PROJECT SUMMARY/ABSTRACT When faced with environmental uncertainty, optimum top-down control facilitates attention shifts and improves performance. Several functionally distinct stages of attention are well stablished in psychology. Recent studies have associated some of these cognitive constructs with specific brain structures. However, less is known about the neurobiological mechanisms that transform contextual information into distinct components of attention control such as selection of relevant sensory inputs, perceptual decision and motor action responsible for adaptive behaviors in humans. Lack of appropriate attention control leads to various attention disorders such as attention-deficit/hyperactivity disorder (ADHD). Our long-term goal is to dissociate distinct neuronal processes underlying adaptive behavior, particularly neuromodulatory contributions to cognitive control within interacting brain structures. Neuronal activity in the anterior cingulate cortex (ACC) and dorso-lateral prefrontal cortex (dLPFC), two crucial brain areas involved in cognitive control are strongly regulated by norepinephrine (NE) neuromodulation from the locus coeruleus (LC) in the brainstem. The LC-NE neuromodulatory system projects throughout the cerebral cortex, and has been linked to sensory processing regulation, arousal and attention. Our preliminary data in monkeys show that spatially selective attention strongly modulates spiking dynamics of NE neurons in the LC including an increased spiking to attended visual stimuli. Moreover, optogenetic activation of these LC-NE neurons enhanced attentional performance. Our central hypothesis is that: 1) the LC receives contextual information about behavioral performance from the ACC, and is activated with increased performance errors; 2) LC-NE neuromodulation differentially regulates neuronal activity in the ACC and dLPFC respectively to mediate motor selection, and sensory and perceptual decision selections of attention control. To test these hypotheses, we will isolate neurophysiological correlates of performance errors, and attentional shifts in sensory relevance, perceptual decision criterion and motor criterion within the LC, ACC and dLPFC in monkeys. We will optogenetically activate LC-NE neurons while simultaneously record from the ACC and dLPFC to test which aspects of LC-NE activity dynamics (tonic and stimulus-locked phasic burst spiking) causally regulate ACC and dLPFC to mediate distinct components of attention control. The results from this proposed study will provide a direct, detailed neurobiological understanding of specialized neuromodulatory contributions that transform contextual information into different stages of attention control in improving adaptive behavioral performance in humans. This will further expedite progress in better classification and identifying potential therapeutic targets for various attention disorders associated with functionally specific deficits.