动物本能行为的机制是一个谜，就连小鼠如何利用强大的嗅觉去识别和逃避捕食者（包括它从未见过的物种）这样简单的问题，至今在分子水平上仍是一无所知。
它们的嗅觉知道谁是可怕的捕食者
哈佛医学院的神经科学家大卫.费雷罗（David Ferrero ）和斯蒂芬.利波尔（Stephen Liberles）发现，食肉动物尿液中一种高浓度的化合物触发小鼠和大鼠本能的逃避反应。科学家首次识别出老鼠远距离嗅察捕食者的化学标记，这一研究从分子水平上揭示了老鼠可识别捕食者气味，且该分子机制是研究神经回路与先天行为之间关系的关键手段。
相关研究发表在6月20日的国家科学院院刊（Proceedings of the National Academy of Science）的网络版上。
这一研究开展于2006年，当时斯蒂芬.利波尔在琳达.巴克（Linda Buck）实验室攻读博士后学位，如今他已是哈佛大学医学院细胞生物学助理教授。巴克是研究小组——由于鉴别出嗅觉神经元识别气味的受体而获得诺贝尔奖——的组成成员，在她的试验室，利波尔筛选出新类型的嗅觉受体——跟踪性胺相关受体（TAARs）。
小鼠使用大约1200种气味受体和14种跟踪性胺相关受体，相比之下，人类只使用350种气味受体和5种跟踪性胺相关受体，这是由于人类主要依靠视觉而不是嗅觉。
利波尔研究表明，一些TAARs受体在小鼠尿液中识别化学物质，尤其是雄性小鼠大量生成的化学物质。他想了解，TAARs受体在老鼠社会行为中发挥什么作用？以及TAARs受体能够识别其它什么类型的天然气味？
哈佛医学院毕业生 David Ferrero着手搜索了TAARs识别的其它天然化合物，通过市售的捕食者和猎物的尿，他发现14个TAARs之一的TAAR4受体可识别许多食肉动物的气味。
看来，他们发现一种类似信息素的利它素，它的基本功能是在不同种类之间传递信息，而不是同物种之间。在此之前，鼠和食肉动物之间的利它素是唯一知道的，它包括由狐狸生成的挥发性化合物和由猫和老鼠生成的2种非挥发性化合物。挥发性化合物能在空气中扩散，进而可在远地方嗅到;非挥发性化合物需要更直接地嗅触。
Ferrero称，真正新颖点之一是广义的捕食者利它素具有挥发性。对于老鼠而言，这是接触死亡的气味。他还说，捕食者气味对老鼠而言是一种极大的威慑，这个道理被认知许久了，但如今我们发现了在这一生态链中发挥关键作用的一个分子。
Ferrero识别出激活TAAR4受体的化合物——2-苯乙胺，紧接着，他从38种哺乳类动物中收集样本。除了一种之外，其它18种食肉动物都具有高浓度的2-苯乙胺，而非食肉动物（包括兔、鹿和长颈鹿）都不具有。
在一系列行为试验中，大鼠和小鼠表现出对2-苯乙胺气味的本能躲避性。利用去除2-苯乙胺气味的食肉动物开展类似的试验，大鼠对去除该气味的捕食者缺乏完全的躲避性，这个试验表明，2-苯乙胺是躲避捕食者的关键触发因子。
缺少TAAR4基因，人类不会像老鼠嗅到2-苯乙胺气味一样表现出躲避行为，对于我们来说，2-苯乙胺是温和无害的气体，但是，人体的TAAR5受体容易受到甲胺（一类衍生的有机化合物）刺激，往往导致人体的极度厌烦。
受体和大脑区域在引起逃避行为方面如何作用至今仍是一个谜。
据利波尔所说，对捕食者气味的反应可用于模拟压力和焦虑症，从化学物质到受体，到神经回路，再到行为是神经科学的各个反应环节。
Ferrero称，神经回路如同一个“黑匣子”，我们识别出一个化学刺激源和一个激发行为的候选受体，并认为这是重要的一步去研究先天行为的神经回路基础。
这项研究由国立耳聋和其它交流障碍研究所资助。(生物探索译文 Pobee)
生物探索推荐英文摘要
The Smell of Danger: Rats Instinctively Avoid Compound in Carnivore Urine
The mechanics of instinctive behavior are mysterious. Even something as simple as the question of how a mouse can use its powerful sense of smell to detect and evade predators, including species it has never met before, has been almost totally unknown at the molecular level until now.
