Previous studies indicated that the locus coeruleus-norepinephrine (LC-NE) system regulates responsiveness to stimuli, and the capacity to process information during stress. Our recent findings have provided several new insights into the role of the LC-NE system in vigilance and attention, some of which suggest important modifications of our previous ideas and those of others. Specifically, we have found that variations in LC activity in the behaving monkey correspond to marked changes in attentiveness. These results lead us to postulate a specific role for the LC in attentional processing. We propose that the LC regulates the stability/lability aspect of attention, denoted here as attentional lability. This dimension of attention rages from focused/selective attention (relatively non-distractible) to scanning/labile attention (easily distractible). The present proposal seeks to extend our recent observations to test this hypothesis and define LC's role in attention. The following studies are proposed: (1) We will record monkey LC neural activity during an attentional disengagement task, designed to measure the ability to change the focus of attention. This will allow analysis of LC's involvement in attentional lability. (2) Local microinjections of selective pharmacologic agents into the LC will be used to transiently and specifically inactivate or activate LC neurons during the attentional detachment task or a vigilance task. The effects of these manipulations on fluctuations in attention (measured by visual fixation performance) will be determined. Effects will also be discerned on behavioral responses in the two tasks. These experiments will test LC's causal role in focused and labile attention, and determine whether different levels of LC activity are sufficient or necessary for such attentional processes. (3) Environmental or cognitive stressors will be administered to determine their effect on LC activity in the behaving primate, and to determine the role of LC in mediating the effects of stress on attentional performance. (4) We will locally microinfuse pharmacologic agents into the LC to control impulse activity during task reversal and test the hypothesis that altered LC activity plays a critical role in the acquisition of stimulus significance. Thus, these experiments will extend our studies to examine the role of the LC in a specific type of learning. The proposed studies will examine in detail both the temporal association (via LC recordings) and functional dependency (via LC manipulations) between the brain noradrenergic LC system and attentional performance during normative as well as during stressful conditions. They will also be the first to examine the role of the primate LC in learning, and investigate the LC as a possible neural substrate for the linkage between attention and learning.

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Aston-Jones, Gary; Cohen, Jonathan D (2005) Adaptive gain and the role of the locus coeruleus-norepinephrine system in optimal performance. J Comp Neurol 493:99-110
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