The locus coeruleus (LC) is the brainstem neuromodulatory nucleus responsible for most of the norepinephrine (NE) released in the brain. The LC has widespread projections throughout the forebrain. Indeed, this small nucleus innervates a greater variety of brain areas than any other single nucleus yet described. It is clear that the neuromodulatory effects of NE must have pervasive influences on cognitive function in humans. However, these influences are poorly understood, in part because of the challenge of linking disparate levels of description: low-level neuromodulatory effects and mental computations. Furthermore, recent theories about LC function are almost exclusively based on animal studies and computational modeling. In contrast, there have been very few empirical studies of LC-NE function in humans. This is not so surprising since the study of this system in humans poses considerable methodological challenges.
The major aim of the proposed research program is to enhance our understanding of the role of the LC-NE system in human cognition through the use of two cutting-edge methods: First, I intend to directly measure BOLD responses in the LC using a set of newly developed MRI methods for brainstem imaging. Second, I propose a number of psychopharmacological studies to directly manipulate LC-NE function and measure the corresponding effects on brain and behavior. These methods will allow me to address a wide range of questions—many of which have not been addressed in animal models—concerning the role of the LC-NE system in optimizing task performance in the context of uncertainty about the environment, performance errors, emotional stimuli, and other demanding situations. The proposed research will be critical in elucidating the role of LC-NE function in human attention and performance, and will have important implications for the study of clinical disorders associated with disturbed LC-NE function.
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