David Ferrero and Stephen Liberles, neuroscientists at Harvard Medical School, have discovered a single compound found in high concentrations in the urine of carnivores that triggers an instinctual avoidance response in mice and rats. This is the first time that scientists have identified a chemical tag that would let rodents sense carnivores in general from a safe distance. The authors write that understanding the molecular basis of predator odor recognition by rodents will provide crucial tools to study the neural circuitry associated with innate behavior.
Their findings were published online in the Proceedings of the National Academy of Science on June 20, 2011.
The search began in 2006, when Stephen Liberles, now Assistant Professor of Cell Biology at Harvard Medical School, was working as a post-doc in the lab of Linda Buck. Buck was part of the team that won the Nobel Prize for identifying the receptors that allow olfactory neurons to detect odors. While in her lab, Liberles identified a new type of olfactory receptor, the trace amine-associated receptors (TAARs).
Mice have about 1200 kinds of odor receptors, and 14 kinds of TAARs. In comparison, humans -- who rely more on vision than smell -- have about 350 odor receptors and five TAARs.
Liberles's initial findings indicated that several of the TAARs detect chemicals found in mouse urine, including a chemical with enriched production by males. He wondered, could TAARs (which appear to have originally evolved from neurotransmitter receptors that mediate behavior and emotion) play a role in the social behavior of rodents? What other kinds of naturally occurring odors might they be able to detect?
In Liberles's lab at Harvard Medical School, graduate student David Ferrero began a search for other natural compounds that were detected by the TAARs. Working with commercially available predator and prey urine (used by gardeners to keep pests out of their crops and by hunters to mask their own scent or as lures for prey), Ferrero discovered that one of the 14 TAARs, TAAR4, detected the odor of several carnivores.
It seemed they had found a kairomone, a chemical that works like a pheromone, except that it communicates between members of different species instead of members of the same species. Prior to this discovery, the only known rodent-carnivore kairomones were a volatile compound produced by foxes, but not in that of other predators, and two non-volatile compounds produced by cats and rats (which prey on mice). Volatile compounds aerosolize and can be smelled at great distances; non-volatile compounds need to be sniffed more directly, something that would not be helpful in avoiding a predator directly but rather their terrain.
"One of the things that's really new here is that this is a generalized predator kairomone that's volatile," said Ferrero.
For rodents, it's the smell of danger.
Ferrero identified the compound that activates TAAR4 as 2-phenylethylamine, a product of protein metabolism. He then obtained specimens from 38 species of mammals and found elevated levels of 2-phenylethylamineby 18 of 19 species of carnivores, but not by non-carnivores (including rabbits, deer, primates, and a giraffe).
"It's been known so long that predator odors are great rodent deterrents, but we've discovered one molecule that's a key part of this ecological relationship," Ferrero said.
In a series of behavior tests, rats and mice showed a clear, innate avoidance to the smell of 2-phenylethylamine. The behavioral studies were repeated using a carnivore samples that had been depleted of 2-phenylethylamine. Rats failed to show full avoidance of the depleted carnivore urine, indicating that 2-phenylethylamine is a key trigger for predator avoidance.
Lacking the gene for TAAR4, humans can't experience anything like what rodents do when they smell 2-phenylethylamine. To us, it has a mildly inoffensive odor. But trimethylamine, a related organic compound that activates TAAR5, a receptor found in humans, is deeply repugnant to people.
What happens between the receptors and the parts of the brain that trigger that avoidance behavior remains a mystery, one with direct medical relevance.
According to Liberles, "In humans, the parts of the brain that deal with likes and dislikes go awry in many diseases, like drug addiction, and predator odor responses have been used to model stress and anxiety disorders. Going from chemicals to receptors to neural circuits to behaviors is a Holy Grail of neuroscience."
"The neural circuits are like a black box, but here we have identified a chemical stimulant and a candidate receptor that trigger one behavior," Ferrero said. "We feel this is an important first step to understanding the neural circuitry of innate behavior."
This research was funded by the National Institute On Deafness And Other Communication Disorders.
