Through the Open Window: How Does the Brain Talk to the Body?

ABSTRACT 摘要

“大脑控制着身体的一举一动，这些举动包括食物的消化、饮水、睡眠周期、血压等等。这些功能在维持身体的内环境稳态中是不可或缺的（内环境稳态是使得身体维持一种稳定平衡的状态）。为了控制内环境稳态，大脑会借助一种被称为“激素（荷尔蒙）”的化学信使（chemical messengers）与大脑沟通。激素通过血流从大脑流遍全身，又从全身流回大脑中。然而，为了保护脆弱的脑细胞免遭不必要的侵袭，脑血管会将自己牢牢封住，从而阻碍大部分分子的通过。那么，大脑是如何绕开这道屏障与身体沟通的呢？答案是：在大脑某些部位的血管含有像窗户一样的开口，这些开口可以允许激素通过。科学家们正在研究一些血管是为什么以及如何敞开这些窗户，而保持其他地方密封着 。”

The brain controls the activities of the body, including food digestion, drinking, sleep cycles, temperature, blood pressure, and more. These functions are essential to keep the body in homeostasis, which is the state of being steady and balanced. To control homeostasis, the brain talks to the body with the help of chemical messengers called hormones. Hormones travel through the blood stream from the brain to the body and back. However, in order to protect the delicate brain cells from unwanted intrusions, the blood vessels of the brain are tightly sealed, preventing the passage of most molecules. How, then, does the brain bypass this barrier to communicate with the body? The answer is that, in certain parts of the brain, the blood vessels contain special window-like openings that allow passage of hormones. Scientists are investigating why and how some blood vessels open their windows while others remain sealed.

维持身体平衡与稳定

KEEPING THE BODY BALANCED AND STEADY

我们所生活的外部世界都是千变万化的。我们身体内部也会在我们吃东西、喝东西、做运动或睡觉后发生变化。然而，尽管有这些连续不断的变化，身体还是能够保持内环境稳定。我们把这种能力称为“稳态”，它是由两个希腊单词构成的：“homeo”的意思是“相似”，“stasis”的意思是“稳定”。例如，人体内的所有细胞都在大约37 ℃下运转功能最好。因此，身体致力维持这个温度。当外界环境炎热时，我们通过排汗使身体降温，当外界环境寒冷时，我们会打颤以产生热量为我们身体提供温暖。如果我们不能控制身体的温度，我们的细胞将不能正常工作。这就是为什么所有生物体，从单细胞细菌或酵母菌到像大象一样的大型动物，都必须维持稳态才能得以继续生存。

The outside world in which we live is constantly changing. The inside of our bodies also changes after we eat, drink, exercise, or sleep. Yet, despite these continuous changes, the body is able to keep its inner environment stable. We call this ability homeostasis, which is a combination of two words in Greek: “homeo,” meaning “similar,” and “stasis” meaning “stable.” For example, all the cells in the human body function best at a temperature of around 37°C. Therefore, the body works to maintain this temperature. When it is hot outside, we cool the body by sweating. When it is cold outside, we warm up by shivering, which produces heat. If we were unable to control body temperature, our cells would fail to function properly. That is why all living organisms, from single-celled bacteria or yeast to large animals, such as elephants, must maintain homeostasis to stay alive.

稳态是通过大脑与身体其他部分之间永无止境的对话实现的。大脑作为身体的总指挥官，会接收许多关于器官组织状态的信息。紧接着它会“决定”下一步需要做什么，以对这些信息作出回应（图1）。如果稳态被扰乱了，大脑会向身体各处发出指令使身体恢复正常状态。这些对话的语言是化学物质。被称为“激素”的特别分子会作为信使在大脑和身体之间，以及身体各部位之间来回运送信息和指令。负责输送血液的循环系统是沟通联系的主要路线。这个错综复杂的管道状网络被称为“血管”，血管贯穿全身，包括脑部。激素和其他信号分子在血液与组织之间的信息传递发生在非常细小的血管中，我们把这种血管称为“毛细血管”。

Homeostasis is achieved by a never-ending “conversation” that takes place between the brain and the rest of the body. The brain, which serves as the main headquarter of the body, receives information about the state of the many organs and tissues. Then it “decides” what needs to be done in response to this information (Figure 1). If homeostasis is disrupted, the brain sends commands to the various body parts to bring bodily conditions back to normal. The language of this conversation is chemical. Special molecules called hormones serve as messengers that carry information and instructions back-and-forth between the brain and the body, as well as between various body parts. The circulatory system, which carries the blood, is the main route of communication. This elaborate network of pipe-like structures called blood vessels runs through the entire body, including the brain. The passage of hormones and other signaling molecules between the blood and the body tissues occurs at very small vessels called capillaries.

