NICOTINIC MECHANISMS IN SENSORY NEOCORTEX

描述(摘自申请者的摘要)：尼古丁是世界上使用最广泛的成瘾物质。尼古丁滥用，以吸烟的形式，在发达国家导致许多慢性病和近20%的死亡。尼古丁成瘾的机制得到了很好的研究。然而，尼古丁具有与其身体上瘾特性不同的行为影响，这也是尼古丁受欢迎的原因。据说尼古丁可以提升情绪和唤醒，减轻疼痛，改善注意力、工作记忆和感官信息的快速处理。尼古丁产生这些影响的机制还知之甚少。大脑中的尼古丁受体最近被认为与一种家族形式的癫痫和其他神经和精神疾病有关，具有尼古丁活性的药物可能在治疗阿尔茨海默氏症和帕金森氏病方面具有潜力。这项提议的目的是研究尼古丁对前脑，特别是感觉新皮质影响的细胞机制。新皮质及其联系占人脑体积的80%，对正常的感觉、运动、记忆和认知是必不可少的。尼古丁对新大脑皮层的直接作用可能是该药物对行为产生不同影响的主要原因。尼古丁与神经元型烟碱型乙酰胆碱受体结合：在新皮质，神经元型烟碱型乙酰胆碱受体大量存在于皮质的输入突触(即丘脑皮质)，以及一些抑制性神经元和锥体神经元上。本研究的目的是验证一种假说，即尼古丁和特定的神经元烟碱型乙酰胆碱受体的激活改变了新大脑皮层输入突触的强度和动力学，调节了突触抑制和抑制性神经元，从而系统地改变了新大脑皮层转换丘脑感觉信息的方式。实验将在大鼠的体感系统中进行体外和体内实验。一个正式的计算模型将被用来理解尼古丁对神经元和突触的影响如何导致新皮质网络复杂但可预测的变化，从而改变感觉。

DESCRIPTION (Adapted From The Applicant's Abstract): Nicotine is the world's most widely used addictive substance. Nicotine abuse, in the form of smoking, causes many chronic diseases and almost 20% of the deaths in developed countries. The mechanisms of nicotine's addictiveness are well studied. However nicotine has behavioral effects distinct from its physically addictive qualities, and these contribute to its popularity. Nicotine is said to elevate mood and arousal, reduce pain, and improve attention, working memory, and the rapid processing of sensory information. The mechanisms for these effects of nicotine are very poorly understood. Nicotine receptor in the brain have recently been implicated in a familial form of epilepsy and other neurological and psychiatric disorders, and drugs with nicotinic activity may have potential in the treatment of Alzheimer's and Parkinson's disease. The goal of this proposal is to study the cellular mechanisms of nicotine's effects on the forebrain, in particular the sensory neocortex. Neocortex and its connections comprise 80% of human brain volume, and it is essential for normal sensation, movement, memory and cognition. Nicotine's direct action on neocortex probably plays a major role in the drug's diverse effects on behavior. Nicotine binds to neuronal nicotinic acetylcholine receptors : in neocortex neuronal nicotinic acetylcholine receptors are abundant on the input (I.e. Thalamocortical) synapses to the cortex, and on some inhibitory and pyramidal neurons. The aims of this investigation are to test the hypothesis that nicotine, and the activation of specific neuronal nicotinic acetylcholine receptors, alters the strength and dynamics of input synapsis to the neocortex, modulates synaptic inhibition and inhibitory neurons, and thus systematically changes the way the neocortex transforms sensory information from the thalamus. Experiments will be performed in vitro and in vivo in the somatosensory system of rats. A formal computational model will be used to understand how nicotine's effects on neurons and synapses lead to complex but predictable alterations of the neocortical network, and thus alter sensation.