Anatomy and neuropharmacology of top-down control

我们如何自愿地关注某个特定的位置，在拥挤的展示中搜索特定的形式，或者自动关注意外响声的来源？这些问题是研究提案的核心。已经有大量研究表明不同的刺激和行为环境如何影响注意力的分配，但我们仍然离从机制上正确理解支配这些能力的神经元和化学过程还有很长的路要走。理解这些原则很重要，因为注意力对于所有更高的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。注意力控制缺陷会导致严重的行为和认知障碍，例如，患有前额叶皮质病变、阿尔茨海默病或注意缺陷多动障碍的患者就会出现这种缺陷。尽管注意力在几乎所有高级认知功能中都扮演着重要的角色，但我们仍然缺乏对大脑不同部分在这一复杂的选择过程中如何相互作用的正确理解，以及大脑不同部分是否在不同种类的注意力中扮演着特定的角色。此外，我们对负责微调这些相互作用的具体化学成分知之甚少。这项拟议的研究将调查大脑中负责调节不同形式注意力的指挥中心，以及基于注意力的物体选择。我们将在经过训练的猕猴身上研究这些过程，同时我们可逆地灭活大脑的选定部分，这些部分被认为是调节上述过程的部分。归根结底，所有的注意力能力都依赖于在正确的时间和正确的位置获得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所对接的感受器而扮演不同的角色(类比是适合不同锁的钥匙)，并且可能在不同的大脑区域扮演不同的角色。我最近改进了一项现有的技术，现在可以在动物执行要求注意力的任务时，以微创和空间高度受控的方式干扰特定大脑化学物质的活动。因此，当我们操纵大脑化学物质的可用性时，我们可以监控那些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特定任务表现中的作用。了解这些细节将极大地提高我们对注意机制的理解，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.