"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.

“人類大腦里大約有860億個(gè)神經(jīng)元，這個(gè)數(shù)量大致相當(dāng)于銀河系中的恒星數(shù)量。在某種意義上，每個(gè)人的大腦都可以看作是一個(gè)廣闊的宇宙。”對(duì)于研究神經(jīng)成像的上?？萍即髮W(xué)周寧教授而言，大腦不僅充滿了神秘，還帶有浪漫的色彩。
最近，周教授和她的團(tuán)隊(duì)在這個(gè)“腦宇宙”中發(fā)現(xiàn)了新的瑰寶：一種新型的海馬體神經(jīng)元。
周寧教授解釋說：“這些神經(jīng)元能夠?qū)⑸锏耐獠靠陀^信息與內(nèi)部的主觀意圖緊密聯(lián)系起來。它們不僅可以映射空間信息，還能表征動(dòng)物的探索意圖?！?br /> 同時(shí)，這些神經(jīng)元的編碼機(jī)制依賴于外側(cè)內(nèi)嗅皮層的信息輸入，這為理解大腦如何整合外界環(huán)境信息與內(nèi)部主觀意圖提供了新的思路，并且也為理解海馬體中位置細(xì)胞的功能開辟了新的視角。
據(jù)悉，海馬體的功能異常與多種腦疾病有著密切的關(guān)聯(lián)，包括阿爾茨海默病、癲癇和精神分裂癥等。
對(duì)海馬體的編碼和記憶機(jī)制的深入了解，將有助于開發(fā)新的腦疾病診斷標(biāo)記物、推動(dòng)腦機(jī)接口的研究，以及開發(fā)新的藥物靶點(diǎn)。

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.

在神經(jīng)科學(xué)領(lǐng)域，人們一直被這樣一個(gè)有趣的問題所困擾：大腦如何確定生物體在空間中的位置，并利用這一信息進(jìn)行導(dǎo)航？
憑借在這一領(lǐng)域的顯著成就，英國(guó)科學(xué)家約翰·奧基夫（John O'Keefe）教授、與挪威科學(xué)家愛德華·莫澤（Edvard Moser）和邁-布里特·莫澤（May-Britt Moser）夫婦（現(xiàn)已離婚），于 2014 年共同獲得諾貝爾生理學(xué)或醫(yī)學(xué)獎(jiǎng)。
早在 1971 年，約翰·奧基夫教授就在研究大鼠時(shí)發(fā)現(xiàn)了海馬體（hippocampus）內(nèi)一種特殊的神經(jīng)元，并將其命名為“位置細(xì)胞”。
當(dāng)人們將記錄電極植入大鼠的海馬體來追蹤神經(jīng)元的活動(dòng)時(shí)，可以觀察到每個(gè)位置細(xì)胞僅在大鼠穿過某個(gè)特定區(qū)域時(shí)激活。
換句話說，每一個(gè)位置細(xì)胞對(duì)應(yīng)著空間中的一個(gè)特定區(qū)域，它們構(gòu)成了動(dòng)物大腦映射外部空間信息的一種索引機(jī)制。
有趣的是，人腦中也存在著類似的定位細(xì)胞，這些細(xì)胞共同構(gòu)成了人腦對(duì)于外部世界的“認(rèn)知地圖”。
多年來，科學(xué)家從未停止對(duì)于位置細(xì)胞形成機(jī)制和功能的探索。
比如，海馬神經(jīng)元是否只局限于表征空間位置？它們是否同樣指示時(shí)間、甚至是更為抽象的概念？
這些神經(jīng)元是否僅僅作為外部世界在大腦中的映射存在？或者它們也會(huì)受到生物體心理狀態(tài)的影響和調(diào)節(jié)？
更進(jìn)一步，海馬神經(jīng)元是否有能力同時(shí)編碼外界客觀信息和大腦主觀意向？
正是這些問題不斷激發(fā)著人們不斷地探索。而對(duì)這些疑問的解答，可能會(huì)幫助我們更進(jìn)一步地揭開大腦認(rèn)知的深層奧秘。

