内容来源：https://www.quantamagazine.org/once-thought-to-support-neurons-astrocytes-turn-out-to-be-in-charge-20260130/

内容总结：

脑科学认知颠覆：曾被视为“配角”的星形胶质细胞实为大脑“总调度”

长期以来，神经科学领域将神经元及其复杂的电信号网络视为大脑功能的核心，认为其独自主导了感知、思维、情绪和行为。然而，2025年《科学》杂志同期发表的三项重磅研究，通过对小鼠、斑马鱼和果蝇的实验，提供了迄今最有力的证据，表明大脑中数量庞大、曾被简单归类为“支持细胞”的星形胶质细胞，实际上扮演着更高级的“管理者”角色，深刻调控着大脑的整体状态。

这些研究发现，星形胶质细胞通过一种称为“神经调节”的机制，像调音师或总开关一样，对广泛神经环路的活跃程度进行整体性调控，从而影响机体的警觉、焦虑或淡漠等状态。例如，在斑马鱼实验中，研究人员观察到，当鱼反复尝试逆流游泳却失败时，星形胶质细胞会累积钙信号，最终释放腺苷等物质来抑制游泳行为，促使动物“放弃”。若人为抑制星形胶质细胞活动，斑马鱼则会不知疲倦地持续游动。

更关键的是，研究揭示了这一调控机制在果蝇、斑马鱼和小鼠中高度相似，表明这是一种进化上保守的核心大脑工作原理。去甲肾上腺素等神经调质并非像传统认为的那样直接作用于神经元，而是首先激活星形胶质细胞，再由后者释放化学物质来大规模调整神经元网络的活性。

这一范式转变意味着，过去一个多世纪主要聚焦于神经元连接（连接组）的研究模型存在重大盲区。正如参与研究的科学家所言，“不理解星形胶质细胞，就无法真正理解大脑如何工作”。新发现为理解睡眠、抑郁等与大脑整体状态密切相关的精神健康问题开辟了全新路径，提示这些疾病可能与星形胶质细胞信号功能障碍有关，并有望为未来药物研发提供革命性的新靶点。脑科学的研究视角，正从单一的“神经元中心”转向更全面的“神经元-胶质细胞协同网络”。

中文翻译：

曾被视为神经元的辅助，星形胶质细胞实为大脑主导

人类大脑是一个由数百亿神经元构成的庞大网络。它们通过传递信号来抑制或激活彼此，产生的信号模式以每秒高达一千次的频率在大脑中扩散。一个多世纪以来，这种令人目眩的复杂神经编码一直被认为是感知、思维、情绪、行为及相关健康状况的唯一仲裁者。若想理解大脑，人们便求助于对神经元的研究——即神经科学。

但2025年《科学》杂志以三篇论文形式发表的、来自多个实验室的最新研究，提供了迄今为止最有力的证据，表明仅聚焦于神经元对于理解大脑运作机制是远远不够的。这些在小鼠、斑马鱼和果蝇身上进行的实验揭示，被称为星形胶质细胞的大型脑细胞实际上扮演着"监管者"的角色。曾被视为仅仅是神经元支持细胞的星形胶质细胞，如今被认为有助于调节神经回路，从而控制大脑的整体状态或情绪——例如我们的警觉、焦虑或冷漠程度。

在许多脑区，星形胶质细胞的数量超过神经元。它们形态复杂多样，有时带有触须状结构，能够包裹数十万乃至数百万个突触（即神经元交换分子信号的连接点）。这种解剖结构使星形胶质细胞处于影响信息流动的绝佳位置，尽管它们是否以及如何改变突触活动长期以来一直存在争议，部分原因是潜在的相互作用机制尚未完全明了。这些新研究揭示了星形胶质细胞如何调节突触间的"对话"，使其影响力变得不容忽视。