图1-大脑维持身体的健康

大脑和身体其他部分之间不断地进行对话，以保持身体状况的稳定平衡--这种状态称为稳态

Figure 1 - The brain maintains the body’s well-being.

A constant conversation between the brain and the rest of the body takes place to keep physical conditions steady and balanced—a state called homeostasis.

例如，让我们来看看我们吃完一顿饭后会发生什么。当我们吃完饭后，血液中一种被称为葡萄糖的糖类含量会增加。一个叫胰腺的器官感受到葡萄糖含量升高，便向大脑发送一种激素的信息。你也可能曾听说过这种激素，这种激素叫胰岛素。大脑接收到来自胰腺的信息后，会引导肝脏吸收血液中过多的糖分。最终结果是：血糖水平恢复正常值。于此同时，肠道会向大脑发送其他激素宣布已经吃饱了。大脑则通过发送一种传递“停止进食”信号的激素以作为回应。

For example, let us look at what happens after we have a meal. After we eat, the amount of a sugar called glucose is increased in the blood. An organ called the pancreas senses the elevated level of glucose and sends a hormone message to the brain. You may have heard of this hormone; it is called insulin. After receiving the message from the pancreas, the brain guides the liver to absorb the excessive sugar from the bloodstream. The end result is that blood sugar levels get back to normal. At the same time, the gut sends other hormones to the brain to announce that the belly is full. The brain reacts by sending a hormone that delivers a “stop eating” signal.

下丘脑：大脑稳态的中心 

THE HYPOTHALAMUS: THE BRAIN’S CENTER OF HOMEOSTASIS

到目前为止，我们已经阐述了大脑是如何从身体中收集信息的，以及是如何决定要发送哪些指令以维持稳态的。大脑中大部分活动发生在一个被称为“下丘脑”的区域，下丘脑在希腊语中意为“在内室的下方”（图2）。下丘脑控制着许多重要的身体机能，如睡眠、血压、温度、饥饿、口渴以及能量的消耗与储存。这更像一个电脑微处理器，下丘脑通过遵循一套规则运行着一套算法来计算这些信息。然后，下丘脑将做一个是否向身体发送信号的决定。这种类型的计算发生在被称为神经元的脑细胞中。下丘脑的神经元可以接收来自身体内部和来自外部环境的反馈，它们还可以产生各种激素。

So far, we have described how the brain collects information from the body and decides which commands to send in order to maintain homeostasis. The specific region of the brain where most of this activity takes place is called the hypothalamus, which means “under the inner chamber” in Greek (Figure 2). The hypothalamus controls many important body functions, such as sleep, blood pressure, temperature, hunger, thirst, and energy consumption and storage. Much like a computer microprocessor, the hypothalamus runs an algorithm that computes the information by following a set of rules. Then, the hypothalamus makes a decision about whether or not to send commands to the body. This type of computation occurs in brain cells called neurons. The neurons in the hypothalamus can receive feedback both from inside the body and from the external environment. They can also produce various hormones.

图2—下丘脑神经元与垂体毛细血管之间的交汇点

在右侧，下丘脑用绿色显示，垂体用蓝色显示。在左侧，你可以看到来自下丘脑的指令沿着神经元传递到垂体。然后，垂体以激素的形式将指令释放到血液中，流过有窗孔的毛细血管。

Figure 2 - The meeting point between hypothalamic neurons and pituitary capillaries.

