Anatomy and neuropharmacology of top-down control

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.

Neurons in a variety of different brain areas become active during attention demanding tasks, as demonstrated by a large number of single unit and fMRI studies. Despite this knowledge, little is known how these areas interact during specific attentional task components such as stimulus selection, working memory, stimulus identification, and response selection. It is also unresolved how inactivation of one area affects attentional processing in other areas. Finally, we do not know how the neuromodulator acetylcholine contributes to attentional selection at the neuronal level, despite knowing that its presence in frontal and parietal cortex is crucial for task performance under many attentional constraints. We will study the role of cortical areas 7a, LIP, and FEF in attentional selection, working memory, and response mapping, their interaction, and their influence on extrastriate area V4 through feedback connections under control conditions and when one of the parietal/frontal areas is reversibly inactivated. This will be done while monkeys perform a task that taxes bottom-up, top-down attention, working memory, and cue dependent response selection. We will also investigate the contribution of different cholinergic receptor mechanisms to the above task components. We will compare attentional signals at the single unit level in the above areas as a function of attentional task component and drug application. Moreover we will determine how neuronal interactions (synchrony, field coherence) within and between areas are affected by the inactivation and cholinergic manipulations. We will map behavioral sensitivity to neuronal sensitivity, and determine how these depend on experimental procedures. The results will yield important insights regarding the contributions of higher cortical areas to specific attentional task components. Moreover it will determine how acetylcholine contributes to these components and which receptor mechanisms mediate their effects.