Cholinergic mechanisms in visual spatial attention

描述（由申请人提供）：啮齿动物研究表明，乙酰胆碱（ACh）是定向注意力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中已经证明了这一点。例如，能够被乙酰胆碱独立调节的最小的皮质组织可能太大，以至于不能在地形上精确地增强处理，而处理似乎是注意力机制的基础。研究胆碱能神经调节在一个物种中的注意力和唤醒是更容易分离的行为任务是必不可少的，然而，这样的举动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在高等哺乳动物。这项工作将通过以下方式解决这一空白：1）使用猕猴的解剖学技术，提供已知参与注意或受注意调节的皮质区域中ACh受体定位的大规模定量数据（例如V4、MT和LIP），（二）在啮齿动物中使用光遗传学技术来检查自然ACh释放对视觉通路的各个阶段的视觉刺激处理的影响体内，和3）使用高分辨率化学传感技术来确定在注意力任务期间a）在光遗传学控制下的麻醉啮齿动物和B）清醒行为的非人灵长类动物的视觉皮层中乙酰胆碱释放的空间和时间分布。 公共卫生相关性：我们将使用尖端技术来阐明乙酰胆碱在视觉和视觉注意力中的功能。胆碱能调节异常与包括阿尔茨海默病（AD）在内的年龄相关性痴呆以及相关的视力和选择性视觉注意力障碍密切相关。了解乙酰胆碱如何辅助正常的认知和感觉处理将有助于阐明AD中所见的缺陷的哪些方面与胆碱能功能的丧失有关，并且还将有助于了解相关的注意力缺陷，包括与精神分裂症，忽视，灭绝和注意力缺陷多动障碍（ADHD）相关的注意力衰竭。

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).