On the right, the hypothalamus is highlighted in green and the pituitary in blue. On the left, you can see that commands from the hypothalamus travel along the neurons to the pituitary gland. The pituitary then releases commands in the form of hormones into the bloodstream, via the fenestrated capillaries

举一个我们日常生活中的例子，当我们在暑气熏蒸的一天中没有摄入足够的水，身体就会向大脑发送一条信息，大脑则反过来向血液释放一种激素，这种激素叫“抗利尿激素”。抗利尿激素吩咐肾脏将身体的水重吸收回血液中。这样就可以阻止我们排尿从而保护我们免受身体水分的进一步流失。与此同时，来自大脑的激素会让我们感到口渴，以让我们喝更多的水来补充我们的水分。

As an example from our daily lives, when we do not drink enough water on a hot day, the body sends a message to the brain which, in turn, releases a hormone called vasopressin into the blood. Vasopressin instructs the kidneys to soak water back up into the blood. This prevents us from urinating and protects us from further loss of water. Simultaneously, hormones from the brain make us feel thirsty so that we drink more and replenish our water supplies.

大脑与血液之间的窗户

INDOWS BETWEEN THE BRAIN AND BLOOD

如上所述，流动的血液就像一个邮递员一样，收集大脑中的化学信息，又将化学信息传递到大脑中。然而，在邮递员的道路上有一块主要的绊脚石。大脑中的血管被一个特殊的防护装置严密地封住了，这个防护装置是“血脑屏障（blood-brain barrier 简称BBB）”。构建血管壁的细胞之间紧密相连，这就和用水泥将砖头粘在一起相类似，因此几乎没有任何东西可以从中穿过（图3底部）。这道屏障的主要作用是保护人脑免受感染。当血脑屏障（BBB）因疾病或受伤而松开时，细菌可能就会进入脑部，造成严重损伤甚至死亡。

As mentioned, the bloodstream acts like a postman, collecting and delivering chemical messages to and from the brain. However, there is a major obstacle in the postman’s path. The blood vessels of the brain are sealed tightly by a special safeguard, called the blood-brain barrier (BBB). The cells that build the blood vessel walls are connected tightly to one another, similar to bricks glued together by cement, so almost nothing can pass through (Figure 3, bottom). The main purpose of this barrier is to protect the brain from infection. When the BBB is loosened as a result of disease or injury, bacteria might enter the brain and cause severe damage or even death.

图3-是要BBB还是不要BBB？

大脑中有两种毛细血管。在顶部，你可以看到缺乏BBB的渗漏性（有窗孔的）毛细血管。毛细血管壁上敞开的窗口允许分子（绿色部分）进出血液。在底部，你可以看到一个密实的BBB毛细血管，它限制了分子的进入，以保证脑细胞的安全。

Figure 3 - To BBB or not to BBB?

There are two types of capillaries in the brain. On the top, you can see fenestrated (windowed) capillaries lacking the BBB. The wide-open windows in the capillary wall allow passage of molecules (green) to and from the bloodstream. On the bottom, you can see a tightly sealed BBB capillary, which restricts entry of molecules to keep brain cells safe.

保护好脑袋固然重要，但是如果血管被BBB密实地封住，下丘脑又是如何与人体沟通以维持稳态呢？答案是，大脑中有些独特的区域是缺乏BBB的，取而代之的是有着特殊有渗漏性的的毛细血管。其中一个有渗漏性的区域是一个叫垂体的器官，垂体位于大脑的底部（图2）。在一个高倍镜放大下的显微镜中观察垂体的毛细血管，会看到这些毛细血管上有十分微小的开口，我们把这种开口称为“窗孔”，它在拉丁文中是窗户的意思（图3顶部）。这些微小的窗口比一缕发丝的尖端还要小一万倍！窗孔允许分子（如激素）在大脑和血液循环之间快速通过，因此，由下丘脑产生的指令会传到垂体中有窗孔的血管（图2）。在那里，指令被释放到血液中，随血液流向各个器官。

Protecting the brain is very important, but if the brain’s blood vessels are firmly sealed by the BBB, how does the hypothalamus communicate with the body to maintain homeostasis? The answer is that there are unique brain regions that lack the BBB and, instead, have special leaky blood capillaries. One of such leaky regions is an organ called the pituitary, which is located at the bottom of the brain [1] (Figure 2). Looking at the pituitary’s capillaries under a microscope with an extremely high magnification reveals that they have very small openings called fenestrae [2], which is the Latin word for windows (Figure 3, top). These tiny windows are ten thousand times smaller than the tip of a hair strand! Fenestrae allow the rapid passage of molecules, such as hormones, between the brain and the blood circulation. Thus, commands that are generated in the hypothalamus travel to the pituitary and meet the fenestrated blood vessels (Figure 2). There, the commands are released to the bloodstream to reach the organs.

