Responsiveness to nicotine of nucleus tractus solitarius neurons

孤束核神经元对尼古丁的反应性

• 批准号: 8288197
• 负责人: Victor V Uteshev
• 金额: $ 32.01万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288197
• 关键词: Acetylcholine; Amygdaloid structure; Anorexia; Area; Autonomic Pathways; Baroreflex; Behavioral; Bilateral; Blood Vessels; Brain; Brain Stem; Cell Nucleus; Cells; Complex; Data; Dependence; Development; Digestion; Digestive System Disorders; Dorsal; Electrophysiology (science); Endocrine; Fiber; Gastrointestinal tract structure; Glutamates; Health; Heart; Heart Rate; Heterogeneity; Homeostasis; Hypothalamic structure; In Situ; Injection of therapeutic agent; Investigation; Knowledge; Label; Laboratories; Lateral; Maintenance; Mediating; Metabolic; Morphology; Motor; Motor Neurons; Neurons; Neurotransmitters; Nicotine; Nicotinic Agents; Nicotinic Receptors; Nucleus solitarius; Obesity; Oral cavity; Organ; Output; Pathway interactions; Pharmacology; Physiological; Physiology; Play; Presynaptic Terminals; Probability; Process; Rattus; Reflex action; Role; Sensory; Sensory Receptors; Signal Transduction; Site; Slice; Stomach; Synapses; Test Result; Testing; Thalamic structure; Therapeutic; Tissues; Tracer; Vagotomy; Visceral; afferent nerve; base; blood pressure regulation; cell motility; cholinergic; dorsal motor nucleus; feeding; gastrointestinal; gastrointestinal function; gastrointestinal system; improved; in vivo; intravenous administration; mind control; nerve supply; neuronal circuitry; novel therapeutics; parabrachial nucleus; patch clamp; postsynaptic; presynaptic; research study; response; transmission process

DESCRIPTION (provided by applicant): The nucleus of the solitary tract (NTS) is a functionally and anatomically heterogeneous group of cells that serves as a principle processing site regulating autonomic functions. Neurons of the NTS receive visceral sensory and gustatory signals and relay the information to visceral motor and other brain areas. Acetylcholine is a major autonomic neurotransmitter and the pre- and postsynaptic neuronal circuitry in the NTS receives a dense cholinergic innervation and expresses functional nicotinic acetylcholine receptors (nAChRs). Intravenous administration of nicotine in anesthetized rats decreases gastric motility and this effect could be significantly suppressed by bilateral vagotomy, indicating the involvement of functional nAChRs of the NTS and other nuclei of the brainstem dorsal vagal complex (DVC) in gastrointestinal reflexes. Despite its heterogeneity, the NTS contains discrete subsets of functionally-specific NTS cells. However, the pre- and postsynaptic cholinergic control of functionally-specific NTS pathways is unknown. Previous studies and recent preliminary data from this laboratory indicate that there are selective pre- and postsynaptic nicotinic effects on specific subsets of caudal NTS cells as defined by their morphology, cytochemical identity, afferent input, and axonal targets. Specifically, a robust enhancement of synaptic release of glutamate by nicotine has been observed in a subset of caudal NTS neurons (these will be referred to as presynaptically-responsive to nicotine) projecting to or through the key gastrointestinal control nucleus, the dorsal motor nucleus of the vagus, but not to the parabrachial nucleus, a primary target for the ascending autonomic and gustatory fibers to higher brain centers. Based on preliminary results, we hypothesize that specific subsets of caudal NTS cells with defined morphology, physiology, and brainstem projection or functional visceral target are differentially regulated by selective subtypes of presynaptic and somatodendritic nAChRs. Proposed experiments aim to: 1) relate nicotine's effects to the projection targets of subsets of caudal NTS neurons, identified using in vivo and ex vivo injections of retrograde tracers combined with patch-clamp electrophysiology (Aim 1); and 2) identify the cellular and synaptic mechanisms of underlying effects of nicotine in NTS brainstem slices (Aim 2). Understanding the mechanisms and pharmacology of nAChR subtypes underlying the effects of nicotinic agents on function- specific subsets of caudal NTS neurons will enhance our knowledge of the role of nAChRs in the processing and integration of gastric and other visceral information. This may result in the development of new therapeutic strategies for selective targeting of specific nicotine-responsive autonomic pathways (e.g., gastrointestinal). Results from the proposed studies could expand available therapeutic options aimed at improving digestive health and treatments of digestive disorders, such as obesity and anorexia. PUBLIC HEALTH RELEVANCE: Nicotine changes the activity of neurons in the brain that regulate the gastrointestinal system and are critical to feeding and digestion, but how this occurs is largely unknown. We have uncovered evidence of a powerful means for nicotine to regulate a small set of neurons that influence how the brain controls the gut, and these mechanisms are the topic of this proposal. The experiments here will point to new ways of using nicotinic mechanisms to modify functions of the gastrointestinal system associated with feeding.

