BDNF in plasticity of chemoafferent pathway

BDNF 在化学传入途径可塑性中的作用

• 批准号: 6564825
• 负责人: David M. Katz
• 金额: $ 26.7万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564825
• 关键词: AMPA receptors; afferent nerve; age difference; brain derived neurotrophic factor; carotid body; chemoreceptors; developmental neurobiology; ganglions; hypoxia; laboratory mouse; laboratory rat; neural plasticity; neurochemistry; neuroregulation; oxygen tension; respiratory hypoxia; solitary tract nucleus

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.

描述（由申请人提供）： 拟议研究的目的是定义脑衍生的作用 神经营养因子（BDNF）在发育过程中的活动依赖性可塑性 化学传入途径。化学传入神经元是周围神经元之间的联系 化学感受器和脑干，从而在 心肺稳态。出生时，化学传入反射尚未成熟， 氧气供应的扰动可能会扰乱出生后的发育 急性缺氧的心肺反应。然而，机制 化学弹性发育和可塑性的基础在很大程度上是不确定的。这 该提议基于我们最近的发现：1）化学传入神经元 新生大鼠结节岩神经节复合体 (NPG) 表达高水平 BDNF信使RNA和蛋白质，2）BDNF蛋白质从NPG神经元释放 体外对图案化电刺激的反应，以及 3) BDNF 急性 抑制二级中继神经元中的谷氨酸能 AMPA 受体 孤束核（nTS），化学传入的主要部位 投射到脑干。这些数据共同表明了新的角色 BDNF 作为初级突触间兴奋性突触传递的调节剂 nTS 中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 BDNF 在长期突触中发挥着关键作用 由于大脑其他部位的可塑性，我们假设 BDNF 起着类似的作用 nTS 中化学传入突触的作用。此外，根据我们的初步 根据数据，我们假设 nTS 中的 BDNF 信号传导受到以下变化的调节： 氧气可用性，从而导致化学反射紊乱 慢性持续或间歇性缺氧后的功能。因此， 拟议的研究旨在进一步明确 BDNF 表达机制 和出生后化学传入神经元中的释放，包括 体内和体外慢性持续和间歇性缺氧。在 此外，我们将描述 BDNF 对 nTS 发展的突触后效应 神经元，包括递质受体表达和树突的调节 生长。此外，我们将确定 BDNF 在功能可塑性中的作用 通过分析转基因中外周化学反射的发育来进行体内研究 BDNF 信号在出生后被选择性破坏的小鼠。经过 PG 和 nTS 中活动依赖性可塑性的定义机制， 拟议的研究可能有助于揭示相关的细胞和分子机制 了解并改善通气不足和呼吸暂停的管理 新生儿和婴儿的综合症，以及导致的机制 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心肺控制的改变 阻塞性肺部疾病。此外，希望能够阐明 该系统的开发反过来将创建神经营养蛋白模型 适用于整个神经系统的功能。