Circuitry of inhibition and selectivity in a Drosophila learning centre

大脑的一个主要作用是协调适当的行为，为此它必须处理各种感官的大量信息，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条件反射，比如从针头中拔出腿，而是可以通过经验塑造的。其中一个例子是我们的嗅觉;人类和动物可以区分各种各样的气味，一种特征性的气味可以唤起高度特定的记忆。我们的大脑能够将特定的气味识别为感知“对象”，这意味着它将气味辨别过程与特定关联（记忆）的形成相结合。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，甚至可能对理解包括精神分裂症在内的疾病有影响，在这些疾病中，对包括气味在内的物体的记忆可能会被不适当地作为幻觉检索出来。果蝇提供了许多优势，以了解神经元电路的歧视和使用特定的气味信息。它可以辨别许多气味;它可以学习和记忆与特定气味相关的经验;值得注意的是，它的嗅觉系统的结构与人类有许多共同的特征;它很容易在实验室中繁殖;它有强大的遗传工具，可以监测和操纵特定神经元的活动。因此，我们有了一个工具箱来解剖神经元回路，包括学习和记忆的神经元回路，并测试它们在行为中的作用，这个工具箱可能比任何其他生物都更强大。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，因为它能够进行嗅觉学习，但与成年苍蝇或脊椎动物相比，它的嗅觉系统在数字上和解剖学上都很简单。它只有21个嗅觉神经元，每个神经元都能感知不同的“气味质量”。然而，就像只有三种感光器可以定义我们的整个色觉范围一样，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。这发生在一个称为蘑菇体的大脑区域，它与人类的感觉皮层有许多相似之处，可能与人类的感觉皮层有着共同的进化起源。蘑菇体是嗅觉学习所必需的，含有数百个称为凯尼恩细胞（KC）的神经元。单个KC可以联合收割机来自21个嗅觉神经元中大约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KC对任何测试的气味都没有反应。因此，KC仅在其~6个输入中的许多输入同时被激活时才做出响应。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KC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，这使得它们在只接受少量嗅觉输入时不会放电。这种激活和抑制之间的平衡对它们的功能至关重要-抑制太少，KCs的选择性就会降低，无法区分气味;抑制太多，KCs永远不会对气味做出反应。我们的目标是了解哪些神经回路引起这种抑制，以及它影响KC选择性的机制，以及最终它对学习和检索与特定气味相关的记忆的影响。这项工作将揭示如何整合嗅觉信息在蘑菇体的调节，在一个简单和高度可及的系统。我们发现的基本原理也应该与人类大脑高级皮层区域的类似过程有关，这是很难研究的。

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.