The Role of the Locus Coeruleus-Norepinephrine System in Flexible Decision-Making

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PROJECT SUMMARY/ABSTRACT Flexible decision making, in which individuals adapt their decision strategies, is a hallmark of human cognition. In particular, humans are able to shift between impulsive (fast, but inaccurate) and deliberative (accurate, but slow) strategies based on situational demands. Observations that this capacity is disrupted in neuropsychiatric disorders motivates the study of the neural mechanisms that regulate this type of flexible decision making. Previous studies suggest that locus-coeruleus norepinephrine (LC-NE) system may play a key role in flexibly switching between impulsive and deliberative decision making. However, we still lack a precise, circuit-level understanding of how the NE-LC system alters information processing in downstream targets to effect decision making. To address this gap in knowledge, we propose to utilize a rat model of flexible decision making to identify how NE-LC alters information processing during flexible decision making. Specifically, we aim to test predictions of a leading computational model, the adaptive gain theory model, which posits that high NE tone alters the gain of information processing in neurons of the cerebral cortex leading to impulsive decision making. Our proposal is separated into three aims. In the first aim, we will use cellular resolution imaging of LC-NE activity and NE release to determine whether changes in NE signaling correlate with changes in impulsivity as organisms respond to environmental demands. In the second aim, we will manipulate the activity of NE neurons in the LC using chemogenics and evaluate whether artificial activation and silencing of LC-NE system is sufficient to drive changes in impulsivity. In the third aim, we will use simultaneous imaging of neuronal dynamics and NE release to determine whether NE tone predicts the strength of cortical responses to decision-related sensory inputs. If successful, this project will achieve a circuit-level understanding of how NE signaling regulates flexible discission making. This improved understanding will provide a critical advance in identifying the neural mechanism of decision making and will provide a foundation for understanding how these mechanisms may be affected in neuropsychiatric disorders.