Cholinergic Mechanisms in Spatial Attention

空间注意力的胆碱能机制

• 批准号: 8092799
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8092799
• 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; 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）：研究正常的功能和感知机制对于识别和理解信息处理和认知的失败是许多神经病理学方面的失败至关重要的。认知和注意力缺陷在许多精神疾病，包括精神分裂症，情绪障碍和痴呆症的痴呆症中都存在。啮齿动物的研究表明，乙酰胆碱（ACH）介导了注意力，胆碱能功能障碍与许多认知神经病理学有关。但是，当人们试图对胆碱能系统建模为空间精确的注意效果的基础时，就会出现问题。具体而言，可以通过ACH独立调节的最小的组织可能太大，无法允许在灵长类动物中注意的构图精确的加工上的地形精确增强。因此，尽管啮齿动物的研究为我们对胆碱能过程的理解做出了很大的贡献，但在行为任务中注意力和唤醒更加可分离的物种中研究胆碱能功能是必不可少的。同样，如果我们要构建在临床实践中推动创新所必需的详细机械描述，那就是对皮质回路中胆碱能作用的彻底理解。目前，由于缺乏有关胆碱能系统的结构和功能以及对ACH释放行为驱动因素的有限理解，我们的进度受到了阻碍。我建议在该奖项的指导和独立阶段进行的工作将通过1）解决这些空白，以1）使用解剖技术来提供有关ACH受体定位的定量数据，该数据是由注意力（两者阶段）调节的皮质区域中的ACH受体定位，2）使用光遗传学技术来检查自然式ACH对当地的ACH的释放（Vivivive insportion of Seprion and satepordional Citie conteming coption inspecored inseperion inspecion inseperion and votive）的效果（确定A）在光遗传控制下（指导阶段）和b）在注意任务（两个阶段）中表现出NHP的ACH释放的空间曲线。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，生理和药理学方面的现有技能。具体来说，我需要学习如何从从事探测注意功能的任务的NHP训练和记录。我还需要一个受保护和创新的环境才能进行工作，同时在行为NHP中开发用于体内化学传感的协议。 Salk Institute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专家之一，在NHPS中关注的生理学，并拥有一个充满活力的实验室，其中创新是研究方法的正常组成部分。 Salk Institute还以一种协作氛围而闻名，该氛围促进了生物科学中创新的方法。在这种令人兴奋的环境中短暂的一段时间之后，我希望准备好开始独立的研究职业，并将在神经科学领域寻求终身任职地位。 公共卫生相关性：我们将使用尖端技术来了解乙酰胆碱在新皮质过程中的作用和选择性关注。胆碱能功能障碍强烈暗示着许多神经病理学中看到的认知缺陷。包括精神分裂症，情绪障碍，注意力缺陷性 - 性质障碍，自闭症和各种病因学的痴呆症。了解乙酰胆碱如何在正常的认知和感知下辅助有助于阐明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，因此可以帮助提出临床干预的途径。