or Medicine.
As early as 1971, Professor John O'Keefe discovered a special type of neuron in the hippocampus while studying rats and named it "place cell."
When recording electrodes were implanted into the hippocampus of rats to track the activity of neurons, each place cell was observed to fire only when the rat passed through a specific area.
In other words, each place cell corresponds to a specific area in space, and they constitute an indexing mechanism for the animal brain to map external spatial information.
Interestingly, there are similar positioning cells in the human brain, and these cells together constitute the human brain's "cognitive map" of the external world.
Over the years, scientists have never stopped exploring the formation and function of place cells.
For example, are hippocampal neurons restricted to representing spatial locations? Do they also indicate time, or even more abstract concepts?
Do these neurons simply exist as a map of the external world in the brain? Or are they also influenced and modulated by the psychological state of the organism?
Furthermore, do hippocampal neurons have the ability to simultaneously encode obxtive information from the outside world and subjective intentions of the brain?
It is these questions that continue to inspire people to continue to explore. The answers to these questions may help us further uncover the deep mysteries of brain cognition.
在神经科学领域，人们一直被这样一个有趣的问题所困扰：大脑如何确定生物体在空间中的位置，并利用这一信息进行导航？
凭借在这一领域的显著成就，英国科学家约翰·奥基夫（John O'Keefe）教授、与挪威科学家爱德华·莫泽（Edvard Moser）和迈-布里特·莫泽（May-Britt Moser）夫妇（现已离婚），于 2014 年共同获得诺贝尔生理学或医学奖。
早在 1971 年，约翰·奥基夫教授就在研究大鼠时发现了海马体（hippocampus）内一种特殊的神经元，并将其命名为“位置细胞”。
当人们将记录电极植入大鼠的海马体来追踪神经元的活动时，可以观察到每个位置细胞仅在大鼠穿过某个特定区域时激活。
换句话说，每一个位置细胞对应着空间中的一个特定区域，它们构成了动物大脑映射外部空间信息的一种索引机制。
有趣的是，人脑中也存在着类似的定位细胞，这些细胞共同构成了人脑对于外部世界的“认知地图”。
多年来，科学家从未停止对于位置细胞形成机制和功能的探索。
比如，海马神经元是否只局限于表征空间位置？它们是否同样指示时间、甚至是更为抽象的概念？
这些神经元是否仅仅作为外部世界在大脑中的映射存在？或者它们也会受到生物体心理状态的影响和调节？
更进一步，海马神经元是否有能力同时编码外界客观信息和大脑主观意向？
正是这些问题不断激发着人们不断地探索。而对这些疑问的解答，可能会帮助我们更进一步地揭开大脑认知的深层奥秘。
In 2011, Zhou Ning independently established a group at China Medical University in Taiwan, China. In 2019, she joined the iHuman Research Institute of ShanghaiTech University as an independent research team leader.
She has long been committed to carrying out basic research related to neurophysiology and pathology through techniques such as fluorescence imaging and electrophysiology.
For example, during his doctoral studies, Zhou Ning often used two-photon fluorescence microscopy technology to image and record brain tissue labeled with fluorescent indicators.
She often observed that the calcium ion fluorescence intensity in cells in living brain slices flickered on and off as the activity of brain cells changed, one after another, like the twinkling of stars in a distant starry sky, which fascinated Zhou Ning.
As mentioned earlier, the human brain has approximately 86 billion neurons. In living animals, the signals hidden behind these intricate networks of neurons are key to understanding how the brain encodes information.
Therefore, Zhou Ning's research direction has gradually focused on using neuroimaging technology in living animals to deeply study how the brain encodes these complex information.
"Every time we analyze the calcium ion activity in neurons, it is like cracking the brain's code, which is full of unknowns and extremely exciting," she said.
Previous research on the hippocampus revealed that place cells may adjust according to the animal's foraging motivation or attentional state.
For example, when an animal searches for food, the hippocampus may activate more place cells to mark the specific location of food.
Likewise, when changes in the external environment draw the animal's attention to signals of change, the number and activity of place cells may adjust accordingly.
These studies led Zhou Ning to question: When organisms are neither driven by food nor attracted by external stimuli, can their subjective wishes be encoded by hippocampal neurons?
Is there a population of neurons that encodes both the statue's location and our willingness to explore? If the answer is yes, then these neurons have the potential to guide us where to go and what to do.
This question filled Zhou Ning's team with passion, especially doctoral student Zeng Yifan, who showed strong interest in it. After careful consideration, they designed an ingenious experiment to explore the above question.
Specifically, they constructed two behavioral boxes with a circular track, trained the mice to run in the same direction, and rewarded the mice with a milk powder ball at a fixed location every time they completed a circle.
At the same time, obxts of different shapes and colors were placed in the other three locations, allowing the mice to stop to observe and explore when approaching these obxts, or to choose to ignore the obxts and continue running. In both cases, the paths taken by the mice were highly consistent.
