The link between neural circuits and behavioral performance has been an enduring mystery in neuroscience. A fundamental observation of both neurons and behavior has been that they both exhibit variability. This variability can manifest on a variety of time scales, from minutes to hours to days, and across many spatial scales, from local populations of neurons to the whole brain. One important missing feature in our understanding of cognition and behavior, that may explain some of the apparent variability, is a lack of insight into the brain’s internal cognitive state while performing any task. The coordination among neurons across the brain is critical to achieving any internal cognitive state, such as attention or arousal. This coordination has been extensively studied at the level of field potentials, but relatively rarely in populations of single neurons. Furthermore, because the coordination among neurons in a pair of brain areas may relate to the action of distant brain circuits, teasing apart the fundamental neural circuits that give rise to coordinated neural activity, and the link in turn to behavior, has been challenging. At the same time, pharmacological approaches targeted at neuromodulatory systems have proved a powerful, if coarse, means to influence behavior and treat disease. We will study neural coordination across scales, from field potentials and neurovascular signals measured at the scalp, to populations of spiking neurons in cortex, to individual neurons in a deep brain structure that modulates cortical activity. Simultaneously, we will measure behavior on cognitive and perceptual tasks as well as the pupil, which we have shown in previous work exhibit slow fluctuations on the time scale of minutes to hours. Our strategy is to identify how neuronal coordination of cortical neurons is indicative of internal cognitive state and neuromodulatory input, and can be modified to alter cognition and behavior. We will do this in a computational framework that links the variability among neurons in a population to internal states of the brain and in turn to behavior. In our first specific aim, we will test the hypothesis that field potentials and neurovascular signals at the scalp are directly linked to neuronal coordination in prefrontal cortex and behavior. In the second aim, we will test the hypothesis that neuronal coordination in prefrontal cortex as well as systemic indicators of arousal are influenced by norepinephrine efflux from the locus coeruleus. Finally, in the third aim, we will test the hypothesis that direct intervention in this circuit by microstimulating the locus coeruleus can alter neuronal coordination in cortex and in turn influence behavior. The overall result of this study will be to establish a direct link between coordinated activity in the cortex, neuromodulatory drive, and cognition and behavior. This will aid in developing treatments for myriad neurological disorders that involve altered states of arousal or changes in norepinephrine drive, and establish a framework for understanding the link between large-scale measures of neuronal coordination (like oscillations in field potentials at the scalp) and neuronal circuit mechanisms.

PROJECT NARRATIVE (RELEVANCE) Perception, cognition and action require the coordination of neurons spanning the entire brain, including the cortex and subcortical regions, and numerous brain disorders involve some form of impairment of that communication and coordination. To better diagnose and treat brain disorders, it is crucial to understand the basic mechanisms by which neural circuits interact across the brain and how those interactions give rise to cognitive processes and behavior. The proposed research investigates how cortical and subcortical circuits give rise to the state of arousal, and how intervention in those circuits can modulate that internal state and influence behavior.