Neurogenetic mechanisms of sensory circuit plasticity

项目摘要 遗传程序建立了指导先天行为的神经回路;它们还实现了 赋予这些电路功能灵活性。确定这些计划如何运作对于提供 理解人类神经回路的典型和病理状态的概念框架。然而，在这方面， 即使在简单的神经系统中，这些机制也没有得到很好的理解。性别差异提供了一个独特的 理解模型系统中不稳定的固有行为的切入点。此外，他们还可以帮助 阐明了在人类神经精神疾病（如自闭症）中产生性别偏见的机制 障碍和焦虑症。在这里，我们建议使用线虫C的异常易处理性进行研究。 elegans推进我们对指定先天行为的遗传机制的理解，并提供 它们具有依赖于状态的可塑性。在最近的工作中，我们发现一对C。elegans 化学感觉神经元称为ADF在确定行为反应的效价中起着关键作用， Ascaroside类性信息素。特别是，ADF神经元的性状态足以确定 一个人是否会被吸引或排斥的信息素混合物，无论生物性别 身体的其他部分在这项工作中，我们将利用这一系统提供的独特机会 （1）了解遗传性别如何在共享的神经回路中实现功能差异，（2）确定 一种保守的神经调节途径（PDF信号传导）差异地影响信息素的手段- 介导的行为，在两性，和（3）确定如何食物的可用性在免疫电路的功能，以提供一个 允许对信息素的行为反应的状态。我们的结果可能会显著 推进对遗传程序塑造神经生理学的基本原理的理解， 电路，并指定他们的能力，以产生灵活的先天行为。

PROJECT SUMMARY Genetic programs build neural circuits that guide innate behaviors; they also implement mechanisms that endow these circuits with functional flexibility. Determining how these programs work is essential for providing a conceptual framework for understanding typical and pathological states of human neural circuits. However, even in simple nervous systems, these mechanisms are not well understood. Sex differences provide a unique entry point for understanding flexible innate behaviors in model systems. Additionally, they could also help illuminate mechanisms that bring about sex bias in human neuropsychiatric conditions like autism spectrum disorder and anxiety disorders. Here, we propose studies using the exceptional tractability of the nematode C. elegans to advance our understanding of the genetic mechanisms that specify innate behaviors and provide them with state-dependent plasticity. In recent work, we have found that a single pair of C. elegans chemosensory neurons called ADF plays a key role in determining the valence of the behavioral response to ascaroside-class sex pheromones. In particular, the sexual state of the ADF neurons is sufficient to determine whether an individual will be attracted to or repelled by a pheromone mixture, regardless of the biological sex of the rest of the body. In this work, we will take advantage of the unique opportunities provided by this system to (1) understand how genetic sex implements functional differences in shared neural circuitry, (2) identify the means by which a conserved neuromodulatory pathway (PDF signaling) differentially influences pheromone- mediated behavior in both sexes, and (3) determine how food availability influences circuit function to provide a state that is permissive for the behavioral response to pheromones. Our results are likely to significantly advance the understanding of basic principles by which genetic programs sculpt the physiology of neural circuits and specify their ability to generate flexible innate behaviors.