科学家发现了大脑的新型海马体神经元[2]
正文翻译
Subsequently, they constructed a series of experiments aimed at studying how oePC jointly encodes exploration intention and spatial information, and tried to explain the mechanism behind it.
By analyzing the activation time points of oePC and the mouse's obxt exploration behavior, they observed that the active period of these cells usually occurs before the animal's exploration behavior (median about 0.8 seconds) and occurs when the obxt is about 3 cm away. , which means that the activation of oePC actually precedes the actual exploration behavior.
When further studying the position field properties of oePC, the team found that when an obxt moved 0.5 cm, 1 cm, 2 cm, or 4 cm from its original position, the activity intensity of oePC gradually weakened or even disappeared as the distance of movement increased, indicating that oePC has the ability to encode at specific locations.
The activity patterns of oePC did not change significantly when replacing old obxts with new ones.
What is puzzling is that earlier studies have pointed out that changing obxts in the environment will significantly change the activity of traditional place cells, so why does oePC not change?
At this point, their first consideration was: Are the old and new obxts too similar for the mice to distinguish?
In order to rule out this possibility, the research team carefully sexted a series of complex obxts with completely different shapes, colors, etc. to test the mice. However, even so, the encoding of oePC still does not produce significant changes.
When they further analyzed those traditional place cells with the same position field, they found that these cells did produce significant coding differences for obxt replacement.
This comparison clearly shows that, unlike traditional place cells, oePCs do not appear to encode features of the obxts themselves.
In another experimental design, the team cleverly hid obxts behind partitions so that the obxts were only visible to mice when they showed exploratory initiative and went through a small door to search.
Interestingly, they observed that the oePC was already preactivated even when the mice approached but had not yet directly seen the obxt.
随后，他们又构建了一系列实验，旨在研究 oePC 是如何联合编码探索意图和空间信息的，并尝试解释其背后的机制。
通过分析 oePC 的激活时间点和与小鼠对物体探索的行为，他们观察到这些细胞的活跃期通常发生在动物的探索行为前（中位数 0.8 秒左右），且距离物体大约 3 厘米时发生，这意味着 oePC 的激活实际上早于实际的探索行为。
进一步研究 oePC 的位置场特性时，该团队发现当物体从其原始位置移动 0.5 厘米、1 厘米、2 厘米或 4 厘米时，oePC 的活动强度随着移动距离的增加会逐步减弱甚至消失，这说明 oePC 具有特定位置进行编码的能力。
用全新物体替换掉旧物体时，oePC 的活动模式并未出现显著变化。
令人费解的是，早先研究曾指出更换环境中的物体，会使得传统位置细胞的活动发生明显改变，那么为何 oePC 不发生变化呢？
这时，他们首先要考虑是：是否新旧物体对于小鼠来说过于相似，以至于它们无法区分？
为了排除这种可能，课题组精心挑选了一系列形状、颜色等方面截然不同的复杂物体对小鼠进行测试。然而，即便如此，oePC 的编码仍然不产生明显变化。
而进一步分析那些具有相同位置场的传统位置细胞时，他们发现这些细胞对于物体的更换确实产生了显著的编码差异。
这一对比结果清晰地表明，与传统位置细胞不同，oePC 似乎并不对物体本身的特征进行编码。
在另一项实验设计中，该团队将物体巧妙地掩藏在隔板后，这样一来只有当小鼠表现出探索的主动性并穿过一个小门去搜寻时，它们才能见到这些物体。
有趣的是，他们观察到即使在小鼠接近但尚未直接看到物体的时候，oePC 便已经预先活动起来。
When those familiar obxts were unexpectedly removed, or when the obxts were suddenly replaced with food in the same location, oePC activity began to decrease significantly.
This phenomenon suggests that these cells are not encoding changes in environmental signals or expressing expectations of potential rewards.
In order to further study the characteristics of oePC, the research team designed a series of experiments, including imaging observations for several consecutive days and behavioral box environment changing tests.
