In vivo mechanisms for integration of contextual information

上下文信息整合的体内机制

• 批准号: 10680305
• 负责人: Manuel Rosero
• 金额: $ 4.29万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680305
• 关键词: Animals; Behavior; Biological Assay; Brain; Caenorhabditis elegans; Candidate Disease Gene; Collection; Color; Coupling; Cyclic GMP; Environment; Enzymes; Esthesia; Experimental Designs; Failure; Genes; Genetic; Goals; Guanylate Cyclase; Health; Human; Illusions; Image; Individual; Invertebrates; Locomotion; Mental disorders; Metabolic Control; Metabolism; Molecular; Nematoda; Nervous System; Neurons; Optical Illusions; Pathway interactions; Perception; Quality of life; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Taxes; Translating; Work; contextual factors; cyclic-nucleotide gated ion channels; design; experience; experimental study; improved; in vivo; interdisciplinary approach; movie; nervous system disorder; neural circuit; neuronal circuitry; novel; phosphoric diester hydrolase; physical property; response; social

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.

抽象的 人脑的一个基本特征是它能够从过去的经验中使用上下文信息到 调节行为。不使用上下文来调节行为会对人类健康产生重大影响。为了 例子，神经和精神障碍的人通常很难理解自己的身体 周围环境和社交环境，降低了他们的生活质量，并损害了他们与他人互动的能力。 虽然行为依赖上下文调制的重要性是明显的，但对分子知之甚少 和促进此关键大脑功能的电路原理。在此提案中，我的目标是发现信号 调整神经回路活性以支持上下文依赖性行为的机制。为此，我会 利用线虫秀丽隐杆线虫的遗传力和电路简单性。我的工作 假设是CGMP信号通过微调神经元的活性来促进上下文依赖性行为 调节行为的电路。了解CGMP信号通路的单个组件如何 我为活动物的上下文依赖性行为做出了贡献，我设计了两个特定目标的实验。 AIM 1将研究一个有效的假设，即环状核苷酸门控（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 CNG-3）是上下文依赖性行为所必需的。要了解CNG渠道的作用，我将确定 税收2和CNG-3功能的神经元，我将确定它们对生活中神经元活动的影响 运动行为的电路。该目标的结果将决定CNG渠道如何影响环境 在生活电路中的整合。 AIM 2将确定CGMP代谢在上下文依赖性中的作用 行为的调节。 CGMP是一个短暂的分子信使。它的综合和降解不在 代谢酶的控制。我的工作假设是CGMP的特定酶 代谢在与生命神经回路的上下文依赖性调节中具有重要作用。与 这个想法，我将三个基因（GCY-12，GCY-12和PDE-4）鉴定为编码CGMP代谢的酶，这是关键 与上下文相关行为的参与者。阐明这些CGMP酶如何调节上下文依赖性 行为，我将确定GCY-12，GCY-12和PDE-4功能的神经元，并证明它们在 将上下文信息的感觉与行为调制结合。该提议中的研究将 阐明CGMP调制背景依赖性行为背后的分子和电路机制。