Functional Properties of Neuronal Nicotinic Receptors

描述(申请人提供)：烟碱型乙酰胆碱受体(NAChRs)位于大脑的许多区域，已知参与学习、记忆和视觉等关键任务。外源性应用乙酰胆碱(ACh)或尼古丁激活nAChRs可产生不同的功能反应。突触前nAChRs介导多种神经递质的释放增强。突触后nAChRs的激活可产生足以引起神经元动作电位的兴奋性反应。尽管这些发现非常重要，但对内源性释放的乙酰胆碱的功能影响以及视觉系统和基底节中重要的生理通路的胆碱能调节知之甚少。这一建议的主要目的是加强我们对内源性ACh激活尼古丁受体对脑片内特定部位突触传递的整体影响的理解。我们方法的主要特点包括使用具有良好特征的模型系统(腹侧膝状体和外侧螺旋状核)，具有强大的突触前和突触后尼古丁反应，以及我们能够研究电刺激内源性ACh释放所导致的尼古丁调制的生理意义。NAChR亚型在这些大脑区域的回路中的定位将使我们能够构建它们在处理传入信息和投射神经元输出中所扮演的角色的模型。功能研究将使用脑片中单个神经元活动的全细胞膜片钳电生理记录进行。将结合谷氨酸和GABA能传递来评估烟碱受体和毒碱受体上胆碱能传递的影响。我们将研究烟碱受体激活的短期和长期影响，并研究胆碱能调节的发育调节。 在美国，吸烟每年导致40多万人过早死亡。尼古丁是烟草中的成瘾原理，在中枢nAChRs中起作用，造成依赖。烟碱受体也参与增强认知和视觉注意，在几种神经退行性疾病中，烟碱受体数量减少。它们在视觉系统和基底节中密度很高，但对它们在这些系统中的功能作用知之甚少。这个项目将扩大我们对这些受体的作用的了解。

DESCRIPTION (provided by applicant): Nicotinic acetylcholine receptors (nAChRs) are located in many brain regions and are known to participate in critical tasks including learning, memory, and vision. Activation of nAChRs by exogenous application of acetylcholine (ACh) or nicotine produces diverse functional responses. Presynaptic nAChRs mediate enhanced release of several neurotransmitters. Activation of postsynaptic nAChRs produces excitatory responses that can be sufficient to elicit action potentials in neurons. Although these findings are critically important, relatively little is known concerning the functional effects of endogenously released acetylcholine and the cholinergic modulation of physiologically important pathways in the visual system and basal ganglia. The major goal of this proposal is to enhance our understanding of the overall impact of nicotinic receptor activation by endogenous ACh on synaptic transmission at defined sites within brain slices. Key features of our approach include the use of well-characterized model systems (ventral lateral geniculate and lateral spiriform nucleus) with robust presynaptic and postsynaptic nicotinic responses, and our ability to examine the physiological significance of nicotinic modulation resulting from the electrically stimulated release of endogenous ACh. Localization of nAChR subtypes within the circuitry of these brain regions will allow us to construct a model for their roles in the processing of incoming information and the output of projection neurons. Functional studies will be done using whole cell patch-clamp electrophysiological recordings of single neuron activity in brain slices. The impact of cholinergic transmission at both nicotinic and muscarinic receptors will be evaluated in relationship to glutamatergic and GABAergic transmission. We will examine both short term and long term effects of activation of nicotinic receptors, and study developmental regulation of cholinergic modulation. Cigarette smoking causes over 400,000 premature deaths per year in the USA. Nicotine is the addictive principle in tobacco, and acts at central nAChRs to create dependence. Nicotinic receptors also mediate enhanced cognition and visual attention, and are reduced in number in several neurodegenerative diseases. They are present at high densities in the visual system and basal ganglia, but their functional roles in these systems are poorly understood. This project will expand our knowledge of the roles of these receptors.