Noradrenergic modulation of emotional arousal and learning

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Project Summary An animal’s level of arousal dramatically influences its ability to filter, classify and associate stimuli in the environment with outcomes. These processes are necessary for an animal to rapidly evaluate dangers and rewards, and the cues that predict them. The assignment of appetitive or aversive value to a stimulus has been studied extensively and is well-understood to involve the amygdala. However, there is little known about how arousal affects emotional learning and behavior. This problem is of critical relevance because individuals with anxiety, addiction, depression, schizophrenia, and attention deficit disorder specifically exhibit impaired arousal as well as disrupted emotional processing. This proposal addresses several important, outstanding questions regarding the neural substrates of arousal, emotional learning and behavior. The locus coeruleus (LC) mediates arousal and has connections with the basolateral amygdala (BLA), but it remains unknown how the LC dynamically modulates neural activity within the BLA to cause changes in emotional learning and behavior. I intend to characterize how LC signaling shapes single-cell and ensemble representations of emotional valence and arousal in BLA, and use this information to probe the efficacy of potential interventions. My proposal has three aims that use state-of-the-art behavioral, molecular/genetic, cellular imaging, and computational techniques. In Aim 1, I utilize a novel, semi-naturalistic, dual-valence behavioral assay to study emotional learning and behavior in combination with two-photon imaging in mice to investigate how manipulations of emotional valence and arousal modulate neural representations in BLA. In Aim 2, I combine optogenetics and imaging to manipulate neural activity in LC while simultaneously measuring the effects on neural representations within the BLA and animal behavior. In Aim 3, I examine natural activity patterns of the LC as an animal transitions between different arousal levels. I will then construct a closed loop behavioral paradigm that decodes arousal levels from the LC neural activity to trigger presentations of CSs and USs to examine whether spontaneous fluctuations in LC activity can be harnessed to reprogram the BLA and its learned stimulus-outcome associations. Because neuromodulatory systems are well conserved, this effort will uncover mechanisms of neuromodulation that are likely similar in other species. My K01 training plan benefits from a team of co-mentors and advisors with extensive, proven expertise in computational approaches for describing neural dynamics, cutting-edge imaging, optogenetics, and brain- machine technologies, and understanding of psychiatric conditions. Additionally, I will complete coursework to enhance my training in contemporary perspectives on brain function, including courses on neural networks and graphical models. I will present data to computational neuroscientists at Columbia’s Center for Theoretical Neuroscience as well as to psychiatrists at the New York State Psychiatric Institute. The scientific and career training detailed in this grant will enable me to secure a tenure-track position at an academic research institution.