Functional Properties of Neuronal Nicotinic Receptors

描述（由申请人提供）：尼古丁乙酰胆碱受体（nachr）位于许多大脑区域，已知参与包括学习，记忆和视觉在内的关键任务。外源乙酰胆碱（ACh）或尼古丁激活nachr可产生多种功能反应。突触前nachr介导几种神经递质的增强释放。突触后nachr的激活产生兴奋性反应，足以引发神经元的动作电位。尽管这些发现是至关重要的，但相对而言，关于内源性释放的乙酰胆碱的功能作用以及视觉系统和基底神经节中重要生理通路的胆碱能调节，我们所知甚少。本提案的主要目标是增强我们对内源性乙酰胆碱对脑切片内特定部位突触传递的尼古丁受体激活的总体影响的理解。该方法的主要特点包括使用具有良好特征的模型系统（腹侧外侧膝状核和外侧棘状核），具有强大的突触前和突触后尼古丁反应，并且我们能够检查由电刺激释放内源性乙酰胆碱引起的尼古丁调节的生理意义。nAChR亚型在这些脑区电路中的定位将使我们能够构建一个模型，以了解它们在处理输入信息和输出投射神经元中的作用。功能研究将使用全细胞膜片钳电生理记录在脑切片单个神经元的活动。在烟碱受体和毒蕈碱受体中胆碱能传递的影响将与谷氨酸能和gaba能传递的关系进行评估。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。

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.