Asynchronous Glutamate Release in Vagal Afferent to NTS Neurotransmission

迷走神经传入 NTS 神经传递的异步谷氨酸释放

• 批准号: 8451342
• 负责人: James Henry Peters
• 金额: $ 31.69万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8451342
• 关键词: Accounting; Action Potentials; Address; Affect; Afferent Neurons; Agonist; American; Attenuated; Body Weight; Brain; Brain Stem; C Fiber; Calcium; Capsaicin; Cardiovascular Diseases; Charge; Cholecystokinin; Communication; Complement; Complex; Data; Development; Diabetes Mellitus; Disease; Eating; Electrophysiology (science); Energy Metabolism; Excitatory Synapse; Fiber; Food Energy; Genetic; Glutamates; Goals; Health Care Costs; Heating; Homeostasis; Image; Investigation; Ion Channel; Measurement; Mediating; Membrane; Mus; Nature; Neurons; Nucleus solitarius; Obesity; Organ; Pathology; Pathway interactions; Peripheral; Pharmacology; Phenotype; Physiological; Positioning Attribute; Prevalence; Process; Publishing; Reflex action; Regulation; Research; Role; Ruthenium Red; Satiation; Signal Transduction; Slice; Subgroup; Synapses; TRP channel; Testing; Therapeutic Intervention; Translating; United States; Vagus nerve structure; Vanilloid; Vesicle; Visceral; Work; base; body system; capsaicin receptor; feeding; hindbrain; in vivo; innovation; interest; mouse model; neurotransmission; new therapeutic target; novel; obesity prevention; postsynaptic; receptor; research study; response; therapeutic target; Accounting; Action Potentials; Address; Affect; Afferent Neurons; Agonist; American; Attenuated; Body Weight; Brain; Brain Stem; C Fiber; Calcium; Capsaicin; Cardiovascular Diseases; Charge; Cholecystokinin; Communication; Complement; Complex; Data; Development; Diabetes Mellitus; Disease; Eating; Electrophysiology (science); Energy Metabolism; Excitatory Synapse; Fiber; Food Energy; Genetic; Glutamates; Goals; Health Care Costs; Heating; Homeostasis; Image; Investigation; Ion Channel; Measurement; Mediating; Membrane; Mus; Nature; Neurons; Nucleus solitarius; Obesity; Organ; Pathology; Pathway interactions; Peripheral; Pharmacology; Phenotype; Physiological; Positioning Attribute; Prevalence; Process; Publishing; Reflex action; Regulation; Research; Role; Ruthenium Red; Satiation; Signal Transduction; Slice; Subgroup; Synapses; TRP channel; Testing; Therapeutic Intervention; Translating; United States; Vagus nerve structure; Vanilloid; Vesicle; Visceral; Work; base; body system; capsaicin receptor; feeding; hindbrain; in vivo; innovation; interest; mouse model; neurotransmission; new therapeutic target; novel; obesity prevention; postsynaptic; receptor; research study; response; therapeutic target

