Neurobiology of baroreceptor perikarya and afferentation

压力感受器周核和传入的神经生物学

• 批准号: 6680645
• 负责人: JOHN H SCHILD
• 金额: $ 31.34万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6680645
• 关键词: afferent nerve; baroreceptors; baroreflex; calcium channel; capsaicin; cardiovascular function; computer simulation; drug receptors; electrophysiology; laboratory rat; mathematics; membrane channels; myelination; neural transmission; neuropharmacology; neuroregulation; potassium channel; sodium channel; tetrodotoxin; voltage /patch clamp; voltage gated channel

DESCRIPTION (provided by applicant): The arterial baroreceptor (BR) reflex plays an essential role in autonomic control of the heart. Altered discharge of BR afferents occurs with hypertension and heart failure and is therefore inextricably linked to autonomic nervous system dysfunction. BR are broadly classified as myelinated or unmyelinated afferents, each exhibiting distinct discharge patterns in response to arterial pressure changes. The micromechanical environment of the peripheral termination certainly plays a role in the process of pressure transduction. However, the operational differences in sensory coding between these two functional phenotypes may also arise from unique distributions of ion channels at critical points along the afferent pathway (e.g. arterial pressoreceptor, cell body, central synapse). Unfortunately, such a bimodal demarcation belies the continuum of physiological properties exhibited by BR and makes difficult the integration of cellular and systems level observations. For example, selective recruitment of myelinated or unmyelinated BR via electrical excitation of voltage-gated ion channels (i.e. activation independent of mechanotransduction) evokes dramatically different heart rate and blood pressure reflex responses. The ionic mechanisms that contribute to the differential sensory encoding properties of myelinated and unmyelinated BR are largely unknown. Here, we use a newly developed adult rat nerve-ganglion preparation for patch clamp study of fluorescently identified aortic baroreceptor neurons which ensures unambiguous classification of sensory modality and afferent fiber type. Preliminary data are suggestive of a differential utilization of voltage- and ligand-gated ion channels that may potentially explain some of the contrasting pressure encoding properties of myelinated and unmyelinated BR. For example, neural discharge from myelinated afferents appears less dependent upon N-type Ca2+. (ICa,N)and BK-type Ca2+-activated K+ (IKCa,BK)ion channels than activity arising from unmyelinated afferents, despite voltage clamp evidence for functional coexpression of ICa,N and IKCa,BK in both phenotypes. Such differential ionic mechanisms may underlie the disparate neural encoding properties of myelinated and unmyelinated BR and could potentially influence brainstem integration of cardiovascular afferent information if similarly represented at the presynaptic terminals. These fundamental details may lead to novel pharmacological strategies in the management of cardiovascular pathologies such as acute hypertension and dysrhythmias that are well known to involve or invoke autonomic reflexes through BR activation.

描述（由申请人提供）：动脉压力感受器（BR）反射在心脏的自主控制中起重要作用。高血压和心力衰竭时BR传入事件的放电改变，因此与自主神经系统功能障碍密不可分。BR大致分为有髓鞘传入和无髓鞘传入，每一种传入都表现出不同的放电模式，以响应动脉压力的变化。外周末端的微力学环境在压力传导过程中肯定起着一定的作用。然而，这两种功能表型之间感觉编码的操作差异也可能源于沿传入通路（如动脉压力受体、细胞体、中枢突触）关键点上离子通道的独特分布。不幸的是，这种双峰划分掩盖了BR所表现出的生理特性的连续性，使细胞和系统水平观察的整合变得困难。例如，通过电压门控离子通道的电激发（即独立于机械转导的激活）选择性地招募有髓鞘的或无髓鞘的BR会引起显著不同的心率和血压反射反应。有髓鞘和无髓鞘BR的不同感觉编码特性的离子机制在很大程度上是未知的。在这里，我们使用一种新开发的成年大鼠神经神经节准备物进行膜片钳研究，荧光识别主动脉压力感受器神经元，确保感觉模式和传入纤维类型的明确分类。初步数据表明，电压和配体门控离子通道的不同利用可能潜在地解释了有髓鞘和无髓鞘BR的一些不同的压力编码特性。例如，髓鞘传入的神经放电似乎不太依赖于n型Ca2+。（ICa，N）和BK型Ca2+激活的K+ （IKCa，BK）离子通道的活性高于无髓鞘传入事件产生的活性，尽管电压钳证据表明，在两种表型中，ICa，N和IKCa，BK的功能共表达。这种不同的离子机制可能是有髓鞘和无髓鞘脑卒中不同的神经编码特性的基础，如果在突触前末端有类似的表现，可能会影响脑干对心血管传入信息的整合。这些基本细节可能会导致心血管疾病管理的新药理学策略，如急性高血压和心律失常，众所周知，通过BR激活涉及或调用自主神经反射。