The locus coeruleus- norepinephrine(LC-NE) system has long been implicated in arousal and alertness. This implies a relatively non-specific role for LC in cognitive function. However, the investigators' recent recordings from LC in the behaving monkey suggest a revision of this view. They have found that LC neurons respond to task-relevant stimuli in a selective, stimulus-specific manner, and that these cells exhibit two modes of activity corresponding to levels of performance in a visual discrimination task. Based on these findings, the investigators hypothesize that the LC helps to regulate the balance between selective vs. flexible behavior. They now have developed a computational model of LC and its influence on performance in cognitive tasks, which delineates mechanisms for such a function. This model predicts that the mode of LC activity influences the state of cortical function to promote either selective responding to task relevant stimuli or responsivity to a broader range of environmental stimuli, each of which may have adaptive value for behavior. Other of the investigators' results indicate that electronic coupling may be an important factor regulating the mode of LC activity. This proposal seeks to test these hypotheses, specifically in the context of tasks that involve visual spatial attention. The following studies are proposed: (1) The investigators will integrate our model of LC function into a model they have already developed of performance in a spatially-cued reaction time SCRT) task. (2) The investigators will record from monkey LC neurons during performance of the SCRT task, and analyze the relationship between LC activity and task performance, to test predictions made by the computational model. (3) The investigators will make local microinjections of selective pharmacologic agents into the monkey LC to transiently manipulate activity of, and electrotonic coupling among, LC neurons. This will test the causal role of LC in task performance, as well as the specific hypothesis that coupling among LC neurons is one means of regulating the mode of LC activity and the corresponding pattern of behavioral performance. (4) They will record visually responsive neurons in parietal cortex while recording and manipulating LC activity, to test mechanistic hypotheses concerning LC-NE influences on cortical function and task performance. The proposed program of research integrates computational modeling, neurophysiology, and behavioral studies to understand the functions of the LC-NE system, its interaction with cortical systems, and its regulation of the balance between task- directed behavior vs. responsivity to unexpected environmental stimuli.
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