Cholinergic Mechanisms in Spatial Attention

描述（由申请人提供）：研究感知和注意力的正常功能和机制对于识别和理解作为许多神经病理学方面的信息处理和认知故障至关重要。认知和注意力缺陷见于许多精神疾病，包括精神分裂症、情绪障碍和各种病因的痴呆症。啮齿类动物的研究表明，乙酰胆碱（ACh）介导的注意力，和胆碱能功能障碍是牵连在许多认知神经病理学。然而，当人们试图将胆碱能系统作为空间精确注意力效应的基础时，问题就出现了，比如在人类和非人类灵长类动物（NHP）中已经证明了这一点。具体来说，能够被乙酰胆碱独立调节的最小的组织可能太大，以至于不能在地形上精确地增强灵长类动物的注意力。因此，虽然啮齿类动物的研究对我们理解胆碱能过程做出了很大贡献，但在注意力和唤醒在行为任务中更加分离的物种中调查胆碱能功能是至关重要的。如果我们要建立推动临床实践创新所需的详细机制描述，还需要彻底了解皮质回路中的胆碱能作用。目前，我们的进展是阻碍了一个惊人的缺乏电路水平的数据有关的结构和功能的胆碱能系统和有限的理解ACh释放的行为驱动程序。我建议在该奖项的指导和独立阶段进行的工作将通过以下方式解决这些差距：1）使用解剖学技术提供关于ACh受体在受注意力调节的皮层区域定位的定量数据（两个阶段），2）使用光遗传学技术来检查自然ACh释放对体内局部皮层回路处理感觉输入的影响（指导阶段），和3）使用高分辨率化学传感来确定a）在光遗传学控制下的麻醉啮齿动物（指导阶段）和B）在注意力任务期间清醒的行为NHP（两个阶段）的感觉皮层中ACh释放的空间分布。为了实现这些目标，我需要进一步的培训，以补充我在解剖学，生理学和药理学方面的现有技能。具体来说，我需要学习如何训练和记录从事探测注意力功能任务的NHP。我还需要一个受保护的和创新的环境中工作，而我开发的协议，化学传感在体内的行为NHP。索尔克研究所是实现这些目标的理想培训环境。我的导师John Reynolds博士是世界上最重要的NHP注意力生理学专家之一，他有一个充满活力的实验室，在这个实验室里，创新是研究方法的正常组成部分。索尔克研究所还以促进生物科学创新方法的合作氛围而闻名。在这个令人兴奋的环境中度过一段短暂的时间后，我希望准备好开始独立的研究生涯，并将寻求神经科学领域的终身职位。 公共卫生相关性：我们将使用尖端技术来了解乙酰胆碱在感知和选择性注意的新皮层过程中的作用。胆碱能功能障碍与许多神经病理学中观察到的认知缺陷密切相关;包括精神分裂症、情绪障碍、注意缺陷多动障碍、自闭症和各种病因的痴呆。了解乙酰胆碱如何使正常的认知和知觉，将有助于阐明在这些疾病中看到的缺陷的哪些方面与胆碱能功能的丧失有关，从而有助于建议临床干预的途径。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: We will use cutting-edge technology to understand the role of acetylcholine in the neocortical processes underlying perception and selective attention. Cholinergic dysfunction is strongly implicated the cognitive deficits seen in many neuropathologies; including schizophrenia, mood disorders, attention deficit-hyperactivity disorder, autism and dementias of various etiology. Understanding how acetylcholine subserves normal cognition and perception will help elucidate which aspects of the deficits seen in these disorders are related to the loss of cholinergic function and can thus help to suggest avenues for clinical intervention.