BDNF in plasticity of chemoafferent pathway

描述(由申请人提供)： 这项拟议的研究的目的是定义大脑衍生的 神经营养因子在发育中活性依赖性可塑性中的作用 化学传入通路。化学传入神经元是连接外周的纽带 化学感受器和脑干，从而在 心肺动态平衡。在出生时，化学传入反射是不成熟的， 而氧气供应的干扰会扰乱婴儿出生后的发育 对急性缺氧的心肺反应。然而，这种机制 潜在的化学反射发育和可塑性在很大程度上是未知的。这 这一建议是基于我们最近的发现：1)化学传入神经元在 新生大鼠结节-岩神经节复合体(NPG)高水平表达 脑源性神经营养因子信使RNA和蛋白质，2)脑源性神经营养因子蛋白由NPG神经元释放 对体外图形电刺激的反应，以及3)BDNF的敏感度 抑制大鼠脑内二阶中继神经元谷氨酸能AMPA受体 孤束核(NTS)是化学传入的主要部位 投射到脑干。总而言之，这些数据表明了 脑源性神经营养因子作为兴奋性突触传递的调节剂 NTS内的化学传入神经元和二级中继神经元。鉴于…… 越来越多的证据表明脑源性神经营养因子在长时程突触中起关键作用 在大脑其他部位的可塑性，我们假设BDNF扮演着类似的角色 在孤束核化学传入突触中的作用。此外，根据我们的初步调查， 数据，我们假设NTS中的BDNF信号是由 氧的可获得性，从而导致化学反射的紊乱 慢性、持续性或间歇性低氧后的功能。因此， 拟议的研究旨在进一步定义BDNF的表达机制 并在出生后在化学传入神经元中释放，包括 体内和体外慢性持续性和间歇性低氧。在……里面 此外，我们还将研究BDNF在NTS发育过程中的突触后效应 神经元，包括递质受体表达的调节和树突状细胞 成长。此外，我们还将确定BDNF在功能可塑性中的作用 通过分析外周化学反射在转基因动物体内的发育 脑源性神经营养因子信号在出生后选择性中断的小鼠。通过 在定义PG和NTS中依赖于活性的塑性的机制时， 拟议的研究可能有助于揭示相关的细胞和分子机制 对低通气量和呼吸暂停的认识和改进管理 新生儿和婴儿的综合征，以及促进 成人阻塞性睡眠呼吸暂停和慢性阻塞性睡眠呼吸暂停患者的心肺控制改变 阻塞性肺病。此外，希望澄清 该系统的开发将反过来创造一个神经营养因子的模型 适用于整个神经系统的功能。

DESCRIPTION (provided by applicant): The aim of the proposed research is to define the role of Brain-Derived Neurotrophic Factor (BDNF) in activity-dependent plasticity in the developing chemoafferent pathway. Chemoafferent neurons are the link between peripheral chemoreceptors and the brainstem, and thereby play a pivotal role in cardiorespiratory homeostasis. At birth, chemoafferent reflexes are immature, and perturbations in oxygen availability can derange postnatal development of cardiorespiratory responses to acute hypoxia. However, mechanisms that underlie chemoreflex development and plasticity are largely undefined. This proposal is based on our recent discoveries that 1) Chemoafferent neurons in the newborn rat nodose-petrosal ganglion complex (NPG) express high levels of BDNF messenger RNA and protein, 2) BDNF protein is released from NPG neurons in response to patterned electrical stimulation in vitro, and 3) BDNF acutely inhibits glutamatergic AMPA receptors in second-order relay neurons in the nucleus tractus solitarius (nTS), the primary site of chemoafferent projections to the brainstem. Together, these data indicate a new role for BDNF as a modulator of excitatory synaptic transmission between primary chemoafferent neurons and second-order relay neurons in nTS. In view of increasing evidence that BDNF plays a critical role in long-term synaptic plasticity elsewhere in the brain, we hypothesize that BDNF plays a similar role at chemoafferent synapses in nTS. Moreover, based on our preliminary data, we hypothesize that BDNF signaling in nTS is regulated by changes in oxygen availability, and thereby contributes to derangements in chemoreflex function following chronic sustained or intermittent hypoxia. Therefore, the proposed research is designed to further define mechanisms of BDNF expression and release in chemoafferent neurons after birth, including the role of chronic sustained and intermittent hypoxia, in vivo and in vitro. In addition, we will characterize postsynaptic effects of BDNF on developing nTS neurons, including regulation of transmitter receptor expression and dendritic growth. Moreover, we will determine the role of BDNF in functional plasticity in vivo by analyzing development of peripheral chemoreflexes in transgenic mice in which BDNF signaling is disrupted selectively after birth. By defining mechanisms of activity-dependent plasticity in the PG and nTS, the proposed research may shed light on cellular and molecular mechanisms relevant to understanding and improved management of hypoventilation and apnea syndromes in neonates and infants, as well as mechanisms that contribute to altered cardiorespiratory control in adult obstructive sleep apnea and chronic obstructive pulmonary disease. Moreover, it is hoped that elucidating development of this system will, in turn, create a model of neurotrophin function applicable to the nervous system as a whole.