2011 年，周宁在位于中国台湾的中国医药大学独立建组。2019 年，她加入上海科技大学 iHuman 研究所担任独立课题组长。
长期以来，她致力于通过荧光成像和电生理等技术，开展神经生理学和病理学相关的基础研究。
比如，在攻读博士期间，周宁常常借助双光子荧光显微镜技术，对那些被荧光指示剂标记的脑片组织进行成像记录。
她经常观察到活脑片细胞中的钙离子荧光强度随着脑细胞的活动变化而忽明忽暗，此起彼伏、如同遥远星空中星辰的闪烁，这让周宁非常着迷。
如前所述，人类大脑有约 860 亿个神经元。而在活体动物中，这些错综复杂的神经元网络背后所的隐藏的信号，是理解大脑如何编码信息的关键所在。
因此，周宁的研究方向逐渐聚焦于通过动物活体的神经成像技术，去深入研究大脑是如何编码这些复杂信息的。
“每一次分析神经元中的钙离子活动，都仿佛是在破解大脑的密码一样，既充满未知、又无比振奋人心。”她说。
而此前关于海马体的研究，揭示了位置细胞可能会随着动物的觅食动机或注意力状态而调整。
例如，在动物搜寻食物时，海马体可能会激活更多的位置细胞以标记食物的具体位置。
同样地，当外部环境发生变化，吸引了动物对变化信号的注意时，位置细胞的数量和活动也可能相应地调整。
这些研究使周宁产生了一个疑问：在生物体既不被食物驱动、也不被外部刺激所吸引的情况下，它们的主观意愿能否被海马神经元编码？
想象一下：当我们每天沿着熟悉的道路去上班或上学，都会路过街角一个熟悉的雕像，有一天我们突然决定停下来仔细观赏它，这时海马体的神经编码会不会与往常有所不同？
是否有一群神经元能够同时编码这个雕像的位置和我们的探索意愿？如果答案是肯定的，那么这些神经元有可能指引我们去哪里以及做什么。
这一问题让周宁团队充满了激情，尤其是博士生曾一凡对此表现出浓厚兴趣。 经过一番深思熟虑，他们设计了一个精巧的实验来探究上述问题。
具体来说，其构建了两个设有环形跑道的行为箱，训练小鼠沿着相同方向奔跑，并在每完成一圈时在固定的位置给予一颗奶粉球作为奖赏。
同时，在其他三个位置摆放了不同形状和不同颜色的物体，允许小鼠在靠近这些物体时停下来进行观察和探索、或者选择忽略物体继续跑动。在这两种情况之下，小鼠所经过的路径都高度一致。
She has long been committed to carrying out basic research related to neurophysiology and pathology through techniques such as fluorescence imaging and electrophysiology.
For example, during his doctoral studies, Zhou Ning often used two-photon fluorescence microscopy technology to image and record brain tissue labeled with fluorescent indicators.
She often observed that the calcium ion fluorescence intensity in cells in living brain slices flickered on and off as the activity of brain cells changed, one after another, like the twinkling of stars in a distant starry sky, which fascinated Zhou Ning.
As mentioned earlier, the human brain has approximately 86 billion neurons. In living animals, the signals hidden behind these intricate networks of neurons are key to understanding how the brain encodes information.
Therefore, Zhou Ning's research direction has gradually focused on using neuroimaging technology in living animals to deeply study how the brain encodes these complex information.
"Every time we analyze the calcium ion activity in neurons, it is like cracking the brain's code, which is full of unknowns and extremely exciting," she said.
Previous research on the hippocampus revealed that place cells may adjust according to the animal's foraging motivation or attentional state.
For example, when an animal searches for food, the hippocampus may activate more place cells to mark the specific location of food.
Likewise, when changes in the external environment draw the animal's attention to signals of change, the number and activity of place cells may adjust accordingly.
These studies led Zhou Ning to question: When organisms are neither driven by food nor attracted by external stimuli, can their subjective wishes be encoded by hippocampal neurons?
Is there a population of neurons that encodes both the statue's location and our willingness to explore? If the answer is yes, then these neurons have the potential to guide us where to go and what to do.
This question filled Zhou Ning's team with passion, especially doctoral student Zeng Yifan, who showed strong interest in it. After careful consideration, they designed an ingenious experiment to explore the above question.
Specifically, they constructed two behavioral boxes with a circular track, trained the mice to run in the same direction, and rewarded the mice with a milk powder ball at a fixed location every time they completed a circle.
At the same time, obxts of different shapes and colors were placed in the other three locations, allowing the mice to stop to observe and explore when approaching these obxts, or to choose to ignore the obxts and continue running. In both cases, the paths taken by the mice were highly consistent.