描述（由申请人提供）：孤立道（NTS）的核是功能和解剖上异质的细胞组，可作为调节自主函数的原理处理位点。 NTS的神经元接收内脏的感觉和味道信号，并将信息传递给内脏运动和其他大脑区域。乙酰胆碱是NTS中主要的自主神经递质，以及突触后和突触后神经元的回路，可接受致密的胆碱能神经支配，并表达功能性的烟碱乙酰胆碱受体（NACHRS）。麻醉大鼠中尼古丁的静脉内给药可降低胃运动，这种作用可以通过双侧迷走道显着抑制，这表明在胃肠道反射剂中，NTS和其他脑干的背腔传导复合物（DVC）的NTS和其他核的功能性NACHR参与。尽管具有异质性，但NTS包含功能特异性NTS细胞的离散子集。但是，功能特定的NTS途径的突触前和突触后胆碱能控制尚不清楚。先前的研究和该实验室的最新初步数据表明，通过其形态，细胞化学认同，传入输入和轴突靶标的定义，对尾状NTS细胞的特定子集有选择性的前和突触后烟碱作用。 Specifically, a robust enhancement of synaptic release of glutamate by nicotine has been observed in a subset of caudal NTS neurons (these will be referred to as presynaptically-responsive to nicotine) projecting to or through the key gastrointestinal control nucleus, the dorsal motor nucleus of the vagus, but not to the parabrachial nucleus, a primary target for the ascending autonomic and脾气纤维到更高的大脑中心。基于初步结果，我们假设具有定义的形态学，生理学和脑干投影或功能内脏靶标的尾状NTS细胞的特定子集受到选择性亚型和somatendendritic nachrs的选择性亚型的调节。拟议的实验旨在：1）将尼古丁的作用与尾状NTS神经元子集的投影靶标相关，并使用体内和体内注射逆行示踪剂结合了斑块钳电生理学（AIM 1）； 2）确定尼古丁在NTS脑干切片中的潜在作用的细胞和突触机制（AIM 2）。了解NACHR亚型的机制和药理学，烟碱剂对尾神经元的功能 - 特定子集的作用的基础，将增强我们对NACHR在胃和其他视觉信息的处理和整合中的作用的了解。这可能导致发展新的治疗策略，以选择性靶向特定的尼古丁反应性自主途径（例如胃肠道）。拟议的研究的结果可以扩大可用的治疗方案，旨在改善消化健康和消化系统疾病的治疗方法，例如肥胖和厌食症。公共卫生相关性：尼古丁改变了调节胃肠道系统的大脑神经元的活性，对于喂养和消化至关重要，但是这种情况的发生在很大程度上是未知的。我们发现了尼古丁调节一小部分神经元的强大手段的证据，这些神经元会影响大脑如何控制肠道，这些机制是该提议的主题。这里的实验将指出使用烟碱机制来修改与进食相关的胃肠道系统功能的新方法。