At this time, oePC shows a similar pattern to classic place cells, which means that the neuronal activity of oePC will show a certain stability in a familiar environment. And in new environments, the potential for reprogramming emerges.
Finally, they set out to explore the impact of the input circuit from the lateral entorhinal cortex (LEC) to the hippocampus on the coding ability of oePC.
By expressing the inhibitory chemical genetic protein hM4Di in LEC and injecting its specific ligand-clozapine-N-oxide (CNO, clozapine-N-oxide) into mice, the function of LEC neurons is inhibited. Activity.
Experiments found that when the function of LEC was inhibited, the activity pattern of oePC was significantly disturbed. In contrast, oePC was not affected in those mice expressing the control protein.
This finding strongly suggests that signals of exploratory intentions are transmitted to neurons in the hippocampal region through the LEC.
当那些熟悉的物体意外被移走，或是在相同的位置突然将物体换成食物时，oePC 的活动开始显著减少。
这一现象表明，这些细胞并不是在编码环境信号的变化，也不是在表达对潜在奖赏的期待。
为了进一步研究 oePC 的特点，课题组设计了一系列实验，包括连续几天的成像观察、以及行为箱环境变换测试。
这时，oePC 与经典位置细胞显示出相似的模式，也就是说 oePC 的神经元活动在熟悉环境中，会表现出一定的稳定性。而在新环境中则显现出重新编程的潜力。
最后，他们着手探讨了外侧内嗅皮层（LEC，lateral entorhinal cortex）至海马体的输入回路对 oePC 编码能力的影响。
通过在 LEC 表达抑制性的化学遗传学蛋白 hM4Di，并给小鼠注射其特异性配体——叠氮平-N-氧化物（CNO，clozapine-N-oxide），以便来抑制 LEC 神经元的活动。
实验发现当 LEC 的功能受到抑制时，oePC 的活动模式受到了显著的干扰。相比之下，那些表达对照蛋白的小鼠中，oePC 则没有受到影响。
这一发现强烈表明，探索意图的信号是通过 LEC 传递到海马区域神经元的。
In general, with the recent series of breakthrough results achieved by the scientific community in the field of hippocampal function research, humankind's understanding of this mysterious brain area has gradually deepened.
For example, it was found that hippocampal neurons in mice can encode abstract cognitive variables, and experiments using hippocampal brain-computer interface technology enabled mice to autonomously control virtual obxts to designated locations.
Despite this, humanity's understanding of the hippocampus is still just the tip of the iceberg.
How the hippocampus maps the external world and transforms this information into individual subjective consciousness and actions is a key issue in revealing the core mechanism of cognition and behavior in animals and even humans.
Therefore, Zhou Ning hopes to continue to uncover the mystery of hippocampal function, which will not only help humans understand the working mechanism of the brain, but may also provide new ideas and strategies for the treatment of related neurological diseases.
Specifically, she plans to delve deeper into the role of these neurons in brain diseases, specifically examining whether the less environmental exploration behavior of autistic individuals is related to abnormal function of oePC neurons.
In addition, he also hopes to cooperate with other teams in the field of computational neurobiology to use advanced algorithms such as closed-loop control to control oePC in real time, so as to accurately study their impact on animal behavior.
And we hope to improve the neural network model through cooperation to simulate the complex functions of the hippocampus and further unlock the secrets of brain operation.