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，周寧在位于中國(guó)臺(tái)灣的中國(guó)醫(yī)藥大學(xué)獨(dú)立建組。2019 年，她加入上?？萍即髮W(xué) iHuman 研究所擔(dān)任獨(dú)立課題組長(zhǎng)。
長(zhǎng)期以來，她致力于通過熒光成像和電生理等技術(shù)，開展神經(jīng)生理學(xué)和病理學(xué)相關(guān)的基礎(chǔ)研究。
比如，在攻讀博士期間，周寧常常借助雙光子熒光顯微鏡技術(shù)，對(duì)那些被熒光指示劑標(biāo)記的腦片組織進(jìn)行成像記錄。
她經(jīng)常觀察到活腦片細(xì)胞中的鈣離子熒光強(qiáng)度隨著腦細(xì)胞的活動(dòng)變化而忽明忽暗，此起彼伏、如同遙遠(yuǎn)星空中星辰的閃爍，這讓周寧非常著迷。
如前所述，人類大腦有約 860 億個(gè)神經(jīng)元。而在活體動(dòng)物中，這些錯(cuò)綜復(fù)雜的神經(jīng)元網(wǎng)絡(luò)背后所的隱藏的信號(hào)，是理解大腦如何編碼信息的關(guān)鍵所在。
因此，周寧的研究方向逐漸聚焦于通過動(dòng)物活體的神經(jīng)成像技術(shù)，去深入研究大腦是如何編碼這些復(fù)雜信息的。
“每一次分析神經(jīng)元中的鈣離子活動(dòng)，都仿佛是在破解大腦的密碼一樣，既充滿未知、又無比振奮人心?！彼f。
而此前關(guān)于海馬體的研究，揭示了位置細(xì)胞可能會(huì)隨著動(dòng)物的覓食動(dòng)機(jī)或注意力狀態(tài)而調(diào)整。
例如，在動(dòng)物搜尋食物時(shí)，海馬體可能會(huì)激活更多的位置細(xì)胞以標(biāo)記食物的具體位置。
同樣地，當(dāng)外部環(huán)境發(fā)生變化，吸引了動(dòng)物對(duì)變化信號(hào)的注意時(shí)，位置細(xì)胞的數(shù)量和活動(dòng)也可能相應(yīng)地調(diào)整。
這些研究使周寧產(chǎn)生了一個(gè)疑問：在生物體既不被食物驅(qū)動(dòng)、也不被外部刺激所吸引的情況下，它們的主觀意愿能否被海馬神經(jīng)元編碼？
想象一下：當(dāng)我們每天沿著熟悉的道路去上班或上學(xué)，都會(huì)路過街角一個(gè)熟悉的雕像，有一天我們突然決定停下來仔細(xì)觀賞它，這時(shí)海馬體的神經(jīng)編碼會(huì)不會(huì)與往常有所不同？
是否有一群神經(jīng)元能夠同時(shí)編碼這個(gè)雕像的位置和我們的探索意愿？如果答案是肯定的，那么這些神經(jīng)元有可能指引我們?nèi)ツ睦镆约白鍪裁础?br /> 這一問題讓周寧團(tuán)隊(duì)充滿了激情，尤其是博士生曾一凡對(duì)此表現(xiàn)出濃厚興趣。 經(jīng)過一番深思熟慮，他們?cè)O(shè)計(jì)了一個(gè)精巧的實(shí)驗(yàn)來探究上述問題。
具體來說，其構(gòu)建了兩個(gè)設(shè)有環(huán)形跑道的行為箱，訓(xùn)練小鼠沿著相同方向奔跑，并在每完成一圈時(shí)在固定的位置給予一顆奶粉球作為獎(jiǎng)賞。
同時(shí)，在其他三個(gè)位置擺放了不同形狀和不同顏色的物體，允許小鼠在靠近這些物體時(shí)停下來進(jìn)行觀察和探索、或者選擇忽略物體繼續(xù)跑動(dòng)。在這兩種情況之下，小鼠所經(jīng)過的路徑都高度一致。
原創(chuàng)翻譯：龍騰網(wǎng) http://www.top-shui.cn 轉(zhuǎn)載請(qǐng)注明出處



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.

在實(shí)驗(yàn)開始前幾周，他們?cè)谛∈蟮念^部植入了一枚梯度變折射率透鏡（Grin Lens），并將海馬體神經(jīng)元標(biāo)記上鈣離子熒光指示劑 GCaMP6f。
這樣，當(dāng)小鼠進(jìn)行各種行為時(shí)，就能通過頭戴式微型顯微鏡，實(shí)時(shí)地記錄海馬體神經(jīng)元的活動(dòng)情況。
微型顯微鏡技術(shù)，是近年來神經(jīng)生物學(xué)領(lǐng)域涌現(xiàn)的一項(xiàng)突破性實(shí)驗(yàn)技術(shù)。盡管重量不到 3 克，它卻集成了傳統(tǒng)顯微鏡的關(guān)鍵功能組件。
這讓其能對(duì)大約 0.4 平方毫米的大腦區(qū)域進(jìn)行亞細(xì)胞級(jí)別的高速成像，并能夠同步捕獲超過 200 個(gè)神經(jīng)元的數(shù)據(jù)。
得益于其輕盈的設(shè)計(jì)，小鼠可以在幾乎不受限制的自然狀態(tài)下攜帶此顯微鏡開展自由活動(dòng)，確保了小鼠動(dòng)作和小鼠行為的自然性。
在課題組設(shè)計(jì)的行為箱中，小鼠可以自主選擇是否探索接近的物體。
在用攝像機(jī)拍攝小鼠行為表現(xiàn)的同時(shí)，該團(tuán)隊(duì)通過微型顯微鏡，來記錄海馬體神經(jīng)元的鈣信號(hào)活動(dòng)。
通過對(duì)所收集數(shù)據(jù)進(jìn)行深入分析，能夠識(shí)別出非常典型的位置細(xì)胞，這些細(xì)胞的特性和此前報(bào)道的傳統(tǒng)位置細(xì)胞高度吻合。