DESCRIPTION (provided by applicant): The increased prevalence of obesity and its associated pathologies, including cardiovascular disease and diabetes mellitus, account for a large percentage of healthcare costs in the United States. Neurocircuitry within the brainstem provides critical controls of food intake and energy homeostasis. In the caudal brainstem the nucleus of the solitary tract (NTS) integrates vagal afferent information arriving from across visceral organ systems to initiate homeostatic reflex pathways, including those essential for the controls of food intake. Centrally, vagal afferents converge to form the solitary tract (ST) and contact second order NTS neurons via strong excitatory synapses. At ST-NTS synapses action-potential invasion releases multiple glutamate vesicles that are precisely synchronized with terminal depolarization. This robust 'synchronous' form of glutamate release is thought to be the predominate mode of fast neurotransmission at the ST-NTS synapse. Recently, however, we identified a novel form of activity-dependent 'asynchronous' glutamate release from a subgroup of vagal afferents. In contrast with synchronous release, this additional form of neurotransmission was only loosely coordinated with depolarization and continued for many seconds, effectively doubling the synaptic strength. As a result of the additional charge transfer the postsynaptic excitatory period was significantly extended, dramatically transforming the nature of information transfer. ST afferents are divided into myelinated (A-fiber) and unmyelinated (C-fiber) phenotypes with physiologically distinct functions. One important difference between subtypes is that C-fiber afferents express the calcium permeable non-selective ion channel 'transient receptor potential vanilloid type 1' (TRPV1). In our preliminary experiments we found all afferents with activity-dependent asynchronous release were also activated by the TRPV1 agonist capsaicin. Further, antagonism of TRPV1 activity selectively reduced the asynchronous release profile with no effect on synchronous. An attenuated asynchronous release process persists in TRPV1 KO mice and is reduced by ruthenium red. Together these findings suggest membrane depolarization endogenously activates TRPV1, and other thermosensitive-TRP channels, expressed in the central terminals of vagal afferents resulting in asynchronous glutamate release. The aims of the current application are 1. to delineate the mechanisms of TRPV1 activation resulting in asynchronous glutamate release, 2. determine the extent to which other thermo- TRPs participate in asynchronous neurotransmission, and 3. utilize selective antagonists and genetic KO mouse models to determine the contribution of asynchronous glutamate release in the control of food intake. The findings from this project will determine the role of asynchronous glutamate release from vagal afferents and its impact on food intake.

描述（由申请人提供）：肥胖症及其相关病理的患病率增加，包括心血管疾病和糖尿病，占美国医疗保健费用的很大一部分。脑干内的神经循环可提供对食物摄入和能量稳态的关键控制。在尾部脑干中，孤立区（NTS）的核整合了从内脏器官系统到达的迷走神经传入信息，以启动体内反射途径，包括那些对食物摄入量控制的必不可少的途径。从集中，迷走神经传入会融合以形成孤立的道（ST），并通过强烈的兴奋性突触接触二阶NTS神经元。在ST-NTS突触，动作势力侵入释放了多种与末端去极化精确同步的谷氨酸囊泡。谷氨酸释放的这种强大的“同步”形式被认为是ST-NTS突触中快速神经传递的主要模式。但是，最近，我们发现了一种新型的活性依赖性“异步”谷氨酸谷氨酸从迷走神经传入的亚组中释放。与同步释放相反，这种额外的神经传递形式仅与去极化相协调并持续了许多秒，有效地使突触强度增加了一倍。由于额外的电荷转移，突触后兴奋期显着扩展，从而极大地改变了信息传递的性质。将ST传入分为具有生理上不同功能的髓鞘（A纤维）和不髓鞘的（C纤维）表型。亚型之间的一个重要区别是，C纤维传入表达钙渗透性的非选择性离子通道“瞬态受体电位1型1'（TRPV1）。在我们的初步实验中，我们发现所有具有活性依赖性异步释放的传入也被TRPV1激动剂辣椒素激活。此外，TRPV1活性的拮抗作用选择性地降低了异步释放曲线，而对同步没有影响。 TRPV1 KO小鼠中持续的异步释放过程持续减弱，并通过红色ruthenium Red降低。这些发现共同表明，膜去极化会在迷走神经传入的中央末端表达，从而内源激活TRPV1和其他热敏感-TRP通道，从而导致异步谷氨酸释放。 The aims of the current application are 1. to delineate the mechanisms of TRPV1 activation resulting in asynchronous glutamate release, 2. determine the extent to which other thermo- TRPs participate in asynchronous neurotransmission, and 3. utilize selective antagonists and genetic KO mouse models to determine the contribution of asynchronous glutamate release in the control of food intake.该项目的发现将确定从迷走神经传入及其对食物摄入的影响的异步谷氨酸释放的作用。