MODULATION OF PHRENIC MOTORNEURON ACTIVITY

刺激颈动脉窦神经(CSN)可导致长时间的 通风促进(LTF)，可持续数分钟至数小时。LTF是 主要表现为膈神经幅度的增加，而不是 呼吸频率，这表明这是由于 吸气性突触驱动的大小。LTF它被认为是 代表呼吸马达回路中的一种形式的“记忆” 据信能在睡眠中间歇性低氧期间稳定通气性。 来自中缝暗带的5-羟色胺能球脊髓神经元 由CSN传入激活，并被认为对 LTF的诱导。中缝神经元具有内源性起搏活性和 以非常低的速度射击。除了5-羟色胺，这些神经元中的许多都会释放 促甲状腺激素释放激素和P物质的共同递质 (SP)以依赖于频率的方式。据推测，拉斐尔 表达共递质的神经元在以下情况下起到“纯”5-羟色胺能神经元的作用 内源性活跃，共递质只有在 主动刺激(如在颈动脉窦神经刺激期间)。在 膈运动核5-羟色胺有两种拮抗作用：增加 在与激活5-羟色胺-2A或5-羟色胺相关的突触后兴奋性 HT-2C受体亚型与神经递质释放的减少 下行运动前呼吸输入与激活 5-羟色胺-1A或5-羟色胺-1B受体亚型。作为这些对抗的结果 动作，5-羟色胺对大鼠脑缺血的影响很小 吸气性突触驱动，提示LTF不能由5-羟色胺介导 独自一人。这个应用程序的基本前提是联合发布 TRH和SP的结合是诱导LTF所必需的，它们共同作用于 传送器通过改变对抗行为之间的平衡来发挥作用 5-羟色胺-2A/2C和5-羟色胺-1A/1B受体 吸气驱动力。根据TRH和SP的初步数据和在 神经系统的其他部分，我们认为LTF的诱导 依赖5-羟色胺介导的突触前抑制的拮抗作用 TRH激活的1A/1B受体与突触后N-甲基-D-天冬氨酸的调节 SP检测天冬氨酸受体。TRH和SP的这些行动将导致 吸气性突触驱动力增强。TRH和SP都已链接到 蛋白激酶C磷酸化途径的激活，我们还 提出LTF的时间进程反映了这一秒的寿命 信使级联。为了验证这些假设，我们将使用两个脊髓 幼年大鼠肺组织切片的制备及运动前呼吸标记 新生大鼠细胞培养中的神经元。中提出的实验 这一应用程序将提供对调制的新见解 在膈运动核内的神经传递，并建立 呼吸马达回路中“记忆”的细胞基础。

Stimulation of the carotid sinus nerve (CSN) can induce a long term facilitation (LTF) of ventilation which may last minutes to hours. LTF is primarily manifest by an increase in phrenic nerve amplitude rather than respiratory frequency, suggesting it is due to an increase in the magnitude of the inspiratory synaptic drive. LTF it is thought to represent a form of "memory" within the respiratory motor circuit and is believed to stabilize ventilation during episodic hypoxia in sleep. Serotonergic (5-HT) bulbospinal neurons from the raphe obscurus are activated by CSN afferents and are thought to be responsible for the induction of LTF. Raphe neurons possess endogenous pacemaker activity and fire at very low rates. In addition to 5-HT, many of these neurons release the co-transmitters thyrotropin-releasing hormone (TRH) and substance P (SP) in a frequency dependent manner. It has been postulated that raphe neurons expressing co-transmitters act as "pure" serotonergic neurons when endogenously active and that co-transmitters are only released during active stimulation (eg. during carotid sinus nerve stimulation). Within the phrenic motor nucleus 5-HT has two antagonistic effects: an increase in postsynaptic excitability associated with activation of a 5-HT-2A or 5- HT-2C receptor subtype and a reduction in neurotransmitter release from descending premotor respiratory inputs linked to the activation of either a 5-HT-1A or 5-HT-1B receptor subtype. As a result of these antagonistic actions, 5-HT has only a minimal effect on the magnitude of the inspiratory synaptic drive, suggesting that LTF cannot be mediated by 5-HT alone. The fundamental premise of this application is that the co-release of TRH and SP is required for the induction of LTF and that these co- transmitters act by shifting the balance between the antagonistic actions of 5-HT-2A/2C and 5-HT-1A/1B receptors in favor of an increased inspiratory drive. Based on preliminary data and actions of TRH and SP in other parts of the nervous system, we propose that the induction of LTF depends upon the antagonism of presynaptic inhibition mediated by 5-HT- 1A/1B receptors by TRH and the modulation of postsynaptic N-methyl-D- aspartate receptors by SP. These actions of TRH and SP would result in an increased inspiratory synaptic drive. Both TRH and SP have been linked to the activation of a protein kinase C phosphorylation pathway and we also propose that the time course of LTF reflects the lifetime of this second messenger cascade. To test these hypotheses we will use both a spinal cord slice preparation from juvenile rats and labeled premotor respiratory neurons in cell culture from neonatal rats. The experiments proposed in this application will provide new insight into the modulation of neurotransmission within the phrenic motor nucleus and establish a cellular basis for "memory" within the respiratory motor circuit.