Neurotrophins and Development of Baroreceptor Pathways.

描述（由申请人提供）：支配心血管、呼吸和胃肠道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，包括动脉气压反射和化学反射，在围产期发育过程中发生了巨大的变化。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。该提议的主要假设是神经营养因子脑源性神经营养因子（BDNF），从内脏感觉传入中枢末端释放，调节突触后目标神经元的活动依赖性成熟。这一假设得到了我们最近发表的数据和初步研究的支持，我们将使用结节神经节一级和二级感觉神经元，以及主动脉压力感受器通路中功能同质的一级和二级神经元作为模型进行验证。所提出的研究将利用一些创新的技术，特别适合于这类研究，来表征：1)结节神经节初级感觉神经元中BDNF活性依赖性表达的发育调节，特别是压力受体传入神经；2)BDNF对发育中的孤束核（NTS）二级感觉神经元（包括压力受体-接力神经元）的电生理和形态学影响。将电场刺激与高灵敏度的原位改良ELISA相结合，将用于表征BDNF蛋白含量在模拟压力感受器传入的生理活动的刺激模式下的变化。揭示BDNF调控内脏初级感觉神经元的细胞机制是理解BDNF在内脏感觉通路中的作用的关键。研究的第二部分将分析BDNF对电压激活钾电流和树突形态的影响，特别是在含有BDNF的内脏感觉神经元和压力感受器传入神经的突触后靶点。这些研究的结果将为我们理解控制感觉通路发展的基本机制提供新的信息。此外，通过以动脉压力受体通路为模型，所提出的研究与理解诸如婴儿猝死综合征（SIDS）等心肺系统发育障碍的发病机制有关。

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).