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: 10662288
• 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/10662288
• 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; skills; 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.

摘要 一个令人惊讶且致命的观察结果是，对高剂量鸦片类药物耐受的吸毒者 在他们习惯使用这些药物的环境中，当他们服用 在陌生的环境中吸毒。这一现象表明，一个认知过程， 对环境线索进行编码，可以调节周围器官的功能， 可能是理解一系列重要的身心互动的关键 为了生存。我认为乙酰胆碱(ACh)通过其受体(尼古丁或 NAChRs和Muscarinic或mAChRs)是协调中枢认知的独特位置 自主和生理的过程，例如依赖于环境的学习 我们生存所需的过程。更重要的是，这项提案中蕴含的重大理念是 如果ACh协调大脑和外周之间的动态平衡反应，不仅 大脑可以控制身体的反应吗？但改变身体可以控制认知 和行为。如果是这样的话，这表明我们可以干预外围国家，以诱导 耐受阿片类药物，防止服药过量，甚至可能治疗阿片成瘾。 使用新的分子遗传学工具，我们将追踪精确的细胞之间的直接联系 外周和大脑中的类型，操纵外周和中枢神经元的活动 单独和联合，调节器官，外周神经元， 中枢呼吸中枢和大脑参与认知的区域，并决定准确的 首次提出了上下文依赖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、单个回路或孤立的大脑，然后开始 为了解决身体和大脑之间持续而复杂的相互作用，即 对于理解我们如何能够在恶劣的环境中生存和适应至关重要。如果 这个项目是成功的，我将从分子和行为神经学家 作为一名综合生理学家，一个擅长理解自主神经的人 系统和呼吸系统生物学家，我的实验室将能够解决机械问题 关于大脑和身体的相互作用，这在以前是不可接近的。

项目成果

microRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity.

• DOI: 10.1038/s41467-021-21107-5
• 发表时间: 2021-02-16
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Horie T;Nakao T;Miyasaka Y;Nishino T;Matsumura S;Nakazeki F;Ide Y;Kimura M;Tsuji S;Rodriguez RR;Watanabe T;Yamasaki T;Xu S;Otani C;Miyagawa S;Matsushita K;Sowa N;Omori A;Tanaka J;Nishimura C;Nishiga M;Kuwabara Y;Baba O;Watanabe S;Nishi H;Nakashima Y;Picciotto MR;Inoue H;Watanabe D;Nakamura K;Sasaki T;Kimura T;Ono K
• 通讯作者: Ono K