In vivo mechanisms for integration of contextual information

摘要 人类大脑的一个基本特征是它能够利用来自过去经验的上下文信息， 调节行为。不利用环境来调节行为对人类健康有很大的影响。为 例如，患有神经和精神障碍的人通常难以理解他们的身体状况。 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明确的，但对分子机制知之甚少。 以及促进这一关键大脑功能的电路原理。在这个提案中，我的目标是揭示信号 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C的遗传能力和电路简单性。优雅我的工作 假设cGMP信号通过精细调节神经元的活性促进情境依赖性行为， 控制行为的回路了解cGMP信号通路的各个组成部分 有助于活动物的情境依赖行为，我设计了两个特定目标的实验。 目的1将检查一个工作假设，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 CNG-3）是上下文相关行为所必需的。为了了解CNG渠道的作用，我将确定 tax-2和cng-3在其中起作用的神经元，我将确定它们对生活中神经元活动的影响。 运动行为的回路该目标的结果将确定CNG通道如何影响上下文 集成在活体电路中。目的2将确定cGMP代谢在环境依赖性中的作用 行为的调节。cGMP是一种短寿命的分子信使。它的合成和降解是在 代谢酶的控制。我的工作假设是，特定的酶基础环鸟苷酸 代谢在活神经回路的情境依赖性调节中具有重要作用。符合 基于这个想法，我确定了三个基因（gcy-12，gcy-18和pde-4），它们编码cGMP代谢酶， 参与者的情境依赖行为。为了阐明这些cGMP酶如何调节环境依赖性 行为，我将确定gcy-12，gcy-18和pde-4功能的神经元，并证明它们在神经元中的作用。 将情境信息的感觉与行为调节相结合。本提案中的各项研究将共同 阐明cGMP调节背景依赖性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.