总的来说，随着近期科学界在海马体功能研究领域取得的一系列突破性成果，人类对这一神秘脑区的认知逐渐深化。
例如，人们发现小鼠的海马神经元能够对抽象认知变量进行编码，以及通过海马脑机接口技术实现小鼠自主控制虚拟物体至指定位置的实验。
尽管如此，人类对于海马体的了解仍然宛如冰山一角。
海马体如何映射外部世界，并将这些信息转化为个体的主观意识和行动，是揭示动物乃至人类认知与行为核心机制的关键问题。
因此，周宁希望继续揭开海马体功能的神秘面纱，不仅有助于人类理解大脑的工作机制，还可能为治疗相关神经疾病提供新的思路和策略。
具体来说，她计划深入探究这类神经元在脑部疾病中扮演的角色，特别是考察自闭症个体较少的环境探索行为是否与 oePC 神经元的功能异常存在关联。
此外，其也期望能与计算神经生物学领域的其他团队合作，利用闭环控制等先进算法对 oePC 进行实时调控，从而精确地研究它们对动物行为的影响。
以及希望通过合作来完善神经网络模型，从而模拟海马体的复杂功能，进一步地解开大脑运作的秘密。
What excites the research team is that in addition to those typical place cells, they discovered a unique group of hippocampal neurons that only activate when the mice explore specific locations.
However, when the mice passed through the same location without engaging in any exploratory behavior, the cells were nearly silent.
This special cellular function had not been described before, so they named it obxt exploration-dependent place cells (oePC).
而令课题组振奋的是：在那些典型的位置细胞之外，他们发现了一群独特的海马神经元，这些细胞仅在小鼠探索特定位置时才激活。
但是，在小鼠经过同一地点但不进行任何探索行为时，这些细胞几乎是沉默的。
这种特殊的细胞功能此前并未被提及过，因此他们将其命名为探索依赖性位置细胞（oePC）
However, when the mice passed through the same location without engaging in any exploratory behavior, the cells were nearly silent.
This special cellular function had not been described before, so they named it obxt exploration-dependent place cells (oePC).
而令课题组振奋的是：在那些典型的位置细胞之外，他们发现了一群独特的海马神经元，这些细胞仅在小鼠探索特定位置时才激活。
但是，在小鼠经过同一地点但不进行任何探索行为时，这些细胞几乎是沉默的。
这种特殊的细胞功能此前并未被提及过，因此他们将其命名为探索依赖性位置细胞（oePC）
Subsequently, they constructed a series of experiments aimed at studying how oePC jointly encodes exploration intention and spatial information, and tried to explain the mechanism behind it.
By analyzing the activation time points of oePC and the mouse's obxt exploration behavior, they observed that the active period of these cells usually occurs before the animal's exploration behavior (median about 0.8 seconds) and occurs when the obxt is about 3 cm away. , which means that the activation of oePC actually precedes the actual exploration behavior.
When further studying the position field properties of oePC, the team found that when an obxt moved 0.5 cm, 1 cm, 2 cm, or 4 cm from its original position, the activity intensity of oePC gradually weakened or even disappeared as the distance of movement increased, indicating that oePC has the ability to encode at specific locations.
The activity patterns of oePC did not change significantly when replacing old obxts with new ones.
What is puzzling is that earlier studies have pointed out that changing obxts in the environment will significantly change the activity of traditional place cells, so why does oePC not change?
At this point, their first consideration was: Are the old and new obxts too similar for the mice to distinguish?
In order to rule out this possibility, the research team carefully sexted a series of complex obxts with completely different shapes, colors, etc. to test the mice. However, even so, the encoding of oePC still does not produce significant changes.
When they further analyzed those traditional place cells with the same position field, they found that these cells did produce significant coding differences for obxt replacement.
This comparison clearly shows that, unlike traditional place cells, oePCs do not appear to encode features of the obxts themselves.
In another experimental design, the team cleverly hid obxts behind partitions so that the obxts were only visible to mice when they showed exploratory initiative and went through a small door to search.
Interestingly, they observed that the oePC was already preactivated even when the mice approached but had not yet directly seen the obxt.
