Cholinergic Mechanisms in Spatial Attention

空间注意力的胆碱能机制

• 批准号: 8261679
• 负责人: Anita A Disney
• 金额: $ 8.75万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261679
• 关键词: Acetylcholine; Achievement; Address; Affect; Agonist; Anatomy; Area; Arousal; Attention; Attention deficit hyperactivity disorder; Attentional deficit; Autistic Disorder; Award; Axon; Basic Science; Behavioral; Behavioral Model; Biological Sciences; Caliber; Cells; Chemicals; Cholinergic Receptors; Clinical; Cognition; Cognitive; Cognitive deficits; Complement; Data; Dementia; Disease; Electric Stimulation; Employee Strikes; Environment; Etiology; Event; Failure; Fostering; Foundations; Functional disorder; Genetic; Goals; Human; Impairment; Institutes; Intervention; Learning; Measures; Mediating; Mental disorders; Mentors; Methods; Modeling; Mood Disorders; Mus; Neuromodulator; Neurons; Neurosciences; Perception; Pharmacology; Phase; Photic Stimulation; Physiological; Physiology; Positioning Attribute; Primates; Process; Protocols documentation; Receptor Cell; Research; Resolution; Rodent; Role; Schizophrenia; Sensory Process; Specificity; Structure; System; Techniques; Technology; Testing; Time; Tissues; Training; Work; area MT; area V1; awake; basal forebrain; base; career; cell type; cholinergic; clinical practice; cognitive function; executive function; gamma-Aminobutyric Acid; in vivo; information processing; innovation; insight; mouse model; neocortical; neuropathology; nonhuman primate; planetary Atmosphere; public health relevance; receptor; receptor function; research study; selective attention; sensory cortex; skills; stimulus processing; stimulus sensitivity

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.

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信息处理和认知方面的失败至关重要，而信息处理和认知方面的失败是许多神经病理学的一个方面。认知和注意力缺陷可见于许多精神疾病，包括精神分裂症、情绪障碍和不同病因的痴呆症。对啮齿动物的研究表明，乙酰胆碱 (ACh) 可以调节注意力，而胆碱能功能障碍与许多认知神经病理学有关。然而，当人们试图将胆碱能系统建模为空间精确注意力效应的基础时，例如在人类和非人类灵长类动物 (NHP) 中得到的证明，问题就出现了。具体来说，可由乙酰胆碱独立调节的最小组织块可能太大，无法实现地形上精确的处理增强，而这似乎是灵长类动物关注的基础。因此，虽然啮齿动物研究对我们对胆碱能过程的理解做出了很大贡献，但研究注意力和唤醒在行为任务中更容易分离的物种的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，还必须彻底了解皮质回路中的胆碱能作用。目前，我们的进展受到明显缺乏有关胆碱能系统的结构和功能的电路级数据以及对乙酰胆碱释放的行为驱动因素的有限了解的阻碍。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）使用解剖技术提供有关注意力调节的皮质区域中乙酰胆碱受体定位的定量数据（两个阶段），2）使用光遗传学技术检查自然 ACh 释放对体内局部皮质回路（指导阶段）感觉输入处理的影响，以及 3) 使用高分辨率化学传感来确定感觉中 ACh 释放的空间分布a) 光遗传学控制下麻醉的啮齿动物（指导阶段）和 b) 在注意力任务期间清醒、有行为的 NHP 的皮层（两个阶段）。为了实现这些目标，我需要进一步的培训，以补充我在解剖学、生理学和药理学方面现有的技能。具体来说，我需要学习如何对从事探索注意力功能任务的 NHP 进行训练和记录。当我开发 NHP 体内化学传感协议时，我还需要一个受保护的创新环境来工作。索尔克学院是实现这些目标的理想培训环境。我的导师约翰·雷诺兹 (John Reynolds) 博士是世界上最重要的 NHP 注意力生理学专家之一，他拥有一个充满活力的实验室，创新是研究方法的正常组成部分。索尔克研究所还因促进生物科学创新方法的协作氛围而闻名。在这个令人兴奋的环境中度过短暂的一段时间后，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质过程中的作用。胆碱能功能障碍与许多神经病理学中的认知缺陷密切相关。包括精神分裂症、情绪障碍、注意力缺陷多动障碍、自闭症和各种病因的痴呆症。了解乙酰胆碱如何促进正常认知和知觉将有助于阐明这些疾病中所见缺陷的哪些方面与胆碱能功能丧失有关，从而有助于提出临床干预的途径。