Neurobiology of baroreceptor perikarya and afferentation

描述(申请人提供)：动脉压力感受器(BR)反射在心脏自主控制中起着重要作用。BR传入神经放电的改变在高血压和心力衰竭时发生，因此与自主神经系统功能障碍密不可分。BR大致分为有髓或无髓传入，每种传入在动脉压力变化时表现出不同的放电模式。外周末端的微机械环境在压力传递过程中起着一定的作用。然而，这两种功能表型在感觉编码上的操作差异也可能是由于离子通道在传入通路(如动脉压力感受器、细胞体、中央突触)临界点的独特分布所致。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体，并使得细胞和系统水平的观察难以整合。例如，通过电刺激电压门控离子通道选择性地招募有髓或无髓BR(即不依赖于机械转导的激活)，会引起显著不同的心率和血压反射反应。有髓和无髓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，我们使用新开发的成年大鼠神经节标本对荧光识别的主动脉压力感受器神经元进行膜片钳研究，这确保了感觉通道和传入纤维类型的明确分类。初步数据提示电压门控和配基门控离子通道的不同利用，这可能潜在地解释了有髓和无髓BR的一些不同的压力编码特性。例如，有髓传入的神经放电似乎较少依赖N型钙离子。(ICa，N)和BK型钙激活的K+(IKa，BK)离子通道的活性高于来自无髓传入的活性，尽管电压钳证据表明ICa，N和IKCa，BK在这两种表型中都有功能共表达。这种不同的离子机制可能是有髓和无髓BR不同神经编码特性的基础，如果在突触前终末表现类似，可能会潜在地影响脑干对心血管传入信息的整合。这些基本的细节可能导致新的药理学策略来管理心血管疾病，如急性高血压和节律失常，众所周知，这些疾病涉及或调用自主神经反射通过BR激活。

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.