"我们生活在连接组学时代，人人都喜欢说，只要理解了（神经元之间的）连接，我们就能理解大脑如何工作。但事实并非如此，"俄勒冈健康与科学大学独立神经科学研究中心沃勒姆研究所所长马克·弗里曼说，他领导了其中一项新研究。"即使（神经元）连接性没有任何变化，神经元的放电模式也可能发生巨大改变。"

星形胶质细胞并不参与神经元在突触处典型的快速信号传递。相反，它们监控并调节更高级别的网络活动，将其调高或调低，以维持或切换大脑的整体状态。其中一篇新论文表明，这种被称为神经调制的功能，可能导致动物的大脑在截然不同的状态之间切换，例如通过判断某个行动何时徒劳无功，并促使动物放弃。

神经调制对于将大脑活动水平保持在功能范围内是必要的，防止其活动过低（如趋于静止）或过高（如引发癫痫发作）。"如果没有这些我们称之为神经调质（介导调节的分子）的持续微调，任何神经回路都无法工作，"斯坦福大学神经科学荣誉教授斯蒂芬·史密斯说。他在20世纪80年代末和90年代初进行了星形胶质细胞信号传导的开创性实验，但未参与这项新研究。

多年来，这种微调被认为是由神经元自身完成的。虽然先前的研究已将星形胶质细胞与某些细胞信号传导联系起来，但最新的实验使用了"先进技术，真正精确地、毫无疑问地证实了星形胶质细胞在大脑神经调制中发挥着关键作用，"未参与新研究的美国国立卫生研究院荣誉神经科学家道格拉斯·菲尔兹说。

在这一角色中，星形胶质细胞可能是广泛扰乱大脑状态的睡眠或精神疾病的主要参与者。"我们必须思考这对神经精神疾病意味着什么，"弗里曼说。

明星诞生

星形胶质细胞是胶质细胞的一种，这类非神经元神经系统细胞像填充物一样铺满大脑，填充神经元之间的空隙。"胶质"（glia）一词在希腊语中意为"胶水"，反映了18世纪中期认为这些细胞的作用仅仅是粘合大脑的观点。

到了20世纪50年代，研究人员知道星形胶质细胞的作用不止于此。在实验中，这些细胞吸收多余的神经递质、缓冲钾离子、并分泌神经元所需的能量物质。像细胞炼金术士一样，星形胶质细胞似乎在监测和调整大脑的"汤液"，为神经元维持有利条件。但科学家们认为它们是相对被动的调节者，直到20世纪80年代末，史密斯为他在耶鲁大学的神经科学实验室建造了一台新显微镜。

史密斯的新型数字视频荧光显微镜旨在利用荧光拍摄神经元活动的电影。当神经元放电时，钙离子涌入细胞。因此，研究人员将荧光传感器放入脑细胞中，当它们遇到钙离子时会发光。显微镜可以探测到光在空间和时间上的明暗变化，揭示细胞的放电模式。"我们当时可能拥有最先进、最灵敏、最酷的设备，"史密斯说。

1989年的一天，史密斯的研究生史蒂夫·芬克拜纳（现为旧金山非营利性格莱斯顿研究所的神经学家）正在使用该显微镜探索神经递质谷氨酸的潜在毒性作用，谷氨酸是大脑中大多数神经元用于通讯的分子。芬克拜纳对星形胶质细胞并不感兴趣，但由于它们有助于维持神经元存活，他将它们放入了细胞培养物中。然后他添加了谷氨酸。

"他突然从他的显微镜装置那里大喊大叫：'嘿，老板，过来！你必须看看这个！'"史密斯回忆道。"它们（星形胶质细胞）完全'疯'了。"荧光像波浪一样在星形胶质细胞层上荡漾，从一个细胞跳到下一个细胞。这些钙波显示出协调的活动，仿佛星形胶质细胞在相互交流。而且由于这些细胞对谷氨酸有反应，它们对神经元产生反应也是合乎逻辑的。在他们1990年描述该实验的论文中，研究人员大胆提出："星形胶质细胞网络可能构成大脑内的长程信号系统。"其他团队很快表明，培养皿、脑切片甚至麻醉动物中的星形胶质细胞对各种神经递质都有反应。