一个两难问题：是要BBB还是不要BBB？

A DILEMMA: TO BBB OR NOT TO BBB?

脑中含有窗孔的区域已经被科学家们熟知有很长一段时间了。然而，目前仍不清楚这些区域的血管是如何保持渗漏性的。脑部的血管正面临着一个两难问题：是冒着被感染的风险让窗孔打开能够与身体沟通，还是通过孤立大脑来保护其免受有害入侵者的侵害？我们有时候会把这个两难问题称为：“要BBB还是不要BBB？”这是来自于威廉 莎士比亚的戏剧《哈姆雷特》中的名句：“To be or not to be, that is a question(生存还是死亡，是个问题)”（图3）。「PS：这里的be相当于BBB。译者注」

Areas of the brain that contain fenestrated blood vessels have been known to scientists for quite a while. However, it is still unclear how the vessels in these regions remain leaky. The blood vessels of the brain face a dilemma: to make fenestrae that enable communication with the body at the risk of infection, or to protect the brain from harmful invaders by isolating it. We sometime call this dilemma “To BBB or not to BBB?” after the famous quote from William Shakespeare’s play Hamlet: “To be or not to be, that is the question” (Figure 3).

我们最近研究了位于下丘脑的神经元与垂体连接处的独特窗孔血管（图2）。我们发现，在这个区域里，血管会从附近的细胞中接收信号，告诉它们形成窗孔，这些附近的细胞被称为“垂体后叶细胞”。垂体后叶细胞多年以来一直被认为有助于下丘脑神经元向血液释放指令。我们鉴定了两类由垂体细胞产生的信号分子，它们能使大脑这部分的血管发生渗漏。一种类型是告诉血管形成窗孔从而保持渗漏性能，而另一种类型则阻碍BBB的形成。当这些信号分子被阻断时，垂体中的血管就会停止形成窗孔，取而代之的是开始形成BBB。这就意味着垂体细胞可以运用两种控制形式确保窗户敞开。这就有点像同时佩戴一条皮带和吊裤带来固定你的牛仔裤一样。这种双重控制保证了激素可以在血液中自由通行。

We recently investigated the unique fenestrated vessels located where the neurons of the hypothalamus make contact with the pituitary (Figure 2). We found that blood vessels in this region receive cues from neighboring cells called pituicytes, telling them to form fenestrae [3, 4]. Pituicytes have been known for many years to help with the release of commands from the neurons of the hypothalamus into the bloodstream. We identified two types of signaling molecules produced by the pituicytes that make the blood vessels in this part of the brain leaky. One type tells the blood vessels to form the fenestrae and thereby remain leaky, while the other type blocks the formation of the BBB. When these signaling molecules are blocked, the blood vessels in the pituitary stop making fenestrae and instead start forming the BBB. This means that the pituicytes ensure that the windows are open using two forms of control. This is a bit like wearing both a belt and suspenders to hold your jeans in place. This double control guarantees the free passage of hormones into the bloodstream.

为何这如此重要？

WHY IS THIS IMPORTANT?

渗漏性血管是大脑和血液之间沟通的重要渠道。然而，在其他器官中，如胰腺、肝脏、肾脏等，也有具有渗漏性的血管。在这些器官中，它们也需要与血液循环系统交换分子。然而我们对窗孔是如何形成的仍知之甚少。揭露窗孔形成的秘密可能会非常有用。例如，在BBB为大脑避免被感染提供保护措施的同时，也会防止药物进入脑部。这就使医生在治疗脑疾病时难上加难。如果我们找到一种方法能在大脑的紧密密封的血管中创建窗孔，它可能会通过BBB输送药物来治疗疾病，如癫痫，帕金森病和自闭症。

Fenestrated blood vessels serve as important gateways that allow communication between the brain and the blood. However, blood vessels with fenestrae are also found in other important organs, such as the pancreas, liver, and kidneys. In these organs, it is also necessary to exchange molecules with the blood circulation. Yet we still know very little about how fenestrae are formed. Revealing the secrets of window-making could be very useful. For example, while the BBB safeguards the brain from infection, it also prevents the passage of medicines into the brain. This makes it difficult for doctors to treat brain diseases. If we find a way to create fenestrae in the tightly sealed blood vessels of the brain, it may be possible to deliver drugs across the BBB to treat disorders, such as epilepsy, Parkinson’s disease, and autism.

