Acetylcholine signaling allows cognitive processes in the brain to regulate physiological responses to the environment: the example of central control of opiate tolerance

乙酰胆碱信号传导允许大脑中的认知过程调节对环境的生理反应：阿片类药物耐受性的中央控制的例子

• 批准号: 10455505
• 负责人: Marina R Picciotto
• 金额: $ 117.25万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455505
• 关键词: Acetylcholine; Address; Area; Autonomic nervous system; Behavior; Behavioral; Brain; Cognition; Complex; Cues; Dose; Drug usage; Environment; Learning; Molecular; Molecular Genetics; Muscarinics; Neurons; Neurosciences; Opiate Addiction; Opioid; Opioid Receptor; Organ; Overdose; Peripheral; Pharmaceutical Preparations; Physiological; Physiological Processes; Physiology; Receptor Signaling; Respiratory Center; Signal Transduction; System; Time; cell type; cognitive process; educational atmosphere; mind body interaction; mind control; opiate tolerance; prevent; programs; receptor; respiratory; response; tool

Abstract A surprising, and lethal, observation is that addicts who are tolerant to high doses of opiates in an environment where they use these drugs habitually, can overdose when they take the drug in an unfamiliar environment. This phenomenon shows that a cognitive process, encoding environmental cues, can regulate the function of peripheral organs in a manner that could be the key to understanding a whole host of mind-body interactions that are important for survival. I propose that acetylcholine (ACh), acting through its receptors (nicotinic or nAChRs, and muscarinic or mAChRs) is uniquely placed to coordinate central cognitive processes, for example context-dependent learning, with autonomic and physiological processes we need for survival. More importantly, the big idea embedded in this proposal is that if ACh coordinates homeostatic responses between the brain and the periphery, not only does the brain control responses in the body, but changing the body can control cognition and behavior. If this is the case, it suggests that we can intervene in the periphery to induce opiate tolerance and prevent overdose, and maybe even treat opiate addiction. Using new molecular genetic tools, we will trace direct connections between precise cell types in the periphery and the brain, manipulate activity of peripheral and central neurons alone and in combination, regulate opioid receptor signaling in organs, peripheral neurons, central respiratory centers and brain areas involved in cognition, and determine the precise mechanisms for context-dependent opioid tolerance for the first time. We will go beyond the focus on specific neurons, one brain area, a single circuit or the brain in isolation, and begin to address the constant and complex interaction between the body and the brain that is essential for understanding how we are able to survive and adapt to a hostile environment. If this program is successful, I will move from being a molecular and behavioral neuroscientist to being an integrative physiologist, someone skilled in understanding the autonomic nervous system and a respiratory biologist, and my lab will be able to tackle mechanistic questions about brain-body interactions that were not approachable previously.

抽象的 令人惊讶的，致命的观察是，对高剂量鸦片的耐受的成瘾者 在他们习惯使用这些药物的环境中，当他们服用这些药物时可能过量服用 在不熟悉的环境中吸毒。这种现象表明，认知过程， 编码环境提示，可以以某种方式调节外围器官的功能 可能是了解重要的一大批思维体互动的关键 生存。我建议乙酰胆碱（ACH）通过其受体作用（烟碱或 nachrs和毒蕈碱或马rs）是独特的，以协调中心认知 通过自主和生理学的过程，例如与上下文相关的学习 我们需要生存的过程。更重要的是，该提案中嵌入的重大想法是 如果ACH协调大脑和外围之间的稳态反应，不仅是 大脑控制反应是否在身体中，但是改变身体可以控制认知 和行为。如果是这种情况，这表明我们可以干预外围 鸦片耐受性并防止服药过量，甚至可以治疗鸦片成瘾。 使用新的分子遗传工具，我们将追踪精确细胞之间的直接连接 外围和大脑中的类型，外周和中央神经元的操纵活动 单独和组合，调节器官，周围神经元中的阿片受体信号传导， 中央呼吸中心和大脑区域涉及认知，并确定精确 首次依赖上下文的阿片类药物耐受的机制。我们将超越 专注于特定的神经元，一个大脑区域，单电路或大脑，然后开始 解决身体与大脑之间恒定而复杂的相互作用 了解我们如何生存和适应敌对的环境至关重要。如果 这个程序是成功的，我将从分子和行为神经科学家转变 成为一名综合生理学家，熟练理解自主神经的人 系统和呼吸生物学家，我的实验室将能够解决机理问题 关于以前无法接近的脑体相互作用。