当时许多神经科学家将星形胶质细胞新发现的特性比作神经元，但回想起来，差异似乎很明显。首先，星形胶质细胞占据相对巨大的区域：一个星形胶质细胞覆盖一大片组织，在人脑中可触及多达200万个突触。星形胶质细胞的工作时间尺度比神经元更长。它们的钙波扩散时间从几秒到几分钟不等——远比神经元沿轴突传递信号和释放神经递质所需的毫秒级时间长。

为了研究星形胶质细胞这种令人惊讶的新观点如何与行为相关，研究小组转向了动物模型。研究人员试图通过用感官刺激（例如用光照眼睛或触摸胡须）来激活实验室小鼠的星形胶质细胞；他们通过荧光显微镜下的颅窗寻找反应。有时细胞有反应，有时没有。然后，在2013年和2014年，两个独立的研究团队报告了一种能可靠引起星形胶质细胞注意的方法：他们通过突然吹气或突然打开脚下的跑步机来惊吓小鼠。惊吓反应在很大程度上是一种无意识的防御机制，也是大脑状态的突然切换，在整个动物界都存在。

当脊椎动物受到惊吓时，脑干中一个称为蓝斑区域的神经元会释放去甲肾上腺素（一种与唤醒相关的神经调质），沿着遍布大脑的纤维扩散。与神经递质传递特定信息不同，神经调质像收音机上的旋钮一样调高或调低大脑活动，并改变大脑的整体状态。这些研究表明，去甲肾上腺素是星形胶质细胞钙波的触发因素，这暗示星形胶质细胞在某种程度上参与了神经调制。

尽管如此，关于星形胶质细胞信号传导的许多方面仍然神秘。已知这些细胞具有去甲肾上腺素受体，但没有人知道去甲肾上腺素的结合如何导致钙波。还有一个问题是，这些钙波向下游神经元发送了什么信号。一些研究人员认为星形胶质细胞会产生自己的"胶质递质"分子作用于神经元，但另一些人对此提出异议。在会议上，研究人员就星形胶质细胞在多大程度上（甚至是否）塑造大脑信息流进行了激烈而大声的辩论。

弗里曼实验室当时在马萨诸塞大学医学院的学生马志国（音译）试图在果蝇大脑中解决这个问题。"请别这么做，"弗里曼回忆道他曾警告他。"这太乱了。"马志国坚持前行。他通过突然将果蝇翻转过来，在果蝇身上复制了惊吓反应。利用分子生物学的精密工具，他追踪了化学接力：果蝇版本的去甲肾上腺素通过打开细胞膜上的通道激活星形胶质细胞，导致胶质递质（可能是腺苷）的释放，从而抑制神经元信号传导。描述这种神经元-星形胶质细胞相互作用至关重要，"因为它们可能代表了一种控制大脑功能的潜在广泛机制，"弗里曼的团队在2016年的《自然》杂志上写道。

对一些人来说，该实验首次证明了星形胶质细胞是神经回路不可或缺的组成部分。但一篇关于果蝇的论文不足以说服怀疑者。近十年后，在脊椎动物身上惊人相似的发现将改变局面。

何时放弃

尽管我们不常这样想，但放弃的行为反映了大脑活动的突然转变。它代表着心理状态从希望到绝望的转变，就像受到惊吓一样，对行为有深远影响。由神经科学家米沙·阿伦斯领导的研究人员在研究是什么让斑马鱼幼体放弃时，发现了星形胶质细胞如何介导这种情绪的突然变化。

斑马鱼放弃时是什么样子？在野外，如果斑马鱼想在流水中保持位置，它会逆流游动。在弗吉尼亚州霍华德·休斯医学研究所珍妮莉亚研究园区的实验室里，阿伦斯的团队利用虚拟现实在斑马鱼缸中模拟水流，这样无论鱼多么拼命地游动，它都会觉得自己在向后滑。鱼起初会游得更用力，但大约20秒后，它通常会放弃。过一会儿，它会再次尝试。