随后，他们又构建了一系列实验，旨在研究 oePC 是如何联合编码探索意图和空间信息的，并尝试解释其背后的机制。
通过分析 oePC 的激活时间点和与小鼠对物体探索的行为，他们观察到这些细胞的活跃期通常发生在动物的探索行为前（中位数 0.8 秒左右），且距离物体大约 3 厘米时发生，这意味着 oePC 的激活实际上早于实际的探索行为。
进一步研究 oePC 的位置场特性时，该团队发现当物体从其原始位置移动 0.5 厘米、1 厘米、2 厘米或 4 厘米时，oePC 的活动强度随着移动距离的增加会逐步减弱甚至消失，这说明 oePC 具有特定位置进行编码的能力。
用全新物体替换掉旧物体时，oePC 的活动模式并未出现显著变化。
令人费解的是，早先研究曾指出更换环境中的物体，会使得传统位置细胞的活动发生明显改变，那么为何 oePC 不发生变化呢？
这时，他们首先要考虑是：是否新旧物体对于小鼠来说过于相似，以至于它们无法区分？
为了排除这种可能，课题组精心挑选了一系列形状、颜色等方面截然不同的复杂物体对小鼠进行测试。然而，即便如此，oePC 的编码仍然不产生明显变化。
而进一步分析那些具有相同位置场的传统位置细胞时，他们发现这些细胞对于物体的更换确实产生了显著的编码差异。
这一对比结果清晰地表明，与传统位置细胞不同，oePC 似乎并不对物体本身的特征进行编码。
在另一项实验设计中，该团队将物体巧妙地掩藏在隔板后，这样一来只有当小鼠表现出探索的主动性并穿过一个小门去搜寻时，它们才能见到这些物体。
有趣的是，他们观察到即使在小鼠接近但尚未直接看到物体的时候，oePC 便已经预先活动起来。
When those familiar obxts were unexpectedly removed, or when the obxts were suddenly replaced with food in the same location, oePC activity began to decrease significantly.
This phenomenon suggests that these cells are not encoding changes in environmental signals or expressing expectations of potential rewards.
In order to further study the characteristics of oePC, the research team designed a series of experiments, including imaging observations for several consecutive days and behavioral box environment changing tests.
At this time, oePC shows a similar pattern to classic place cells, which means that the neuronal activity of oePC will show a certain stability in a familiar environment. And in new environments, the potential for reprogramming emerges.
Finally, they set out to explore the impact of the input circuit from the lateral entorhinal cortex (LEC) to the hippocampus on the coding ability of oePC.
By expressing the inhibitory chemical genetic protein hM4Di in LEC and injecting its specific ligand-clozapine-N-oxide (CNO, clozapine-N-oxide) into mice, the function of LEC neurons is inhibited. Activity.
Experiments found that when the function of LEC was inhibited, the activity pattern of oePC was significantly disturbed. In contrast, oePC was not affected in those mice expressing the control protein.
This finding strongly suggests that signals of exploratory intentions are transmitted to neurons in the hippocampal region through the LEC.
当那些熟悉的物体意外被移走，或是在相同的位置突然将物体换成食物时，oePC 的活动开始显著减少。
这一现象表明，这些细胞并不是在编码环境信号的变化，也不是在表达对潜在奖赏的期待。
为了进一步研究 oePC 的特点，课题组设计了一系列实验，包括连续几天的成像观察、以及行为箱环境变换测试。
这时，oePC 与经典位置细胞显示出相似的模式，也就是说 oePC 的神经元活动在熟悉环境中，会表现出一定的稳定性。而在新环境中则显现出重新编程的潜力。
最后，他们着手探讨了外侧内嗅皮层（LEC，lateral entorhinal cortex）至海马体的输入回路对 oePC 编码能力的影响。
通过在 LEC 表达抑制性的化学遗传学蛋白 hM4Di，并给小鼠注射其特异性配体——叠氮平-N-氧化物（CNO，clozapine-N-oxide），以便来抑制 LEC 神经元的活动。
实验发现当 LEC 的功能受到抑制时，oePC 的活动模式受到了显著的干扰。相比之下，那些表达对照蛋白的小鼠中，oePC 则没有受到影响。
这一发现强烈表明，探索意图的信号是通过 LEC 传递到海马区域神经元的。
Zhou Ning said: "This microscope is based on the open source project of miniscope at the University of California, Los Angeles. Its architecture and principles are not unfamiliar to me. I have built a two-photon fluorescence microscope system before and have accumulated experience in it. acquired certain optical technology and practical experience."
