Solving conflicts: Modulation of choices and actions in the fly.

有效的行动选择包括评估来自外部世界的信息和我们的内在需求，以选择最适合每种情况的行动。然而，外界和内部的线索是如何在大脑中权衡和整合以确定行动的优先顺序的，人们对此知之甚少。本项目使用果蝇来研究这一基本的生物学问题，果蝇是研究行为机制基础的优秀系统。我们将建立在我们最近的知识的关键神经元，介导之间的选择喂养和交配（Cheriyamkunnel等。例如，Curr.Biol 2021）来阐明整合调节信号以优先考虑行动的机制。果蝇的大脑只有10万个神经元，其中大部分已经被绘制出来。由于新的遗传工具，可以在果蝇中操纵和记录单个神经元，其时间，空间和遗传精度在任何其他模式生物中都不可用。有了这些工具，我们就可以研究来自环境和动物体内的线索如何在大脑回路中被评估，以选择适当的行动。食物或性别之间的选择是一个非常基本的选择-我们必须吃才能生存，我们必须繁殖才能将我们的基因传递给下一代。我们最近创建了一个试验，在该试验中，食物和性剥夺的苍蝇面临着是否优先进食或交配的决定。这些行为不能同时在苍蝇身上表现出来，迫使动物做出决定，优先考虑做什么。至关重要的是，我们对求偶和进食行为的神经基础了解很多。因此，这种分析非常适合于确定可能适用于其他行为冲突和其他生物大脑的行为选择的基本原则。我们发现，如果一只雄性苍蝇非常饥饿并且性唤起，他会选择吃而不是追求雌性。然而，选择还取决于其他因素，如提供的食物质量以及动物的饥饿程度和性剥夺程度。我们发现，告诉苍蝇去吃东西或去交配的神经元本质上是相互竞争的。如果进食的需求非常迫切，进食神经元就会接管;如果饥饿的威胁较小，那么繁殖的冲动就会获胜。此外，我们发现，雌性的存在使雄性吃得更快，使它们能够很快地进行性行为。这些发现表明，相互冲突的状态（例如进食和繁殖的欲望）并不总是相互抑制，而是相互帮助。我们的工作提供了一个独特的机会来了解苍蝇如何整合感官线索来做出这些行为选择，并询问它揭示了大脑功能的方式。在这个项目中，我们将识别传达饥饿状态的信号，以及向大脑中的行动选择中心广播潜在伴侣存在的线索。我们将研究这些信号如何整合到引导动物行动的神经元中，使每个选择或多或少地具有吸引力。在目标1中，我们将定义饥饿信号如何整合到大脑中，以促进进食而不是求偶。在目标2中，我们将研究交配的动机如何使雄性吃得更快，从而使他能够快速移动到雌性。在目标3中，我们将揭示雄性如何决定何时停止特定行为（例如，喂食）以从事另一重要任务（例如，交配）。这种行为选择是动物需要解决的日常冲突的一个例子，但在哺乳动物中很难解决。通过研究大脑如何在分子，细胞和电路水平上做出决定，在一个更简单的系统中，我们的目标是揭示行动选择的基本原则，这可能是许多物种共同的。反过来，这些知识将提供对其他更复杂的大脑如何工作的洞察力，比如我们自己的大脑。

Effective action-selection involves evaluating information from the outside world and our intrinsic needs to select the most appropriate action for each situation. Yet little is known about how external and internal cues are weighed and integrated in the brain to prioritise actions.This project investigates this fundamental biological problem using the fruit fly Drosophila, an excellent system to investigate the mechanistic basis of behaviour. We will build on our recent knowledge of the key neurons that mediate the choice between feeding and mating (Cheriyamkunnel et. al., Curr.Biol 2021) to characterise the mechanism that integrates modulatory signals to prioritise actions.Fruit flies have a brain of only 100,000 neurons, most of which have been mapped. Thanks to new genetic tools, single neurons can be manipulated and recorded in Drosophila with a level of temporal, spatial and genetic precision that is not available in any other model organism. With these tools, we can study how cues from the environment and from inside the animal are evaluated in brain circuits to select appropriate actions.The choice between food or sex is a pretty fundamental one - we have to eat to live and we have to reproduce to pass on our genes to the next generation. We have recently created an assay where food- and sex-deprived flies are confronted with the decision of whether to prioritise feeding or mating. These behaviours cannot be simultaneously displayed in flies, forcing the animal to make a decision and prioritise what to do. Crucially, we know a great deal about the neural basis of courtship and feeding behaviours. Thus, this assay is well suited to identify fundamental principles of action-selection that might apply to other behavioural conflicts and the brains of other organisms.We discovered that if a male fly is very hungry and sexually aroused, he will choose to eat over courting a female. However, the choice also depends on other factors like the quality of the food on offer and on how hungry and sex deprived the animal is. We found that the neurons that tell the fly to go and eat, or to go and mate are essentially competing with each other. If the need to eat is most urgent, the feeding neurons will take over; if the threat of starvation is less, then the urge to reproduce will win. Further, we found that the presence of a female makes the males eat faster, allowing them to move on to sex very quickly. These findings suggest that conflicting states (e.g. the urge to eat and to reproduce) do not always inhibit each other but may help each other. Our work provides the unique opportunity to understand how flies integrate sensory cues to make these behavioural choices, and ask what it reveals about the way the brain functions. In this project, we will identify the signals that convey hunger state, as well as the cues that broadcast the presence of a potential mate, to the action-selection centre in the brain. We will study how these signals are integrated in the neurons that steer the animal's actions, making each option more or less attractive. In objective 1, we will define how hunger signals are integrated in the brain to promote feeding over courtship. In objective 2, we will study how the motivation to mate makes the male eat faster, allowing him to quickly move to the female. In objective 3, we will reveal how males determine when to stop a given behaviour (e.g., feeding) to engage in another important task (e.g., mating). This action-selection is an example of the everyday conflicts animals need to solve but are difficult to tackle in mammals. By studying how the brain makes decisions at a molecular, cellular and circuit level, in a simpler system, we aim to reveal fundamental principles of action-selection that might be common to many species. This knowledge, in turn, will provide insight into how other more complex brains work, like our own.