与此同时，研究人员使用先进的全脑成像技术监测斑马鱼大脑中的神经元和星形胶质细胞。当鱼徒劳地对抗水流时，释放去甲肾上腺素的神经元放电；作为回应，钙在星形胶质细胞中积累。这种积累与鱼试图对抗水流的次数平行，仿佛星形胶质细胞在计数——直到某个时刻它们发出停止信号，斑马鱼便放弃了。

当阿伦斯的团队用激光使星形胶质细胞失活时，鱼从未停止游动。而如果人工激活星形胶质细胞，鱼会立即停止。"这是首次证明星形胶质细胞在行为状态切换中起作用，"阿伦斯说。

在随后于2025年发表在《科学》杂志上的论文中，研究人员揭示了星形胶质细胞如何引起这些行为变化。使用针对不同分子的荧光传感器，他们发现当星形胶质细胞中积累足够的钙时，它们会释放能量分子ATP（三磷酸腺苷的缩写）。在细胞外，ATP被转化为腺苷，作用于神经元——在这种情况下，通过激活抑制游动的神经元和抑制游泳神经元。这一序列与马志国和弗里曼在果蝇中观察到的现象相呼应。

根据华盛顿大学医学院托马斯·帕普安领导并于同期《科学》杂志发表的研究，同样的分子事件链也出现在小鼠大脑中。帕普安的团队正在研究改变神经元间通讯的突触变化，这是一种神经可塑性形式，是思维和行为持续变化的基础。人们曾认为去甲肾上腺素通过直接作用于神经元来产生这些变化。但令帕普安惊讶的是，即使神经元上的去甲肾上腺素受体被移除，其效果仍然明显。这个过程完全依赖于星形胶质细胞。

"我们确实预计，去甲肾上腺素对突触的影响在很大程度上是由星形胶质细胞介导的，"帕普安说。"但我们没想到全部都是！"

在果蝇、斑马鱼和小鼠等如此不同的物种中发现平行的分子通路，指向了"一种进化上保守的方式，星形胶质细胞可以通过这种方式深刻影响神经回路，"弗里曼说。

这些结果表明了先前神经调制理论中的一个巨大漏洞。"过去，神经科学家研究神经调质，知道它们在调节神经回路功能中很重要，但他们的思考、图表、模型中除了神经元之外什么都没有，"菲尔兹说。"现在我们看到他们错过了故事的一大块。"

弗里曼团队的果蝇研究指出了脊椎动物研究的下一步方向；在同一期《科学》杂志上，该团队报告说，去甲肾上腺素改变了星形胶质细胞对神经元输入的反应方式。弗里曼的博士后凯文·古滕普兰用果蝇版本的去甲肾上腺素浸浴了一个解剖的果蝇大脑。"突然之间，星形胶质细胞从对其他神经递质毫无反应转变为对所有神经递质都有反应，"古滕普兰说。去甲肾上腺素及其在果蝇中的类似物似乎能使星形胶质细胞"听到"神经元的分子信息，然后调节它们的活动。

这种动态有助于解释星形胶质细胞如何能快速地将大脑从一种状态切换到另一种状态。"如果去甲肾上腺素水平低，意味着低唤醒度，星形胶质细胞根本不太'听'其他突触的信号，"弗里曼说。"但一旦你唤醒动物，周围有了去甲肾上腺素，星形胶质细胞现在可以'听'每一个突触，并且它们可以反过来改变神经元对此的放电方式。"

这些结果揭示了大脑处理信息方式的新复杂性，古滕普兰说。"在已经复杂的连接组（神经元网络）之上，你还有这整个另一层调节。"

情绪调节器

尽管星形胶质细胞信号传导机制的细节正逐渐清晰，但它们仍落后于已知的神经传递知识。"这是一个激动人心的时刻，"斑马鱼论文的第一作者、哈佛医学院学生亚历克斯·陈说。"对于星形胶质细胞领域，至少在概念上，我们并不比20世纪50年代现代神经科学起步时人们对神经元的认识领先多少。"

