Chemoreflex plasticity and BDNF

描述(申请人摘要)：拟议研究的目的是确定脑源性神经营养因子(BDNF)在 发育中的化学传入通路中的活性依赖可塑性。 化学传入神经元是连接外周化学感受器和 脑干，从而在心肺动态平衡中发挥关键作用。在… 出生、化学传入反射是不成熟的，氧气中的扰动 可获得性会扰乱心肺反应的出生后发展 到急性缺氧。然而，化学反射发育和基础的机制 可塑性在很大程度上是不确定的。这项建议是基于我们最近 新生大鼠结石区化学传入神经元的发现 神经节复合体(NPG)高水平表达BDNF信使RNA和蛋白质， 2)脑源性神经营养因子蛋白从NPG神经元释放 3)脑源性神经营养因子显著抑制谷氨酸能 孤束核二级中继神经元的AMPA受体 (NTS)，化学传入投射至脑干的主要部位。 总之，这些数据表明了BDNF作为兴奋性调节器的新角色。 初级化学传入神经元与二级神经元之间的突触传递 孤束核内的中继神经元。鉴于越来越多的证据表明BDNF在 我们推测，在大脑其他部位长期突触可塑性中所起的作用 BDNF在NTS的化学传入突触中起着类似的作用。此外， 根据我们的初步数据，我们假设NTS中的BDNF信号是 受氧气可获得性变化的调节，从而有助于 慢性阻塞性肺疾病后化学反射功能的紊乱 间歇性缺氧。因此，拟议的研究旨在进一步 明确脑源性神经营养因子在化学传入神经元中的表达和释放机制 分娩，包括慢性、持续性和间歇性缺氧的作用 活的和体外的。此外，我们还将研究突触后效应。 脑源性神经营养因子对NTS神经元发育的影响，包括递质受体的调节 表达和树突生长。此外，我们还将确定BDNF的作用 从外周发育分析体内功能可塑性 脑源性神经营养因子信号受阻转基因小鼠的化学反射 有选择地在出生后。通过定义活动依赖的机制 在PG和NTS中的可塑性，拟议的研究可能会对细胞 和分子机制相关的理解和改进管理 新生儿和婴儿的呼吸不足和呼吸暂停综合征，以及 成人心肺控制改变的机制 阻塞性睡眠呼吸暂停和慢性阻塞性肺病。此外，它还 希望阐明这一系统的发展将反过来创造一个 神经营养因子功能模型适用于整个神经系统。

DESCRIPTION (Applicant's abstract): 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 vivoand 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.