Diversity of Nicotinic Synapses in Sympathetic Ganglia

该项目的长期目标是确定神经元烟碱受体的细胞表达多样性如何影响哺乳动物交感神经节的突触功能。这项研究将在乌克兰基辅进行，作为NIH拨款#R01 NS21065的延伸。该项目的中心假设认为，作为调节快速兴奋性突触后电位持续时间的一种手段，服务于不同效应模式的神经元表达了不同的尼古丁受体亚基组合，从而控制神经节前活动的突触放大。提出的实验将使用电生理学来评估大鼠交感和副交感神经元中的尼古丁受体。具体目的1是确定在交感和副交感神经元的功能亚群上区分尼古丁受体的动力学特征。这些数据的综合结果将使用模拟自主神经节突触活动的计算模型进行评估。具体目标2是通过系统表征新型开放通道阻滞剂和抗血清对烟碱受体α亚基的作用，扩展血管舒缩交感神经元突触受体的药理学特征。目标是为设计对血管舒缩交感神经元和其他自主神经模式具有高度选择性的新化合物建立一个合理的基础。这些化合物可用于进一步剖析不同自主细胞群的作用，并可能具有临床应用价值。具体目的3是确定-班加罗毒素敏感的烟碱受体是否参与交感神经节的快速突触传递。这将测试最近对鸟类自主神经节的研究是否也适用于已知表达α -7烟碱亚基的哺乳动物神经元。解决每个具体目标所带来的问题，将对我们理解神经节整合产生根本性的影响。自主神经节中的尼古丁突触对公共卫生很重要，因为它们对于因衰老和神经系统疾病而中断的自主行为（例如心血管对运动的适应、生殖、体温调节和对压力的防御适应）至关重要。

The long-term goal of this project is to determine how diversity in the cellular expression of neuronal nicotinic receptors contributes to synaptic function in mammalian sympathetic ganglia. This research will be done in Kiev, Ukraine as an extension of NIH grant #R01 NS21065. The project's central hypothesis states that neurons serving different effector modalities express distinct combinations of nicotinic receptor subunits, as a means for regulating the duration of fast excitatory postsynaptic potentials and thereby controlling the synaptic amplification of preganglionic activity. The proposed experiments will use electrophysiology to assess nicotinic receptors in rat sympathetic and parasympathetic neurons. Specific aim 1 is to identify kinetic features that distinguish nicotinic receptors on functional subsets of sympathetic and parasympathetic neurons. The integrative consequences of these data will then be evaluated using computational models that simulate synaptic activity in autonomic ganglia. Specific aim 2 is to extend the pharmacological profile of synaptic receptors on vasomotor sympathetic neurons by systematic characterization of novel open-channel blockers and antisera against alpha-subunits of nicotinic receptors. The goal is to develop a rational basis for designing new compounds that would be highly selective for vasomotor sympathetic neurons and other autonomic modalities. Such compounds could be used to further dissect the roles of different autonomic cell groups and may have clinical applications. Specific aim 3 is to determine whether alpha-bungarotoxin-sensitive nicotinic receptors contribute to fast synaptic transmission in sympathetic ganglia. This will test whether recent work on avian autonomic ganglia also holds true in mammalian neurons that are known to express the alpha-7 nicotinic subunit. Resolving the issues posed by each specific aim would have fundamental implications for our understanding of ganglionic integration. Nicotinic synapses in autonomic ganglia are important for public health because they are essential for autonomic behaviors that are disrupted by aging and neurological disease (e.g. cardiovascular adaptation to exercise, reproduction, thermoregulation and defensive adaptation to stress).