与此同时，研究人员正在聚焦于星形胶质细胞介导的关键大脑功能。一些研究表明，星形胶质细胞随时间积累信息的能力（如斑马鱼游泳尝试所发生的那样）延伸到了睡眠-觉醒周期。星形胶质细胞似乎通过钙的积累来记录人们全天不断增加的睡眠负债，并分泌改变大脑活动的促眠分子。

"我们看到星形胶质细胞与涉及重大状态转换的行为有关——比如睡眠、饥饿、唤醒——这些行为需要在大片区域上以较慢的时间尺度开启和关闭多种类型的神经回路，"古滕普兰说。

这些行为可能反映心理健康状况。去年，研究人员揭示了一种由压力触发并导致小鼠产生类似抑郁行为的神经元-星形胶质细胞脑回路。一些精神健康障碍可能是星形胶质细胞信号传导障碍。阿伦斯说，人们的情绪变化相对较慢，这个过程部分由神经调质驱动。星形胶质细胞在神经调制中的作用表明它们作为药物靶点的潜力。

"一个世纪以来，神经科学只关心神经元，而我们还没有治愈任何一种脑部疾病的方法，"帕普安说。他说，改变这一现状的方法是接受星形胶质细胞等非神经元细胞的存在和影响，并将它们纳入模型和实验中。

弗里曼说，大多数神经科学家还没有收到这个信息。"99%从事神经回路实验的人甚至不考虑星形胶质细胞可能在做什么。而它可能对该回路的功能产生非常深远的影响。"