Glossary 术语表

Homeostasis: ↑ A process by which an organism maintains inner environment stable while adjusting to conditions that are best for its survival.

稳态：生物体维持内部环境稳定的同时调整到最适合自己生存的条件的过程。

Hormones: ↑ Molecules produced by glands and the brain, which serve as chemical messengers. Hormones are transported by the blood to organs all over the body, to regulate the body’s function.

激素（荷尔蒙）：由腺体和大脑产生的作为化学信使的分子。激素由血液输送到全身各器官，以调节身体的功能。

Capillary: ↑ The smallest type of blood vessel, which delivers nutrients and oxygen to all cells of the body.

毛细血管：血管的最小类型，它为身体的所有细胞输送营养物质和氧气。

Hypothalamus: ↑ A region of the brain that controls many important body functions, including sleep, blood pressure, temperature, hunger, and thirst.

下丘脑：大脑的一个控制许多重要身体功能的区域，包括睡眠、血压、体温、饥饿和口渴。

Neuron: ↑ A basic unit of the nervous system, also called a nerve cell. Neurons can process and transmit information to other nerve cells and to other cell types, such as muscle cells.

神经元：神经系统的一个基本单位，也叫神经细胞。神经元可以处理信息并将信息传递给其他神经细胞和其他类型的细胞，如肌肉细胞。

Blood-brain Barrier: ↑ Physical barrier within the blood vessels of the brain that prevents substances from passing into the brain, keeping the environment of the brain safe and stable.

血脑屏障：在大脑血管内的物理屏障，其阻止物质进入大脑，保持大脑环境的安全和稳定。

Fenestrae: ↑ Tiny openings in capillary walls that allow passage of molecules to and from the bloodstream. Fenestrated capillaries are found in organs where the rapid exchange of information between the blood and the tissue is required (pancreas, intestines, some brain regions, etc.).

窗孔：毛细血管壁上的微小开口，它允许分子进出血液。在血液和组织之间需要快速交换信息的器官（胰腺、肠道、一些大脑区域等）中发现有窗孔的毛细血管。

Pituicytes: ↑ Specialized cells of the pituitary gland that help the release of hormones from neurons into the bloodstream. Pituicytes have recently been shown to help keep pituitary blood vessels leaky.

垂体后叶细胞：垂体上的专有细胞，帮助神经元释放激素到血液中。垂体细胞最近被证明有助于保持垂体血管具有渗漏性。

附上作者信息：

作为一名科学家，我对大脑血管的生物学很着迷。这些血管有一种特殊的保障，叫做血脑屏障。这个屏障保护大脑免受危险物质的侵害。虽然血脑屏障早在一个世纪前被发现，但人们对它的工作原理知之甚少。我很高兴能研究血脑屏障形成和功能的机制。闲暇时，我会和家人呆在一起。我出生在白俄罗斯，在以色列长大并完成了我的博士学位，目前是哈佛医学院的一名研究员。

生于Tel-Aviv，在Tel-Aviv大学获得理学士和硕士学位，在Weizmann科学研究所获得博士学位。之后我被调到位于旧金山的基因泰克股份有限公司担任博士后研究员，并在Palo Alto的Rinat-Neuroscience公司领导一个项目，进行阿尔茨海默氏症和帕金森氏症的研究。自从回到以色列担任Weizmann研究所教授后，我的实验室一直在使用斑马鱼研究与抑郁症、压力、自闭症和肥胖症相关的下丘脑神经元。除了对科学的热情，我还喜欢水上运动，尤其是皮划艇、竞技划船和帆船。