Cholinergic mechanisms in visual spatial attention

描述(申请人提供)：对啮齿动物的研究表明，乙酰胆碱(ACh)是定向注意生物学基础的重要组成部分。然而，当一个人试图将胆碱能系统建模为空间和时间上精确的注意效应的基础时，问题就出现了，比如已经在人类和非人类灵长类动物中证明了这一点。例如，可以被ACh独立调制的最小的皮质组织可能太大，以至于不能在地形图上精确地增强处理，这似乎是注意力机制的基础。在一个注意和觉醒在行为任务中更容易分开的物种中，研究胆碱能神经调节是必不可少的，然而，由于关于高等哺乳动物胆碱能系统结构和功能的电路水平数据的惊人缺乏，这样的研究受到了阻碍。拟议的工作将通过以下方式解决这一差距：1)使用猕猴的解剖学技术来提供有关ACh受体在已知涉及注意力或受注意力调节的皮质区域(例如V4、MT和Lip)的大规模定量数据，2)使用啮齿动物的光遗传学技术来检查自然主义ACh释放对体内视觉通路不同阶段的视觉刺激处理的影响，3)使用高分辨率化学传感技术来确定a)在光遗传控制下麻醉的啮齿动物和b)在注意任务中清醒行为的非人类灵长类动物的视皮层中乙酰胆碱释放的空间和时间分布。 与公共健康相关：我们将使用尖端技术来阐明乙酰胆碱在视觉和视觉注意中的功能。胆碱能调节异常与老年性痴呆有关，包括阿尔茨海默病(AD)以及与之相关的视力障碍和选择性视觉注意。了解乙酰胆碱是如何促进正常的认知和感觉加工的，将有助于阐明AD患者的哪些方面的缺陷与胆碱能功能的丧失有关，也将有助于理解相关的注意力缺陷，包括与精神分裂症、忽视、消退和注意缺陷多动障碍(ADHD)有关的注意力障碍。

DESCRIPTION (provided by applicant): Studies in rodents have suggested that the acetylcholine (ACh) is an essential component of the biological basis for directed attention. Questions arise, however, when one tries to model the cholinergic system as the basis for spatially and temporally precise attentional effects such as have been demonstrated in human and non-human primates. For example the smallest piece of cortical 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 attentional mechanisms. Studying cholinergic neuromodulation in a species where attention and arousal are more easily separable in behavioral tasks is essential, however such a move is hampered by a striking lack of circuit-level data regarding the structure and function of the cholinergic system in higher mammals. The proposed work will address this gap by 1) using anatomical techniques in the macaque to provide large-scale quantitative data on ACh receptor localization in cortical areas known to be involved in or modulated by attention (e.g. V4, MT and LIP), 2) using optogenetic techniques in rodents to examine the effect that naturalistic ACh release has on the processing of a visual stimulus at various stages of the visual pathway in vivo, and 3) using a high-resolution chemical sensing technique to determine the spatial and temporal profile of acetylcholine release in the visual cortex of the a) anesthetized rodent under optogenetic control and of the b) awake-behaving nonhuman primate during an attention task. PUBLIC HEALTH RELEVANCE: We will use cutting-edge technology to elucidate the function of acetylcholine in vision and visual attention. Abnormal cholinergic modulation is strongly implicated in age-related dementias including Alzheimer's disease (AD) and associated failures of vision and selective visual attention. Understanding how acetylcholine subserves normal cognitive and sensory processing will help elucidate which aspects of the deficits seen in AD are related to loss of cholinergic function and will also aid in understanding related deficits of attention, including attentional failures associated with Schizophrenia, neglect, extinction and Attention-Deficit- Hyperactivity-Disorder (ADHD).