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).

而令課題組振奮的是：在那些典型的位置細(xì)胞之外，他們發(fā)現(xiàn)了一群獨(dú)特的海馬神經(jīng)元，這些細(xì)胞僅在小鼠探索特定位置時(shí)才激活。
但是，在小鼠經(jīng)過同一地點(diǎn)但不進(jìn)行任何探索行為時(shí)，這些細(xì)胞幾乎是沉默的。
這種特殊的細(xì)胞功能此前并未被提及過，因此他們將其命名為探索依賴性位置細(xì)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.

隨后，他們又構(gòu)建了一系列實(shí)驗(yàn)，旨在研究 oePC 是如何聯(lián)合編碼探索意圖和空間信息的，并嘗試解釋其背后的機(jī)制。
通過分析 oePC 的激活時(shí)間點(diǎn)和與小鼠對(duì)物體探索的行為，他們觀察到這些細(xì)胞的活躍期通常發(fā)生在動(dòng)物的探索行為前（中位數(shù) 0.8 秒左右），且距離物體大約 3 厘米時(shí)發(fā)生，這意味著 oePC 的激活實(shí)際上早于實(shí)際的探索行為。
進(jìn)一步研究 oePC 的位置場(chǎng)特性時(shí)，該團(tuán)隊(duì)發(fā)現(xiàn)當(dāng)物體從其原始位置移動(dòng) 0.5 厘米、1 厘米、2 厘米或 4 厘米時(shí)，oePC 的活動(dòng)強(qiáng)度隨著移動(dòng)距離的增加會(huì)逐步減弱甚至消失，這說明 oePC 具有特定位置進(jìn)行編碼的能力。
用全新物體替換掉舊物體時(shí)，oePC 的活動(dòng)模式并未出現(xiàn)顯著變化。
令人費(fèi)解的是，早先研究曾指出更換環(huán)境中的物體，會(huì)使得傳統(tǒng)位置細(xì)胞的活動(dòng)發(fā)生明顯改變，那么為何 oePC 不發(fā)生變化呢？
這時(shí)，他們首先要考慮是：是否新舊物體對(duì)于小鼠來說過于相似，以至于它們無法區(qū)分？
為了排除這種可能，課題組精心挑選了一系列形狀、顏色等方面截然不同的復(fù)雜物體對(duì)小鼠進(jìn)行測(cè)試。然而，即便如此，oePC 的編碼仍然不產(chǎn)生明顯變化。
而進(jìn)一步分析那些具有相同位置場(chǎng)的傳統(tǒng)位置細(xì)胞時(shí)，他們發(fā)現(xiàn)這些細(xì)胞對(duì)于物體的更換確實(shí)產(chǎn)生了顯著的編碼差異。
這一對(duì)比結(jié)果清晰地表明，與傳統(tǒng)位置細(xì)胞不同，oePC 似乎并不對(duì)物體本身的特征進(jìn)行編碼。
在另一項(xiàng)實(shí)驗(yàn)設(shè)計(jì)中，該團(tuán)隊(duì)將物體巧妙地掩藏在隔板后，這樣一來只有當(dāng)小鼠表現(xiàn)出探索的主動(dòng)性并穿過一個(gè)小門去搜尋時(shí)，它們才能見到這些物體。
有趣的是，他們觀察到即使在小鼠接近但尚未直接看到物體的時(shí)候，oePC 便已經(jīng)預(yù)先活動(dòng)起來。


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.

當(dāng)那些熟悉的物體意外被移走，或是在相同的位置突然將物體換成食物時(shí)，oePC 的活動(dòng)開始顯著減少。
這一現(xiàn)象表明，這些細(xì)胞并不是在編碼環(huán)境信號(hào)的變化，也不是在表達(dá)對(duì)潛在獎(jiǎng)賞的期待。
為了進(jìn)一步研究 oePC 的特點(diǎn)，課題組設(shè)計(jì)了一系列實(shí)驗(yàn)，包括連續(xù)幾天的成像觀察、以及行為箱環(huán)境變換測(cè)試。
這時(shí)，oePC 與經(jīng)典位置細(xì)胞顯示出相似的模式，也就是說 oePC 的神經(jīng)元活動(dòng)在熟悉環(huán)境中，會(huì)表現(xiàn)出一定的穩(wěn)定性。而在新環(huán)境中則顯現(xiàn)出重新編程的潛力。
最后，他們著手探討了外側(cè)內(nèi)嗅皮層（LEC，lateral entorhinal cortex）至海馬體的輸入回路對(duì) oePC 編碼能力的影響。
通過在 LEC 表達(dá)抑制性的化學(xué)遺傳學(xué)蛋白 hM4Di，并給小鼠注射其特異性配體——疊氮平-N-氧化物（CNO，clozapine-N-oxide），以便來抑制 LEC 神經(jīng)元的活動(dòng)。
實(shí)驗(yàn)發(fā)現(xiàn)當(dāng) LEC 的功能受到抑制時(shí)，oePC 的活動(dòng)模式受到了顯著的干擾。相比之下，那些表達(dá)對(duì)照蛋白的小鼠中，oePC 則沒有受到影響。
這一發(fā)現(xiàn)強(qiáng)烈表明，探索意圖的信號(hào)是通過 LEC 傳遞到海馬區(qū)域神經(jīng)元的。
原創(chuàng)翻譯：龍騰網(wǎng) http://nxnpts.cn 轉(zhuǎn)載請(qǐng)注明出處


