Neurotrophins and Development of Baroreceptor Pathways

描述(由申请人提供)：支配心血管、呼吸和胃肠系统的内脏感觉通路对自主神经稳态的反射控制至关重要。众所周知，内脏反射的功能特征，包括动脉压力反射和化学反射，在围生期发育过程中会发生巨大变化。然而，内脏反射功能成熟背后的细胞机制在很大程度上是未知的。这一设想的主要假设是，从内脏感觉传入的中央终末释放的神经营养因子脑源性神经营养因子(BDNF)调节突触后靶神经元的活性依赖性成熟。这一假说得到了我们最近发表的数据和初步研究的支持，将以结状神经节初级和二级感觉神经元以及主动脉压力感受器通路中功能均一的初级和二级感觉神经元作为模型进行验证。建议的研究将利用几种特别适合于这类研究的创新技术来表征：1)BDNF在结状神经节初级感觉神经元，特别是压力感受器传入神经元中的活性依赖性表达的发育调节，以及2)BDNF对发育中的孤束核(NTS)的二级感觉神经元(包括压力感受器-中继神经元)的电生理和形态影响。一种新的电场刺激与高灵敏、改良的原位酶联免疫吸附试验相结合，将用于表征BDNF蛋白含量在模拟压力感受器传入生理活动的刺激模式下的变化。揭示BDNF调节内脏初级感觉神经元的细胞机制是理解BDNF在内脏感觉通路中作用的关键。拟议工作的第二部分将分析BDNF对含有BDNF的内脏感觉神经元和压力感受器传入的特定突触后靶点的电压激活钾电流和树突形态的影响。这些研究的结果将为我们理解支配感觉通路发展的基本机制提供基本的新信息。此外，通过使用动脉压力感受器通路作为模型，所提出的研究对于了解心肺系统发育障碍的发病机制，如婴儿猝死综合征(SIDS)具有重要意义。

DESCRIPTION (provided by applicant): Visceral sensory pathways that innervate the cardiovascular, respiratory and gastrointestinal systems are critical for reflex control of autonomic homeostasis. It is well established that functional characteristics of visceral reflexes, including arterial baro- and chemoreflexes, changes dramatically during perinatal development. However, the cellular mechanisms underlying the functional maturation of visceral reflexes are largely unknown. The leading hypothesis of this proposal is that the neurotrophin Brain-Derived Neurotrophic Factor (BDNF), released from the central terminals of visceral sensory afferents, regulates the activity-dependent maturation of postsynaptic target neurons. This hypothesis, supported by our recently published data and preliminary studies, will be tested using nodose ganglion primary and second-order sensory neurons, as well as functionally homogenous primary and second-order neurons in the aortic baroreceptor pathway, as a model. The proposed studies will utilize several innovative techniques, uniquely suited for studies of this kind, to characterize: 1) developmental regulation of activity-dependent expression of BDNF in nodose ganglion primary sensory neurons in general, and baroreceptor afferents in particular, and 2) electrophysiological and morphological effects of BDNF on second-order sensory neurons, including baroreceptor-relay neurons, from the developing nucleus tractus solitarius (NTS). A novel combination of electrical field stimulation with a highly sensitive, modified ELISA in situ, will be used to characterize changes in BDNF protein content in response to patterns of stimulation that mimic the physiological activity of baroreceptor afferents. Revealing the cellular mechanisms of BDNF regulation in visceral primary sensory neurons is a key to understanding BDNF role in visceral sensory pathways. A second part of the proposed work will analyze BDNF effects on voltage-activated potassium currents and dendritic morphology in specifically identified postsynaptic targets of BDNF-containing visceral sensory neurons and baroreceptor afferents. Results of these studies will provide new information fundamental to our understanding of basic mechanisms that govern development of sensory pathways. Moreover, by using the arterial baroreceptor pathway as a model, the proposed studies are relevant to understanding pathogenesis of developmental disorders of the cardio-respiratory system, such as Sudden Infant Death Syndrome (SIDS).