Cholinergic Mechanisms in Spatial Attention

摘要 研究感知和注意的正常功能和机制对于识别和 理解信息处理和认知的失败，这是许多神经病理学的一个方面。 认知和注意力缺陷见于许多精神疾病，包括精神分裂症，情绪， 各种病因的疾病和痴呆。啮齿动物研究表明，乙酰胆碱（ACh）介导 注意力和胆碱能功能障碍与许多认知神经病理学有关。问题出现了， 然而，当人们试图模拟胆碱能系统作为空间精确注意效应的基础时， 例如在人类和非人类灵长类动物（NHP）中已经证明的。确切地说，最小的一片 组织中可以被ACh独立调节的蛋白质可能太大， 灵长类动物注意力的基础--信息处理的精确增强。因此，虽然啮齿动物研究 对我们理解胆碱能过程做出了很大贡献，研究了 注意力和唤醒在行为任务中更容易分离的物种是必不可少的。也是必要的，如果 我们要建立详细的机械描述，以推动临床实践中的创新，是一个 深入了解皮层回路中的胆碱能作用。目前，我们的进展受到一个 关于胆碱能系统的结构和功能的回路水平数据的显著缺乏， 了解乙酰胆碱释放的行为驱动因素。我建议在辅导期间进行的工作 该奖项的独立阶段将通过以下方式解决这些差距：1）使用解剖技术， ACh受体定位的定量数据在皮质区调制的注意（两个阶段），2）使用 光遗传学技术来检查自然ACh释放对感觉神经元加工的影响。 通过体内局部皮层回路输入（指导阶段），以及3）使用高分辨率化学传感， 测定a）麻醉的啮齿动物的感觉皮层中ACh释放的空间分布， 光遗传学控制（指导阶段）和B）注意力任务期间清醒的行为NHP（两个阶段）。 为了实现这些目标，我需要进一步的培训，以补充我现有的解剖学，生理学， 和药理学。具体来说，我需要学习如何培训和记录从事任务的NHP 它探测注意力功能。我还需要一个受保护和创新的工作环境， 用于在行为NHP中进行体内化学感测的方案。索尔克学院是理想的培训环境 为了实现这些目标。我的导师约翰·雷诺兹博士是世界上最重要的 NHP的注意力生理学，并拥有一个充满活力的实验室，其中创新是方法的正常部分 去做研究索尔克研究所还以促进创新的合作氛围而闻名。 在生物科学的方法。在这个令人兴奋的环境中呆了一小段时间后，我希望能准备好 开始独立的研究生涯，并将寻求神经科学的终身职位。

Abstract Studying the normal functions and mechanisms of perception and attention is essential to identifying and understanding the failures in information processing and cognition that are aspects of many neuropathologies. Cognitive and attentional deficits are seen in a number of mental illnesses including schizophrenia, mood disorders and dementias of varying etiology. Studies in rodents suggest that acetylcholine (ACh) mediates attention, and cholinergic dysfunction is implicated in many cognitive neuropathologies. Questions arise, however, when one tries to model the cholinergic system as the basis for spatially precise attentional effects such as have been demonstrated in humans and non-human primates (NHPs). Specifically, the smallest piece of tissue which can be independently modulated by ACh may be too large to allow for the topographically precise enhancement of processing which appears to underlie attention in primates. Thus, while rodent studies have contributed much to our understanding of cholinergic processes, investigating cholinergic function in a species in which attention and arousal are more separable in behavioral tasks is essential. Also necessary, if we are to build the detailed mechanistic descriptions necessary to drive innovation in clinical practice, is a thorough understanding of cholinergic action in cortical circuits. Currently, our progress is hampered by a striking lack of circuit-level data regarding the structure and function of the cholinergic system and by a limited understanding of the behavioral drivers of ACh release. The work I propose to conduct during the mentored and independent phases of this award will address these gaps by 1) using anatomical techniques to provide quantitative data on ACh receptor localization in cortical areas modulated by attention (both phases), 2) using optogenetic techniques to examine the effect that naturalistic ACh release has on the processing of sensory input by a local cortical circuit in vivo (mentored phase), and 3) using high-resolution chemical sensing to determine the spatial profile of ACh release in the sensory cortex of a) the anesthetized rodent under optogenetic control (mentored phase) and b) the awake, behaving NHP during an attention task (both phases). To achieve these aims I need further training that will complement my existing skills in anatomy, physiology and pharmacology. Specifically, I need to learn how to train and record from NHPs that are engaged in tasks which probe attentional function. I also need a protected and innovative environment to work in while I develop protocols for chemical sensing in vivo in the behaving NHP. The Salk Institute is the ideal training environment for the achievement of these goals. Dr. John Reynolds, my mentor, is one of the world's foremost experts on the physiology of attention in NHPs and has a vibrant lab in which innovation is a normal part of the approach to research. The Salk Institute is also renowned for a collaborative atmosphere that fosters innovative approaches in the biological sciences. After a short period in this exciting environment, I expect to be ready to embark upon an independent research career and will seek a tenure-track position in Neuroscience.