Spatiotemporal dynamics of locus coeruleus norepinephrine release in a learned behavior

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Project Summary The locus coeruleus (LC), a small brainstem nucleus, is the primary source of the neuromodulator norepinephrine (NE) in the brain. The LC receives input from widespread brain regions and projects throughout the forebrain, brainstem, cerebellum, and spinal cord. LC neurons release NE tonically to regulate baseline arousal, and phasically in the context of a variety of sensory-motor and behavioral functions. However, despite its brain-wide effects, the modes of NE action during behavior are poorly understood. One prevailing theory suggests that NE acts to control the gain of output circuits, thereby modulating task performance by enhancing or dampening responses to stimuli. However, another theory suggests that NE release in cortical output regions acts to reset network activity, enabling task-switching or learning of new rules. Neither of these theories adequately explains the many observed roles of the LC-NE system in learning and behavior. I propose a new hypothesis of LC function, that spatiotemporal dynamics and modular circuits enable dissociated roles for the LC in behavioral execution and reinforcement learning during learned behaviors. Here, I propose to examine multiple features of this hypothesis using innovative approaches combining advanced 2-photon imaging of NE release in target regions and optogenetic manipulation of LC neurons and axons. In Aim 1, I will manipulate the activity of LC neurons in mice performing an instrumentally conditioned task in which they detect auditory tones of variable intensity, execute a response, and receive positive or negative reinforcement. I will examine the hypothesis that LC-NE activity pre-lever press facilitates task execution on high uncertainty trials, and LC-NE activity post-reinforcement facilitates task optimization. In Aim 2, I will assess the anatomical modularity of LC projections to motor cortex (MC) or prefrontal cortex (PFC), and monitor the fast kinetics of NE release in MC and PFC to examine the hypothesis that NE is preferentially released in MC pre-task execution and released globally post-negative reinforcement. In Aim 3, I will examine the hypothesis that differential integration of NE release in MC versus globally facilitates task execution and learning, respectively. I will measure the impact on behavior of silencing NE activity in these cortical targets using optogenetic silencing of NE axons. These data will provide essential information for a new theory of the role of LC in cognition, and provide a mechanistic basis for understanding the role of LC-NE dysfunction in a range of neuropsychiatric disorders. Through the completion of this project, I will become an expert in applying a wide range of systems neuroscience techniques, practice project management and mentoring students, improve my communication skills through publications, posters, and presentations, and interact with and learn from my scientific mentors as well as the community outside my lab and MIT. This training will enable me to achieve my goal of becoming and independent scientist.