英文来源：

Once Thought To Support Neurons, Astrocytes Turn Out To Be in Charge
Introduction
The human brain is a vast network of billions of neurons. By exchanging signals to depress or excite each other, they generate patterns that ripple across the brain up to 1,000 times per second. For more than a century, that dizzyingly complex neuronal code was thought to be the sole arbiter of perception, thought, emotion, and behavior, as well as related health conditions. If you wanted to understand the brain, you turned to the study of neurons: neuroscience.
But a recent body of work from several labs, published as a trio of papers in Science in 2025, provides the strongest evidence yet that a narrow focus on neurons is woefully insufficient for understanding how the brain works. The experiments, in mice, zebra fish, and fruit flies, reveal that the large brain cells called astrocytes serve as supervisors. Once viewed as mere support cells for neurons, astrocytes are now thought to help tune brain circuits and thereby control overall brain state or mood — say, our level of alertness, anxiousness, or apathy.
Astrocytes, which outnumber neurons in many brain regions, have complex and varied shapes, and sometimes tendrils, that can envelop hundreds of thousands or millions of synapses, the junctions where neurons exchange molecular signals. This anatomical arrangement perfectly positions astrocytes to affect information flow, though whether or how they alter activity at synapses has long been controversial, in part because the mechanisms of potential interactions weren’t fully understood. In revealing how astrocytes temper synaptic conversations, the new studies make astrocytes’ influence impossible to ignore.
“We live in the age of connectomics, where everyone loves to say [that] if you understand the connections [between neurons], we can understand how the brain works. That’s not true,” said Marc Freeman, the director of the Vollum Institute, an independent neuroscience research center at Oregon Health and Science University, who led one of the new studies. “You can get dramatic changes in firing patterns of neurons with zero changes in [neuronal] connectivity.”
Astrocytes do not engage in the rapid-fire signaling typical of neurons at synapses. Instead, they monitor and tune higher-level network activity, dialing it up or down to maintain or switch the brain’s overall state. This function, termed neuromodulation, may cause an animal’s brain to switch between dramatically different states, such as by gauging when an action is futile and prompting the animal to give up, one of the new papers shows.
Neuromodulation is necessary for keeping the brain’s activity level in a functional range, preventing it from either flatlining or erupting in seizures. “No neural circuit would work at all without continual fine-tuning by these things we call neuromodulators, [the molecules that mediate the adjustments],” said Stephen Smith, an emeritus professor of neuroscience at Stanford University who conducted pioneering experiments in astrocyte signaling in the late 1980s and early 1990s and was not involved in the new research.
For many years, that fine-tuning was thought to be conducted by neurons themselves. While previous work has implicated astrocytes in some cellular signaling, the latest experiments use “advanced techniques to really pinpoint and satisfy beyond a doubt that astrocytes are having a key role in neuromodulation in the brain,” said Douglas Fields, an emeritus neuroscientist at the National Institutes of Health who was not involved in the new research.
In that role, astrocytes could be major participants in sleep or psychiatric disorders that broadly disrupt the state of the brain. “We have to think about what this means for neuropsychiatric disease,” Freeman said.
A Star Is Born
Astrocytes are a type of glial cell, a class of non-neuronal nervous system cells that tile the brain, filling the space between neurons like packing peanuts. Greek for “glue,” the name “glia” reflects the mid-18th-century idea that the cells’ purpose was simply to hold the brain together.
By the 1950s, researchers knew that astrocytes did more than that. In experiments, the cells sucked up excess neurotransmitters, buffered potassium, and secreted substances that neurons require for energy. Like cellular alchemists, astrocytes seemed to be monitoring and adjusting the broth of the brain, keeping conditions favorable for neurons. But scientists considered them relatively passive regulators until the late 1980s, when Smith built a new microscope for his neuroscience lab at Yale University.
Lyn Flaim Healy
Smith’s novel digital video fluorescence microscope was designed to take movies of neuronal activity using fluorescent light. When a neuron fires, calcium rushes into the cell. So the researchers put fluorescent sensors into brain cells that glowed when they encountered calcium. The microscope could detect the light as it brightened and dimmed over space and time, revealing the cells’ firing patterns. “We had probably the most advanced, sensitive, coolest setup going,” Smith said.
One day in 1989, Smith’s graduate student Steve Finkbeiner (now a neurologist at the nonprofit Gladstone Institutes in San Francisco) was using the microscope to explore the potentially toxic effects of the neurotransmitter glutamate, the molecule most neurons in the brain use to communicate. Finkbeiner was not interested in astrocytes, but because they help keep neurons alive, he put them in his cell culture. Then he added glutamate.