2011 年，周宁在位于中国台湾的中国医药大学独立建组。2019 年，她加入上海科技大学 iHuman 研究所担任独立课题组长。
长期以来，她致力于通过荧光成像和电生理等技术，开展神经生理学和病理学相关的基础研究。
比如，在攻读博士期间，周宁常常借助双光子荧光显微镜技术，对那些被荧光指示剂标记的脑片组织进行成像记录。
她经常观察到活脑片细胞中的钙离子荧光强度随着脑细胞的活动变化而忽明忽暗，此起彼伏、如同遥远星空中星辰的闪烁，这让周宁非常着迷。
如前所述，人类大脑有约 860 亿个神经元。而在活体动物中，这些错综复杂的神经元网络背后所的隐藏的信号，是理解大脑如何编码信息的关键所在。
因此，周宁的研究方向逐渐聚焦于通过动物活体的神经成像技术，去深入研究大脑是如何编码这些复杂信息的。
“每一次分析神经元中的钙离子活动，都仿佛是在破解大脑的密码一样，既充满未知、又无比振奋人心。”她说。
而此前关于海马体的研究，揭示了位置细胞可能会随着动物的觅食动机或注意力状态而调整。
例如，在动物搜寻食物时，海马体可能会激活更多的位置细胞以标记食物的具体位置。
同样地，当外部环境发生变化，吸引了动物对变化信号的注意时，位置细胞的数量和活动也可能相应地调整。
这些研究使周宁产生了一个疑问：在生物体既不被食物驱动、也不被外部刺激所吸引的情况下，它们的主观意愿能否被海马神经元编码？
想象一下：当我们每天沿着熟悉的道路去上班或上学，都会路过街角一个熟悉的雕像，有一天我们突然决定停下来仔细观赏它，这时海马体的神经编码会不会与往常有所不同？
是否有一群神经元能够同时编码这个雕像的位置和我们的探索意愿？如果答案是肯定的，那么这些神经元有可能指引我们去哪里以及做什么。
这一问题让周宁团队充满了激情，尤其是博士生曾一凡对此表现出浓厚兴趣。 经过一番深思熟虑，他们设计了一个精巧的实验来探究上述问题。
具体来说，其构建了两个设有环形跑道的行为箱，训练小鼠沿着相同方向奔跑，并在每完成一圈时在固定的位置给予一颗奶粉球作为奖赏。
同时，在其他三个位置摆放了不同形状和不同颜色的物体，允许小鼠在靠近这些物体时停下来进行观察和探索、或者选择忽略物体继续跑动。在这两种情况之下，小鼠所经过的路径都高度一致。
A few weeks before the start of the experiment, they implanted a gradient refractive index lens (Grin Lens) into the head of the mouse and labeled the hippocampal neurons with the calcium ion fluorescent indicator GCaMP6f.
In this way, when the mice perform various behaviors, the activity of hippocampal neurons can be recorded in real time through the head-mounted micro-microscope.
Micromicroscope technology is a breakthrough experimental technology that has emerged in the field of neurobiology in recent years. Although it weighs less than 3 grams, it integrates the key functional components of a traditional microscope.
This enables high-speed, subcellular-level imaging of a brain area of approximately 0.4 square millimeters and the ability to simultaneously capture data from more than 200 neurons.
Thanks to its lightweight design, mice can carry this microscope and carry out free activities in a natural state with almost no restrictions, ensuring the naturalness of mouse movements and behavior.
In the behavior box designed by the research team, mice can independently choose whether to explore approaching obxts.
While using a camera to record the mice's behavioral performance, the team used a miniature microscope to record the calcium signaling activity of hippocampal neurons.
Through in-depth analysis of the collected data, very typical place cells were identified, and the characteristics of these cells are highly consistent with those of previously reported traditional place cells.
在实验开始前几周，他们在小鼠的头部植入了一枚梯度变折射率透镜（Grin Lens），并将海马体神经元标记上钙离子荧光指示剂 GCaMP6f。
这样，当小鼠进行各种行为时，就能通过头戴式微型显微镜，实时地记录海马体神经元的活动情况。
微型显微镜技术，是近年来神经生物学领域涌现的一项突破性实验技术。尽管重量不到 3 克，它却集成了传统显微镜的关键功能组件。
这让其能对大约 0.4 平方毫米的大脑区域进行亚细胞级别的高速成像，并能够同步捕获超过 200 个神经元的数据。
得益于其轻盈的设计，小鼠可以在几乎不受限制的自然状态下携带此显微镜开展自由活动，确保了小鼠动作和小鼠行为的自然性。
在课题组设计的行为箱中，小鼠可以自主选择是否探索接近的物体。
在用摄像机拍摄小鼠行为表现的同时，该团队通过微型显微镜，来记录海马体神经元的钙信号活动。
通过对所收集数据进行深入分析，能够识别出非常典型的位置细胞，这些细胞的特性和此前报道的传统位置细胞高度吻合。
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