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.

周寧說：“這套顯微鏡基 于美國加州大學(xué)洛杉磯分校 miniscope 的開源項(xiàng)目，它的架構(gòu)和原理對(duì)我來說并不陌生，我以前曾親手搭建過一臺(tái)雙光子熒光顯微鏡系統(tǒng)，并在此前積累了一定的光學(xué)技術(shù)和實(shí)踐經(jīng)驗(yàn)。”
然而，在搭建微型顯微鏡的過程中，周寧遇到了一個(gè)意想不到的挑戰(zhàn)。
由于這臺(tái)顯微鏡體積之小、結(jié)構(gòu)之精密，她需要在不足一毫米寬的接口上進(jìn)行電子焊接。
這時(shí)問題來了：課題組的電烙鐵尖端直徑超過了幾個(gè)毫米，這意味著操作空間極小，稍有不慎就可能導(dǎo)致短路、焊點(diǎn)不牢固甚至燒毀芯片。
對(duì)于一個(gè)以生物學(xué)為背景的研究者來說，這樣的技術(shù)要求無疑是一個(gè)巨大的挑戰(zhàn)。
為此，她不斷嘗試各種手法，甚至考慮是否要去電子制造廠的流水線上取經(jīng)。經(jīng)過多次試驗(yàn)和失敗，周寧終于掌握了焊接要點(diǎn)。
“現(xiàn)在在團(tuán)隊(duì)中我的技術(shù)還是算數(shù)一數(shù)二的，也算是個(gè)熟練工了，因此還得繼續(xù)承擔(dān)微型顯微鏡的日常維護(hù)工作?！彼硎尽?br /> 總之，在種種努力之下她和團(tuán)隊(duì)終于揭示了一群新型海馬神經(jīng)元（oePC）的存在。
日前，相關(guān)論文以《海馬體探索意圖和空間信息的聯(lián)合編碼》為題發(fā)在自然通訊上。
曾一凡是第一作者，周寧擔(dān)任通訊作者。


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.

總的來說，隨著近期科學(xué)界在海馬體功能研究領(lǐng)域取得的一系列突破性成果，人類對(duì)這一神秘腦區(qū)的認(rèn)知逐漸深化。
例如，人們發(fā)現(xiàn)小鼠的海馬神經(jīng)元能夠?qū)Τ橄笳J(rèn)知變量進(jìn)行編碼，以及通過海馬腦機(jī)接口技術(shù)實(shí)現(xiàn)小鼠自主控制虛擬物體至指定位置的實(shí)驗(yàn)。
盡管如此，人類對(duì)于海馬體的了解仍然宛如冰山一角。
海馬體如何映射外部世界，并將這些信息轉(zhuǎn)化為個(gè)體的主觀意識(shí)和行動(dòng)，是揭示動(dòng)物乃至人類認(rèn)知與行為核心機(jī)制的關(guān)鍵問題。
因此，周寧希望繼續(xù)揭開海馬體功能的神秘面紗，不僅有助于人類理解大腦的工作機(jī)制，還可能為治療相關(guān)神經(jīng)疾病提供新的思路和策略。
具體來說，她計(jì)劃深入探究這類神經(jīng)元在腦部疾病中扮演的角色，特別是考察自閉癥個(gè)體較少的環(huán)境探索行為是否與 oePC 神經(jīng)元的功能異常存在關(guān)聯(lián)。
此外，其也期望能與計(jì)算神經(jīng)生物學(xué)領(lǐng)域的其他團(tuán)隊(duì)合作，利用閉環(huán)控制等先進(jìn)算法對(duì) oePC 進(jìn)行實(shí)時(shí)調(diào)控，從而精確地研究它們對(duì)動(dòng)物行為的影響。
以及希望通過合作來完善神經(jīng)網(wǎng)絡(luò)模型，從而模擬海馬體的復(fù)雜功能，進(jìn)一步地解開大腦運(yùn)作的秘密。