“He’s all of a sudden yelling and screaming from his microscope setup: ‘Hey boss, come here! You’ve got to see this!’” Smith recalled. “They [the astrocytes] went completely nuts.” Fluorescence rippled across the bed of astrocytes in waves, hopping from one cell to the next. These calcium waves showed coordinated activity, as if the astrocytes were communicating with each other. And because the cells responded to glutamate, it was only logical that they would also respond to neurons. In their 1990 paper describing the experiment, the researchers boldly proposed that “networks of astrocytes may constitute a long-range signaling system within the brain.” Other teams soon showed that astrocytes in dishes, brain slices, and even anesthetized animals responded to various neurotransmitters.
Many neuroscientists at the time likened astrocytes’ newfound properties to those of neurons, but in retrospect the differences seem glaring. For one thing, astrocytes occupy relatively massive territory: One astrocyte covers a large expanse of tissue, reaching as many as 2 million synapses in the human brain. Astrocytes work on longer timescales than neurons do. Their calcium waves spread over a period ranging from seconds to minutes — much longer than the milliseconds it takes for neurons to propagate signals down their axons and release neurotransmitters.
To study how this surprising new view of astrocytes related to behavior, research groups turned to animal models. Researchers tried to activate astrocytes in lab mice by bombarding them with sensory stimuli, such as by shining light in their eyes or touching their whiskers; they looked for a response through a cranial window under a fluorescent microscope. Sometimes the cells responded, sometimes they didn’t. Then, in 2013 and 2014, two independent research teams reported a sure-fire way to get astrocytes’ attention: They startled the mice by surprising them with a puff of air or by abruptly turning on a treadmill under their feet. The startle response is a largely unconscious defense mechanism and a sudden switch in brain state, found throughout the animal kingdom.
When vertebrate animals are startled, neurons in a brainstem region called the locus coeruleus release norepinephrine, a neuromodulator associated with arousal, along fibers that fan out across the brain. Instead of sending a specific message, as neurotransmitters do, neuromodulators dial brain activity up or down and change the brain’s overall state like a dial on a radio. The studies indicated that norepinephrine was the trigger for the astrocyte waves, implicating astrocytes in neuromodulation in some capacity.
Johns Hopkins University
Still, so much about astrocyte signaling remained mysterious. The cells were known to have norepinephrine receptors, but no one knew how the binding of norepinephrine led to the calcium waves. And there was still the question of what signal those waves sent to downstream neurons. Some researchers thought astrocytes produced their own “gliotransmitter” molecules that acted upon neurons, but others disputed that notion. At meetings, researchers engaged in loud, heated debates over how much — indeed, whether — astrocytes shape the flow of information in the brain.
A student in Freeman’s lab, Zhiguo Ma, then at the University of Massachusetts Medical School, sought to settle the issue in a fruit fly brain. “Please don’t,” Freeman recalled warning him. “It’s such a mess.” Ma forged ahead. He replicated the startle response in fruit flies by suddenly flipping them upside down. Using the delicate tools of molecular biology, he traced the chemical relay: The fly versions of norepinephrine activated astrocytes by opening a channel in the cell membrane, causing the release of a gliotransmitter — likely adenosine — that squelched neuronal signaling. It was critical to characterize such neuron–astrocyte interactions, “as they would represent a potentially widespread mechanism for controlling brain function,” Freeman’s team wrote in Nature in 2016.
To some, the experiment provided the first proof that astrocytes are integral parts of neural circuits. But one fruit fly paper was not enough to sway skeptics. Nearly a decade later, eerily parallel findings in a vertebrate would tip the scales.
When To Give Up
Although we don’t often think of it this way, the act of giving up reflects a sudden shift in brain activity. It represents a change in mental state from hope to hopelessness that, like being startled, has profound effects on behavior. Researchers led by the neuroscientist Misha Ahrens were studying what made zebra fish larvae give up when they made a discovery about how astrocytes mediate such a sudden change in mood.
© HHMI, photo by Toby Hayman
What does it look like when a zebra fish gives up? In the wild, if a zebra fish wants to stay put in flowing water, it will swim against the current. In the lab at the Howard Hughes Medical Institute’s Janelia Research Campus in Virginia, Ahrens’ team used virtual reality to create a simulation of a current in the zebra fish tank, so that a fish would think it was slipping backward no matter how furiously it swam. The fish would swim harder at first, but after about 20 seconds, it would typically give up. A little while later, it would try again.
All the while, the researchers monitored neurons and astrocytes in the zebra fish’s brain using advanced whole-brain imaging techniques. As the fish fruitlessly fought the current, neurons that release norepinephrine fired; in response, calcium built up in astrocytes. The buildup paralleled the number of attempts the fish made to fight the current, as if the astrocytes were keeping track — until at some point they issued a stop signal, and the zebra fish gave up.
