Molecular mechanisms controlling neuronal circuits for decision-making

决策是在一组两个或多个备选方案中选择一个行动的过程。导致决策的分子、细胞和电路事件仍然没有完全理解。特别是，我们对不同尺度下发生的事件之间的因果关系知之甚少。分子信号的亚细胞变化如何对控制决策的神经元回路产生宏观影响？该项目的目标是通过研究指导斑马鱼幼虫简单决策的电路来回答这个问题，斑马鱼是一种具有小而半透明大脑的模式生物，可以使用强大的成像和遗传技术来监测和操纵体内大群神经元的活动。动物经常面临的两个重要决定是是否接近食物来源或避免潜在的捕食者。动机和内部状态，如恐惧和饥饿，强烈影响这种类型的选择。例如，我们之前表明饥饿的斑马鱼幼虫在寻找食物时会冒更大的风险，更经常接近模糊但可能可食用的物体。我们还表明，在神经元水平上，这种调制发生在视觉处理的非常早期的阶段，并涉及肾上腺素能系统和下丘脑-垂体-肾间轴，一个主要参与应激反应的途径。我们现在想了解调节神经元兴奋性的分子事件是如何调节这些神经元回路的功能的。为此，我们计划在斑马鱼中进行一系列的行为和功能脑成像研究，这些斑马鱼携带一种突变，破坏了这些细胞内信号通路之一。此外，我们将研究受这些分子改变影响的神经元的活动如何控制神经元回路的潜在方法/避免决策。该项目将通过揭示将动物的需求和动机转化为调节行为的分子和神经元事件的机制，更好地理解指导决策的神经元回路。

Decision-making is the process to choosing an action among a set of two or more alternatives. The molecular, cellular, and circuit events leading to a decision are still not fully understood. In particular, we know very little about the causal links between events happening at different scales. How do subcellular changes in molecular signaling induce macroscopic effects on neuronal circuits controlling decision-making? The objective of this project is to contribute to answer this question by studying the circuits guiding simple decisions in the larval zebrafish, a model organism with a small and translucent brain which allows to use powerful imaging and genetic techniques to monitor and manipulate the activity of large groups of neurons in vivo. Two important decisions animals often face are whether to approach a food source or avoid potential predators. Motivation and internal states, such as fear and hunger, strongly influence this type of choices. For example, we previously showed that hungry zebrafish larvae take more risks when looking for food, approaching more often ambiguous but possibly edible objects. We also showed that at the neuronal level, this modulation occurs at very early stages of visual processing, and involves the serotonergic system and the hypothalamus-pituitary-interrenal axis, a pathway chiefly involved in responses to stress. We now want to understand how molecular events regulating neuronal excitability in a subset of neurons modulate function of these neuronal circuits. To this end, we plan to carry out a series of behavioral and functional brain imaging studies in zebrafish harboring a mutation disrupting one of these intracellular signaling pathways. Furthermore, we will investigate how activity of neurons affected by these molecular alterations control neuronal circuits underlying approach/avoid decisions. This project will lead to a better understanding of the neuronal circuits guiding decision-making by revealing mechanisms translating the needs and motivation of an animal into the molecular and neuronal events regulating behavior.