Anatomy and neuropharmacology of top-down control

我们是如何主动地关注某个特定的位置，在拥挤的展示中寻找特定的形式，或者自动地关注一个意想不到的响亮声音的来源？这些问题是研究建议的核心。有大量的研究表明，不同的刺激和行为环境如何影响注意力的分配，但我们仍然有很长的路要走，从一个适当的机制理解的神经元和化学过程，管理这些能力。理解这些原则很重要，因为注意力对于所有高级认知功能都是必要的。它有助于感知，它确保我们有能力在当前环境下做出适当的反应，它对学习和记忆至关重要。注意力控制的缺陷导致大量的行为和认知缺陷，例如在患有前额叶皮层病变、阿尔茨海默病或注意力缺陷多动障碍的患者中所见。尽管注意力在几乎所有高级认知功能中都发挥着重要作用，但我们仍然缺乏正确的理解，大脑的不同部分在这个复杂的选择过程中如何相互作用，以及大脑的不同部分是否在不同类型的注意力中发挥特定的作用。此外，我们对负责这些相互作用的微调的特定化学成分知之甚少。拟议的研究将调查大脑中调解不同形式的注意力的指挥中心，以及基于注意力的物体选择。具体来说，它将研究当注意力自动被吸引到一个特定的位置时，不同的中枢如何影响感觉信息的处理（例如，当有人突然大叫），当注意力被自愿引导到场景的特定位置时（例如，当我们寻找车钥匙时），以及如何将关注的刺激灵活映射到特定的行为反应（例如，当我们饿了，我们伸手去拿那块巧克力，当我们已经吃了两个布丁时，我们可能会把它推开或包起来以备将来食用）。我们将在受过训练的猕猴中研究这些过程，同时我们将可逆性地选择大脑的某些部分，这些部分被认为是介导上述过程的。最终，所有的注意力能力都取决于在大脑中正确的时间和正确的位置拥有适量的特定大脑化学物质。虽然这听起来很简单，但大脑化学物质根据它们停靠的受体发挥不同的作用（类比将是适合不同锁的钥匙），并且可能在不同的大脑区域发挥不同的作用。我最近改进了一种现有的技术，现在可以在动物执行需要注意力的任务时，以微创和空间高度控制的方式干扰特定大脑化学物质的作用。因此，我们可以在控制大脑化学物质的可用性的同时，监测被认为与任务表现相关的神经元的活动。这将使我们能够确定特定化学物质在灵长类动物大脑中执行特定任务时的作用。了解这些细节将大大提高我们对注意力机制的理解，从而对注意力和行为障碍具有重要的临床意义。

How do we voluntarily attend to a certain location, search for a specific form in a crowed display, or automatically attend to the source of an unexpected loud sound? These questions lie at the heart of the research proposal. A plethora of studies exist which show how different stimuli and behavioral circumstances affect the allocation of attention, but we are nevertheless still a long way from a proper mechanistic understanding of the neuronal and chemical processes that govern these abilities. Understanding these principles is important since attention is necessary for all higher cognitive functions. It aids perception, it ensures we have the ability to make appropriate responses given the current circumstances, and it is crucial for learning and memory. Deficiencies in attentional control result in substantial behavioral and cognitive deficits, as seen in patients with prefrontal cortex lesions, Alzheimer disease or attention deficit hyperactivity disorder, for example. Despite the important role of attention in virtually all higher cognitive functions, we still lack a proper understanding how different parts of the brain interact during this complicated selection process, and whether different parts of the brain have specific roles in the different varieties of attention. Furthermore we know very little regarding the specific chemical components that are responsible for the fine tuning of these interactions. The proposed research will investigate the command centers in the brain that mediate different forms of attention, and attention based object selection. Specifically it will investigate how different centers influence the processing of sensory information when attention is drawn automatically to a specific location (e.g. when someone yells suddenly), when attention is directed voluntarily to a specific location of a scene (e.g. when we search for our car key), and how the flexible mapping of attended stimuli to specific behavioral responses is mediated (e.g. when we are hungry we reach out for the piece of chocolate, when we already had 2 puddings, we may push it away or wrap it for future consumption). We will study these processes in trained macaque monkeys, while we reversible inactivate selected parts of the brain, those parts which are presumed to mediate the above processes. Ultimately all the attentional abilities are dependent on having the right amount of specific brain chemicals available at the right time and right location in the brain. Although this sounds simple, brain chemicals play different roles depending on the receptor they dock to (the analogy would be the key that fits different locks), and may play different roles in different brain areas. I recently refined an existing technique that now allows to interfere with the action of specific brain chemicals in a minimally invasive and spatially highly controlled manner while animals perform attention demanding tasks. We can thus monitor the activity of neurons that are assumed to be relevant in task performance while we manipulate the availability of brain chemicals. This will allow us to determine the role of a specific chemical during specific task performance in the primate brain. Understanding these details will greatly improve our understanding of the mechanisms of attention and thus have important clinical implications for attentional and behavioral disorders.