Circuitry of inhibition and selectivity in a Drosophila learning centre

大脑的主要作用是协调适当的行为，为此，它必须处理一系列感官的大量信息，并在每种感官中识别影响输出行为的“对象”。这些行为并不局限于简单的反射，比如把腿从针里抽出来，而是可以通过经验来塑造的。其中一个例子就是我们的嗅觉；人类和动物可以辨别各种各样的气味，一种特殊的气味可以唤起高度特定的记忆洪流。我们的大脑将特定气味识别为感知“对象”的能力，意味着它将气味辨别过程与特定联想（记忆）的形成结合起来。了解这是如何发生的是神经生物学的一个重大挑战。这不仅对基础脑科学有影响，而且对理解人类行为也有影响，甚至可能对包括精神分裂症在内的疾病也有影响，在精神分裂症中，对包括气味在内的物体的记忆可能被不恰当地当作幻觉来检索。果蝇为理解辨别和使用特定气味信息的神经回路提供了许多优势。它能辨别许多气味；它可以学习和记忆与特定气味相关的经历；值得注意的是，它的嗅觉系统结构与人类有许多共同特征；在实验室容易繁殖；它拥有强大的基因工具，可以监控和操纵特定神经元的活动。因此，我们有一个工具包来解剖神经回路，包括学习和记忆回路，并测试它们在行为中的作用，这个工具包可能比任何其他生物体都更强大。我们的实验系统是果蝇幼虫。它包含一个功能齐全的嗅觉系统，因为它有嗅觉学习的能力，但与成年苍蝇或脊椎动物相比，它的嗅觉系统在数字和解剖学上都很简单。它只有21个嗅觉感觉神经元，每个神经元感知不同的“气味质量”。然而，就像只有三种光感受器可以定义我们整个颜色视觉范围一样，来自这21个神经元的输入可以组合起来定义潜在的数千种气味。这发生在一个叫做蘑菇体的大脑区域，它与人类的感觉皮层有很多相似之处，它可能有一个共同的进化起源。蘑菇体是嗅觉学习所必需的，它包含几百个被称为凯尼恩细胞（KCs）的神经元。单个KCs可以结合来自21个嗅觉神经元中的6个的输入，但它们对气味的反应更具选择性，有时选择性如此之高，以至于许多KCs对任何气味测试都没有反应。因此，KCs只有在多个~6个输入同时被激活时才有响应。因此，气味是由它激活的感觉神经元的组合以及整合这种组合的少量KCs来定义的。KCs的高选择性是由于它们受到其他神经元的抑制，这使得它们在只接收少量嗅觉输入时不会放电。激活和抑制之间的平衡对它们的功能至关重要——抑制过少，KCs的选择性就会降低，无法区分不同的气味；太多的抑制作用，KCs将永远不会对气味做出反应。我们的目标是了解哪些神经元回路导致这种抑制，以及它影响KCs选择性的机制，并最终影响与特定气味相关的记忆的学习和检索。这项工作将揭示嗅觉信息在蘑菇体中的整合是如何被调节的，在一个简单和高度可访问的系统中。我们发现的基本原理也应该与人类大脑高级皮质区域的类似过程有关，这是更难研究的。

A major role of the brain is to coordinate appropriate behavior and for this it has to process an enormous palette of information across a range of senses, and within each sense, recognize 'objects' that influence output behaviors. These behaviors are not limited to simple reflexes, like withdrawal of the leg from a needle, but can be shaped by experience. One example of this is our sense of smell; humans and animals can discriminate a vast range of odors, and a characteristic smell can evoke a highly specific flood of memories. The ability of our brain to recognize a particular smell as a perceptual 'object', implies that it combines a process of odor discrimination with formation of specific associations (memories). Understanding how this happens is a major challenge for neurobiology. This has implications not only for basic brain science but also for understanding human behavior, and potentially even conditions including schizophrenia, in which memories of objects including smells may be inappropriately retrieved as hallucinations. The fruitfly Drosophila offers many advantages to understand the neuronal circuits that discriminate and use specific odor information. It can discriminate many odors; it can learn and remember experiences associated with specific odors; remarkably the structure of its olfactory system shares many common features with humans; it is easy to breed in the laboratory; it has powerful genetic tools that can monitor and manipulate activity in specific neurons. We therefore have a toolkit to dissect neuronal circuits including those for learning and memory and to test their roles in behavior, a toolkit that is probably more powerful than in any other organism. Our experimental system is the Drosophila larva. It contains a fully functional olfactory system, since it is capable of olfactory learning, but has a numerically and anatomically simple olfactory system, compared to either adult flies or vertebrates. It has only 21 olfactory sensory neurons, each sensing a different 'odor quality'. However, just as only three kinds of photoreceptor can define our entire range of color vision, inputs from these 21 neurons can be combined to define potentially thousands of smells. This occurs in a brain region called the mushroom body, which has many similarities to human sensory cortex, with which it may share a common evolutionary origin. The mushroom body is required for olfactory learning, and contains several hundred neurons called Kenyon cells (KCs). Individual KCs can combine inputs that originate from around 6 of the 21 olfactory neurons, but their responses to odors are much more selective, sometimes so selective that many KCs do not respond to any odor tested. Therefore KCs only respond when many of their ~6 inputs are activated simultaneously. Therefore a smell is defined by the combination of sensory neurons that it activates, and by the small number of KCs that integrate this combination. The high selectivity of KCs results from their inhibition by other neurons, which keeps them from firing when they receive only a small number of olfactory inputs. This balance between activation and inhibition is critical to their function - too little inhibition, and KCs will become less selective and unable to discriminate among odors; too much inhibition, and KCs will never respond to odors. Our goal is to understand which neuronal circuits cause this inhibition, and the mechanisms by which it affects the selectivity of KCs, and ultimately its consequences for both learning and retrieval of memories that are associated with specific odors. This work will reveal how integration of olfactory information in the mushroom bodies is regulated, in a simple and highly accessible system. The basic principles that we uncover should also be relevant to similar processes in higher cortical areas of the human brain, which is much harder to study.