In vivo mechanisms for integration of contextual information

摘要 人脑的一个基本特征是它能够利用过去经验中的上下文信息来 调节行为。未能利用情境来调节行为对人类健康有很大影响。为 例如，患有神经和精神障碍的人通常难以理解他们的生理 环境和社会环境，降低他们的生活质量，损害他们与他人互动的能力。 虽然依赖于环境的行为调节的重要性是显而易见的，但人们对这种分子知之甚少。 以及促进这一关键大脑功能的电路原理。在本提案中，我的目标是揭示信令 调节神经回路活动以支持上下文相关行为的机制。为此，我将 利用线虫的遗传力和电路简单性。我的工作 假设cGMP信号通过微调神经元的活动来促进上下文相关的行为 调节行为的回路。为了了解cGMP信号通路的各个组成部分是如何 为了促进活体动物的上下文依赖行为，我设计了两个具体的实验。 目标1将检验一个工作假说，即环核苷酸门控(CNG)通道调节上下文- 依赖行为。为了支持这一假设，我发现CNG通道亚基的两个基因(Tax-2和Tax-2) CNG-3)是上下文相关行为所必需的。为了理解CNG渠道的作用，我将确定 神经元(S)，其中TAX-2和CNG-3发挥作用，我将确定它们对神经元活动的影响 用于运动行为的电路。这一目标的结果将决定CNG渠道如何影响背景 在带电电路中的集成。目标2将确定cGMP代谢在上下文依赖中的作用 行为的调节。CGMP是一种短命的分子信使。其合成和降解正在进行中 代谢酶的控制。我的工作假设是cGMP背后的特定酶 新陈代谢在生命神经回路的上下文相关调节中起着重要作用。与一致 在这个想法中，我发现编码cGMP代谢酶的三个基因(gcy-12、gcy-18和pde-4)是关键 玩家的行为依赖于上下文。为了阐明这些cGMP酶是如何调节上下文依赖的 行为，我将确定Gcy-12、Gcy-18和Pde-4在其中发挥作用的神经元，并展示它们在 将背景信息的感觉与行为调节相结合。总而言之，这项提案中的研究将 阐明cGMP调控上下文相关行为背后的分子和电路机制。

ABSTRACT A fundamental feature of human brain is its ability to use contextual information from past experience to modulate behavior. Failure to use context to modulate behavior has a great impact in human health. For instance, individuals with neurological and mental disorders often have difficulties understanding their physical surroundings and social settings, lowering their quality of life, and damaging their ability to interact with others. While the importance of context-dependent modulation of behavior is clear, little is known about the molecular and circuit principles that facilitate this key brain function. In this proposal I aim to uncover signaling mechanisms that tune the activity of neural circuits to support context-dependent behavior. To this end, I will take advantage of the genetic power and the circuit simplicity of the nematode C. elegans. My working hypothesis is that cGMP signals facilitate context-dependent behavior by fine tuning the activity of neuronal circuits that regulate behavior. To understand how individual components of a cGMP signaling pathway contribute to context-dependent behavior in living animals, I have designed experiments with two specific aims. Aim 1 will examine a working hypothesis that cyclic nucleotide-gated (CNG) channels regulate context- dependent behavior. In support of this hypothesis, I found that two genes of CNG channel subunits (tax-2 and cng-3) are required for context-dependent behavior. To understand the role of CNG channels, I will identify the neuron(s) in which tax-2 and cng-3 function, and I will determine their impact on neuronal activity in living circuits for locomotor behavior. Results from this Aim will determine how CNG channels influence context integration in living circuits. Aim 2 will Determine the role of cGMP metabolism in context-dependent modulation of behavior. cGMP is a short-lived molecular messenger. Its synthesis and degradation are under the control of metabolic enzymes. My working hypothesis is that specific enzymes underlying cGMP metabolism have an important role in context-dependent modulation of living neural circuits. Consistent with this idea, I identified three genes (gcy-12, gcy-18, and pde-4), encoding enzymes of cGMP metabolism, as key players in context-dependent behavior. To elucidate how these cGMP enzymes modulate context-dependent behavior, I will determine the neurons where gcy-12, gcy-18, and pde-4 function and demonstrate their role in coupling the sensation of contextual information to behavior modulation. Together, studies in this proposal will elucidate the molecular and circuit mechanisms behind the cGMP modulation of context-dependent behavior.