Cholinergic Mechanisms in Spatial Attention

摘要 研究知觉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方面的失败，这是许多神经病理学的方面。 认知和注意力缺陷可见于许多精神疾病，包括精神分裂症、心境障碍 不同病因的障碍和痴呆。对啮齿动物的研究表明，乙酰胆碱(ACh)在 注意，胆碱能功能障碍与许多认知神经病理有关。问题就出现了， 然而，当一个人试图将胆碱能系统建模为空间精确注意效应的基础时 例如已经在人类和非人类灵长类动物(NHP)身上证明了这一点。具体来说，最小的一块 可由ACh独立调制的组织的大小可能太大而不能在地形上 灵长类动物注意的基础--加工的精确增强。因此，在啮齿动物研究的同时， 对我们理解胆碱能过程做出了很大贡献，研究了胆碱能功能 在行为任务中注意力和唤醒更容易分离的物种是必不可少的。也是必要的，如果 我们将建立推动临床实践创新所需的详细机制描述，这是一个 彻底了解大脑皮层环路中的胆碱能作用。目前，我们的进展受到一个 明显缺乏有关胆碱能系统结构和功能的电路级数据，并受到限制 了解ACH释放的行为驱动因素。我建议在被指导期间进行的工作 该奖项的独立阶段将通过1)使用解剖学技术来解决这些差距 注意力调节的皮层区域ACh受体定位的定量数据(两个阶段)，2)使用 光遗传学技术检测自然界ACh释放对感觉加工的影响 由活体局部皮质回路输入(指导阶段)，以及3)使用高分辨率化学传感来 测定麻醉啮齿动物a)感觉皮层ACh释放的空间分布 光遗传控制(指导阶段)和b)清醒的，在注意力任务中表现为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、生理学技能。 和药理学。具体地说，我需要学习如何从从事任务的NHP那里进行培训和记录 它探测了注意力的功能。我还需要一个受保护和创新的环境，以便在我发展的同时工作 NHP在体内进行化学传感的方案。索尔克学院是理想的培训环境 为了实现这些目标。约翰·雷诺兹博士，我的导师，是世界上最重要的 NHP中的注意力生理学，并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 生物科学中的方法。在这个激动人心的环境中度过一小段时间后，我希望能做好准备 开始独立的研究生涯，并将在神经科学领域寻求终身教职。

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.