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）： 这项研究的目的是确定脑源性的作用， 神经营养因子（BDNF）在发育中的活动依赖性可塑性 化学传入通路化学传入神经元是连接外周神经元 化学感受器和脑干，从而发挥关键作用， 心肺平衡出生时，化学传入反射还不成熟， 氧气供应的紊乱会扰乱出生后的发育， 对急性缺氧的心肺反应。然而， 化学感受器反射的发展和可塑性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）脑中的化学传入神经元 新生大鼠结节岩神经节复合体（NPG）表达高水平的 BDNF信使RNA和蛋白，2）BDNF蛋白从NPG神经元释放 在体外对模式电刺激的反应，和3）BDNF急性 抑制海马神经元中二级中继神经元的多巴胺能AMPA受体， 孤束核（nTS），化学传入的主要部位 投射到脑干总之，这些数据表明， 脑源性神经营养因子作为兴奋性突触传递的调节剂 nTS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在长期突触中起着关键作用， 在大脑其他地方的可塑性，我们假设BDNF发挥类似的作用， nTS中化学传入突触的作用。此外，根据我们初步的 数据，我们假设nTS中的BDNF信号转导受以下变化的调节： 氧的可用性，从而导致化学反射紊乱 慢性持续性或间歇性缺氧后的功能。因此 这项研究旨在进一步确定BDNF表达的机制， 出生后在化学传入神经元中的释放，包括 慢性持续性和间歇性缺氧，在体内和体外。在 此外，我们将描述BDNF对发育中的nTS的突触后作用 神经元，包括调节递质受体的表达和树突状细胞 增长此外，我们将确定BDNF在功能可塑性中的作用， 通过分析转基因小鼠外周化学反射的发展， 出生后BDNF信号被选择性破坏的小鼠。通过 定义PG和nTS中活动依赖性可塑性的机制， 拟议的研究可能会揭示相关的细胞和分子机制 了解和改善通气不足和呼吸暂停的管理 新生儿和婴儿的综合征，以及导致 成人阻塞性睡眠呼吸暂停综合征和慢性阻塞性睡眠呼吸暂停综合征患者的心肺控制改变 阻塞性肺病此外，希望阐明 这一系统的发展将反过来创造一个神经营养因子的模型， 它适用于整个神经系统。