Cholinergic mechanisms in visual spatial attention

描述（由申请人提供）：对啮齿动物的研究表明，乙酰胆碱（ACh）是定向注意的生物学基础的重要组成部分。然而，当人们试图将胆碱能系统作为空间和时间上精确的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身上已经得到了证明。例如，可以由乙酰胆碱独立调节的最小皮质组织可能太大，无法在地形上精确地增强处理，而这似乎是注意机制的基础。在行为任务中注意和觉醒更容易分离的物种中，研究胆碱能神经调节是必不可少的，然而，由于缺乏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，这一举动受到了阻碍。本研究将通过以下方法解决这一问题：1)利用猕猴的解剖学技术，提供已知参与或受注意力调节的皮质区域（如V4、MT和LIP）中乙酰胆酸受体定位的大规模定量数据；2)利用光遗传学技术，在啮齿动物中研究自然释放乙酰胆酸对体内视觉通路不同阶段视觉刺激处理的影响。3)利用高分辨率化学传感技术确定a)在光遗传控制下麻醉的啮齿动物和b)清醒行为的非人灵长类动物在注意力任务期间视觉皮层乙酰胆碱释放的时空分布。

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).