When Ahrens’ team disabled the astrocytes using a laser, the fish never stopped swimming. And if the astrocytes were artificially activated, the fish stopped right away. “It was the first time that it was shown that astrocytes had a role in behavioral state switching,” Ahrens said.
In an ensuing Science paper, published in 2025, the researchers revealed how astrocytes caused these changes in behavior. Using fluorescent sensors for various molecules, they found that when enough calcium builds up in astrocytes, they release the energy molecule ATP, short for adenosine triphosphate. Outside the cell, the ATP is converted into adenosine, which acts on neurons — in this case, by exciting neurons that inhibit swimming and suppressing swim neurons. This sequence echoes what Ma and Freeman observed in the fruit fly.
Science Source
The same molecular chain of events also showed up in the mouse brain, according to research led by Thomas Papouin at Washington University School of Medicine and published in the same Science issue. Papouin’s team was studying changes at synapses that alter communication between neurons, a form of neuroplasticity that underlies ongoing shifts in thought and behavior. Norepinephrine was thought to produce these shifts by acting directly on neurons. But to Papouin’s surprise, norepinephrine’s effects were apparent even when its receptors on neurons had been removed. The process depended solely on astrocytes.
“We did expect that, in large part, the effect of norepinephrine on synapses would be mediated by astrocytes,” Papouin said. “But we did not expect all of it to be!”
The finding of parallel molecular pathways in such distinct species as fruit flies, zebra fish, and mice points to “an evolutionarily conserved way in which astrocytes can profoundly affect neural circuits,” Freeman said.
The results suggest a gaping hole in previous theories of neuromodulation. “In the past, neuroscientists studied neuromodulators and knew they were important in regulating neural circuit function, but none of their thinking, none of their diagrams, none of their models had anything in them other than neurons,” Fields said. “Now we see that they missed a big part of the story.”
Courtesy of Thomas Papouin
The fruit fly research by Freeman’s team indicates the next steps in research in vertebrates; in the same Science issue the group reported that norepinephrine changes how astrocytes respond to input from neurons. Freeman’s postdoc Kevin Guttenplan doused a dissected fly brain with the fly versions of norepinephrine. “All of a sudden, the astrocytes went from responding to none of the other neurotransmitters to responding to all of them,” Guttenplan said. Norepinephrine and its analogues in the fly seem to enable astrocytes to “hear” neurons’ molecular messages and then modulate their activity.
This dynamic helps explain how astrocytes can rapidly switch the brain from one state to another. “If there’s low norepinephrine, which would mean low arousal, astrocytes don’t listen much at all to other synapses,” Freeman said. “But as soon as you arouse the animal, and there is norepinephrine around, now astrocytes can listen to every synapse, and they can turn around and change how neurons fire in response to that.”
The results reveal a new complexity to how the brain processes information, Guttenplan said. “On top of the already complicated connectome [network of neurons], you have this whole other layer of regulation.”
Mood Meter
Although the details of astrocytes’ signaling mechanism are coming into focus, they still lag behind what is known about neurotransmission. “It’s an exciting time,” said Alex Chen, a student at Harvard Medical School and first author of the zebra fish paper. “For the astrocyte field, at least conceptually, we are not very far ahead of where people were for neurons” at the onset of modern neuroscience in the 1950s.
Courtesy of Harvard_MCB
Meanwhile, researchers are homing in on critical brain functions that astrocytes mediate. Some research suggests that astrocytes’ ability to accumulate information over time (as happened with the zebra fish’s swim attempts) extends to the sleep-wake cycle. Astrocytes appear to keep track of people’s increasing sleep debt throughout the day, likely through a buildup of calcium, and secrete sleep-inducing molecules that alter brain activity.
“We see astrocytes implicated in behaviors associated with big state transitions — like sleep, hunger, arousal — where you need multiple types of circuits over a very large area to get turned on and off, especially on a slower timescale,” Guttenplan said.
Those behaviors may reflect mental health conditions. Last year, researchers revealed a neuron-astrocyte brain circuit that was triggered by stress and produced behavior resembling depression in mice. It’s possible that some mental health disorders are disorders of astrocyte signaling. People’s moods change relatively slowly, Ahrens said, in a process partly driven by neuromodulators. Astrocytes’ role in neuromodulation points to their promise as a drug target.
“Neuroscience has only cared about neurons for a century now, and we don’t yet have a cure for a single brain disorder,” Papouin said. The way to change that, he said, is to accept the existence and influence of non-neuronal cells such as astrocytes, and to include them in models and experiments.
Most neuroscientists haven’t received that memo, Freeman said. “Ninety-nine percent of people who are out there doing experiments on circuits don’t even think about what the astrocyte might be doing. And it could have really profound effects on how that circuit functions.”