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

摘要 一个令人惊讶的，致命的观察是，对高剂量阿片类药物耐受的成瘾者 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， 在陌生的环境中使用药物。这一现象表明，一个认知过程， 编码环境线索，可以调节外周器官的功能， 可能是理解一系列重要的身心互动的关键 为了生存我建议乙酰胆碱（ACh），通过其受体（烟碱或 nAChR和毒蕈碱或mAChR）被独特地放置以协调中枢认知 过程，例如上下文相关的学习，具有自主和生理 我们生存所需的过程。更重要的是，这个提议中的大想法是， 如果ACh协调大脑和外周之间的稳态反应，不仅 大脑控制身体的反应，但改变身体可以控制认知 和行为。如果是这样的话，这表明我们可以在外围进行干预， 阿片耐受性和防止过量，甚至可能治疗阿片成瘾。 利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， 在外周和大脑中的类型，操纵外周和中枢神经元的活动 单独和组合调节器官，外周神经元， 中枢呼吸中心和参与认知的大脑区域，并决定精确的 第一次发现了情境依赖性阿片类药物耐受机制。我们将超越 专注于特定的神经元，一个大脑区域，一个单一的回路或孤立的大脑，并开始 来解决身体和大脑之间持续而复杂的相互作用， 这对理解我们如何生存和适应敌对环境至关重要。如果 如果这个项目成功了，我将从一个分子和行为神经科学家 成为一个综合生理学家，一个精通自主神经的人， 我的实验室将能够解决机械问题， 关于大脑和身体之间的相互作用，这在以前是无法理解的。

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.