Chemoreflex plasticity and BDNF

描述（申请人摘要）：拟议研究的目的是 定义脑源性神经营养因子（BDNF）在 活性依赖性可塑性在发展中的化学传入途径。 化学传入神经元是外周化学感受器和神经元之间的联系。 脑干，从而在心肺平衡中发挥关键作用。在 出生，化学传入反射不成熟，氧气扰动 可用性可扰乱出生后心肺反应的发育 急性缺氧然而，化学反射发展的基础机制和 可塑性在很大程度上是不确定的。这一建议是根据我们最近的 发现：1）新生大鼠结节-岩骨的化学传入神经元 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，以响应模式化的 3）BDNF急性抑制海马神经元的神经元兴奋性， 孤束核内二级中继神经元的AMPA受体 (nTS)化学传入投射到脑干的主要部位。 总之，这些数据表明BDNF作为兴奋性神经元的调节剂的新作用。 初级化学传入神经元和二级化学传入神经元之间的突触传递 nTS的中继神经元。鉴于越来越多的证据表明，BDNF在神经系统中起着关键的作用， 在大脑其他地方的长期突触可塑性中的作用，我们假设 BDNF在nTS的化学传入突触中起着类似的作用。此外，委员会认为， 基于我们的初步数据，我们假设nTS中的BDNF信号是 受氧气可用性变化的调节，从而有助于 慢性持续性或慢性炎症后化学反射功能紊乱 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， 出生，包括慢性持续性和间歇性缺氧的作用， 体内和体外。此外，我们将描述突触后效应， BDNF对发育中的nTS神经元的作用，包括对递质受体的调节 表达和树突状生长。此外，我们将确定BDNF的作用， 在功能可塑性在体内通过分析发展的周边 BDNF信号传导被破坏的转基因小鼠的化学反射 出生后的选择。通过定义活动依赖的机制， PG和nTS的可塑性，拟议的研究可能会揭示细胞 和分子机制相关的理解和改善管理 新生儿和婴儿的通气不足和呼吸暂停综合征，以及 导致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疾病。而且 希望阐明这一系统的发展，反过来， 神经营养素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.