However, in the process of building a miniature microscope, Zhou Ning encountered an unexpected challenge.
Due to the small size and precise structure of this microscope, she needed to perform electronic welding on an interface less than one millimeter wide.
At this time, a problem arises: the tip diameter of the research team's soldering iron exceeds several millimeters, which means that the operating space is extremely small. A little carelessness may cause a short circuit, weak solder joints, or even burn the chip.
For a researcher with a background in biology, such technical requirements are undoubtedly a huge challenge.
To this end, she kept trying various techniques and even considered whether to go to the assembly line of an electronics manufacturing factory to learn from it. After many trials and failures, Zhou Ning finally mastered the key points of welding.
"Now my skills are among the best in the team, and I am considered a skilled worker, so I have to continue to do the daily maintenance of the micromicroscope," she said.
In short, after all kinds of efforts, she and her team finally revealed the existence of a new group of hippocampal neurons (oePC).
Recently, a related paper was published in Nature Communications [1] under the title "Conjunctive encoding of exploratory intentions and spatial information in the hippocampus".
Zeng Yifan is the first author, and Zhou Ning serves as the corresponding author.
周宁说：“这套显微镜基 于美国加州大学洛杉矶分校 miniscope 的开源项目，它的架构和原理对我来说并不陌生，我以前曾亲手搭建过一台双光子荧光显微镜系统，并在此前积累了一定的光学技术和实践经验。”
然而，在搭建微型显微镜的过程中，周宁遇到了一个意想不到的挑战。
由于这台显微镜体积之小、结构之精密，她需要在不足一毫米宽的接口上进行电子焊接。
这时问题来了：课题组的电烙铁尖端直径超过了几个毫米，这意味着操作空间极小，稍有不慎就可能导致短路、焊点不牢固甚至烧毁芯片。
对于一个以生物学为背景的研究者来说，这样的技术要求无疑是一个巨大的挑战。
为此，她不断尝试各种手法，甚至考虑是否要去电子制造厂的流水线上取经。经过多次试验和失败，周宁终于掌握了焊接要点。
“现在在团队中我的技术还是算数一数二的，也算是个熟练工了，因此还得继续承担微型显微镜的日常维护工作。”她表示。
总之，在种种努力之下她和团队终于揭示了一群新型海马神经元（oePC）的存在。
日前，相关论文以《海马体探索意图和空间信息的联合编码》为题发在自然通讯上。
曾一凡是第一作者，周宁担任通讯作者。
However, in the process of building a miniature microscope, Zhou Ning encountered an unexpected challenge.
Due to the small size and precise structure of this microscope, she needed to perform electronic welding on an interface less than one millimeter wide.
At this time, a problem arises: the tip diameter of the research team's soldering iron exceeds several millimeters, which means that the operating space is extremely small. A little carelessness may cause a short circuit, weak solder joints, or even burn the chip.
For a researcher with a background in biology, such technical requirements are undoubtedly a huge challenge.
To this end, she kept trying various techniques and even considered whether to go to the assembly line of an electronics manufacturing factory to learn from it. After many trials and failures, Zhou Ning finally mastered the key points of welding.
"Now my skills are among the best in the team, and I am considered a skilled worker, so I have to continue to do the daily maintenance of the micromicroscope," she said.
In short, after all kinds of efforts, she and her team finally revealed the existence of a new group of hippocampal neurons (oePC).
Recently, a related paper was published in Nature Communications [1] under the title "Conjunctive encoding of exploratory intentions and spatial information in the hippocampus".
