Defining gastric vagal mechanisms underlying emetic activation using novel electrophysiological and optical mapping technology

 描述(申请人提供)：恶心和呕吐伴随着多种内科治疗和疾病，包括癌症化疗和糖尿病胃轻瘫，这可能导致食欲下降和营养失衡。我认为胃迷走神经回路的激活在呕吐信号中起主要作用；然而，胃迷走神经呕吐信号基本上仍然是一个“黑匣子”。以下基本机制问题尚未得到解答：(1)迷走神经中的呕吐信号是如何通过激活特定的纤维亚型、时间模式或胃感受野而编码的？(2)不同的呕吐刺激是否产生相同的迷走神经呕吐“信息”？(3)胃呕吐系统的历史依赖性机制是什么？该项目的目标是开发联合电生理学和红外线(IR)技术，使控制胃呕吐通路的详细功能神经电路映射成为潜在的恶心和呕吐治疗方法。我们的团队拥有实现这一目标的独特专业知识。霍恩博士开发了一种系统来询问和分析单个迷走神经单位的活动，同时记录呕吐 麝鼠的反射(大鼠和小鼠没有呕吐反射)。詹金斯博士和齐尔博士已经开始了使用IR技术的工作，这种技术可以以高空间精度刺激或抑制轴突亚群。刘易斯博士在选择性激活/抑制迷走神经亚群和监测与迷走神经活动相关的分子生物学机制方面拥有专业知识。我们将完成两个目标：(1)发展电生理/IR标测技术，并应用它来表征迷走神经内胃传入的形态和纤维类型。为了确定携带胃传入信号的纤维在迷走神经内是如何在地形图上组织的，我们将开发一种新的电生理/IR标测技术。我们将开发一种多光纤设备，允许对不同区域进行圆周照明，并将其与检查迷走神经束中单个单位的电生理技术相结合。(2)扩展电生理学/IR技术，以确定和控制迷走神经活动的时间模式，以响应经典和临床相关的催眠刺激。 我们将研究迷走神经活动的模式，以及IR激光抑制在胃相关呕吐刺激、机械膨胀、化学刺激(使用硫酸铜)和癌症化疗药物顺铂时的作用。我们的方法是创新的，因为我们结合了尖端的电生理学和IR技术来开发胃迷走器官系统的空间和时间地图。这个项目意义重大，因为它将阐明必须调节以控制呕吐的精确迷走神经呕吐机制；因此，产生关键的知识库，以促进开发新的治疗顽固性恶心和呕吐的策略。更广泛地说，这项技术对于了解迷走神经和周围神经功能的其他方面可能有很大的帮助。

 DESCRIPTION (provided by applicant): Nausea and vomiting occur with numerous medical treatments and diseases, including cancer chemotherapy and diabetic gastroparesis, which can lead to reduced appetite and nutritional imbalance. Activation of a gastric vagal neural circuit i believed to play a primary role in emetic signaling; however, gastric vagal emetic signaling essentially remains a "black box." The following fundamental mechanistic questions are unanswered: (1) how are emetic signals coded in the vagus by activation of specific fiber subtypes, temporal patterns, or gastric receptive fields? (2) Do different emetic stimuli produce the same vagal emetic "message"? (3) What are the mechanisms responsible for the history-dependence of the gastric emetic system? The goal of this project is to develop joint electrophysiology and infrared (IR) technology that will permit detailed functional neural circuit mapping for the control of the gastric emetic pathway as a potential therapy for nausea and emesis. Our team has the unique expertise to achieve this goal. Dr. Horn has developed a system to interrogate and analyze the activity of individual vagal units while recording the emetic reflex in the musk shrew (emetic reflexes are absent in rats and mice). Drs. Jenkins and Chiel have initiated work using an IR technology that can stimulate or inhibit sub-populations of axons with high spatial precision. Dr. Lewis has expertise in selectively activating/inhibiting vagal su-populations and in monitoring the molecular biological mechanisms associated with vagal activity. We will complete two AIMS: (1) Develop electrophysiology/IR mapping technology and apply it to characterize the topography and fiber types of gastric afferents within the vagus. To determine how fibers carrying gastric afferent signals are organized topographically within the vagus, we will develop a novel electrophysiology/IR mapping technology. We will develop a multi-optical fiber device that allows illumination of different regions circumferentially, and combine this with an electrophysiological technique that examines individual units in vagal fascicles. (2) Extend the electrophysiology/IR technology to determine and control temporal patterns of vagal activity in response to classical versus clinically relevant emetogenic stimuli. We will examine the patterning of activity in the vagus, and role of IR laser inhibition, in response to stomach-related emetic stimuli, mechanical distension, chemical irritation (using copper sulfate), and the cancer chemotherapy agent cisplatin. Our approach is innovative because we are combining cutting edge electrophysiology and IR technology to develop spatial and temporal maps of the gastric vagal organ system. This project is significant because it will elucidate precise vagal emetic mechanisms that must be modulated to control emesis; therefore, producing the critical knowledge base urgently needed to facilitate the development of new strategies to treat patients with intractable nausea and vomiting. More generally, the technology could have great utility for understanding other aspects of vagal and peripheral nerve function.