Zeng Yifan is the first author, and Zhou Ning serves as the corresponding author.
周宁说：“这套显微镜基 于美国加州大学洛杉矶分校 miniscope 的开源项目，它的架构和原理对我来说并不陌生，我以前曾亲手搭建过一台双光子荧光显微镜系统，并在此前积累了一定的光学技术和实践经验。”
然而，在搭建微型显微镜的过程中，周宁遇到了一个意想不到的挑战。
由于这台显微镜体积之小、结构之精密，她需要在不足一毫米宽的接口上进行电子焊接。
这时问题来了：课题组的电烙铁尖端直径超过了几个毫米，这意味着操作空间极小，稍有不慎就可能导致短路、焊点不牢固甚至烧毁芯片。
对于一个以生物学为背景的研究者来说，这样的技术要求无疑是一个巨大的挑战。
为此，她不断尝试各种手法，甚至考虑是否要去电子制造厂的流水线上取经。经过多次试验和失败，周宁终于掌握了焊接要点。
“现在在团队中我的技术还是算数一数二的，也算是个熟练工了，因此还得继续承担微型显微镜的日常维护工作。”她表示。
总之，在种种努力之下她和团队终于揭示了一群新型海马神经元（oePC）的存在。
日前，相关论文以《海马体探索意图和空间信息的联合编码》为题发在自然通讯上。
曾一凡是第一作者，周宁担任通讯作者。
In general, with the recent series of breakthrough results achieved by the scientific community in the field of hippocampal function research, humankind's understanding of this mysterious brain area has gradually deepened.
For example, it was found that hippocampal neurons in mice can encode abstract cognitive variables, and experiments using hippocampal brain-computer interface technology enabled mice to autonomously control virtual obxts to designated locations.
Despite this, humanity's understanding of the hippocampus is still just the tip of the iceberg.
How the hippocampus maps the external world and transforms this information into individual subjective consciousness and actions is a key issue in revealing the core mechanism of cognition and behavior in animals and even humans.
Therefore, Zhou Ning hopes to continue to uncover the mystery of hippocampal function, which will not only help humans understand the working mechanism of the brain, but may also provide new ideas and strategies for the treatment of related neurological diseases.
Specifically, she plans to delve deeper into the role of these neurons in brain diseases, specifically examining whether the less environmental exploration behavior of autistic individuals is related to abnormal function of oePC neurons.
In addition, he also hopes to cooperate with other teams in the field of computational neurobiology to use advanced algorithms such as closed-loop control to control oePC in real time, so as to accurately study their impact on animal behavior.
And we hope to improve the neural network model through cooperation to simulate the complex functions of the hippocampus and further unlock the secrets of brain operation.
总的来说，随着近期科学界在海马体功能研究领域取得的一系列突破性成果，人类对这一神秘脑区的认知逐渐深化。
例如，人们发现小鼠的海马神经元能够对抽象认知变量进行编码，以及通过海马脑机接口技术实现小鼠自主控制虚拟物体至指定位置的实验。
尽管如此，人类对于海马体的了解仍然宛如冰山一角。
海马体如何映射外部世界，并将这些信息转化为个体的主观意识和行动，是揭示动物乃至人类认知与行为核心机制的关键问题。
因此，周宁希望继续揭开海马体功能的神秘面纱，不仅有助于人类理解大脑的工作机制，还可能为治疗相关神经疾病提供新的思路和策略。
具体来说，她计划深入探究这类神经元在脑部疾病中扮演的角色，特别是考察自闭症个体较少的环境探索行为是否与 oePC 神经元的功能异常存在关联。
此外，其也期望能与计算神经生物学领域的其他团队合作，利用闭环控制等先进算法对 oePC 进行实时调控，从而精确地研究它们对动物行为的影响。
以及希望通过合作来完善神经网络模型，从而模拟海马体的复杂功能，进一步地解开大脑运作的秘密。
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