SUMMARY Norepinephrine (NE) is a neurotransmitter released by a small number of neurons in the locus coeruleus (LC), with extensive innervation of the neocortex. Prior work in humans and other mammals led to the hypothesis that LC-NE neurons modulate multiple forms of decision making. This proposal aims to test this overall hypothesis by studying LC-NE neurons in mice performing multiple decision-making tasks. The behaviors to be studied include two types of flexible decision making: how to learn from reinforcement over tens of seconds to minutes in a dynamic choice task and how to rapidly change a motor program based on sensory feedback over hundreds of milliseconds to seconds. The goal of the project is to link action potentials from identified LC-NE neurons to both types of behavior, and determine how large populations of neurons in multiple cortical areas are modulated by NE input to achieve flexible behavior. Three aims test three hypothesis that address different mechanistic questions about the functions of norepinephrine in neocortex: 1) LC-NE neurons modulate reinforcement learning during a dynamic choice task; 2) norepinephrine regulates sensory-driven motor program switching; 3) LC-NE modulates orofacial and prefrontal cortex for effective reinforcement learning and motor program switching. Measurements and manipulation (activation and inactivation) of the activity of NE neurons and their targets in neocortex, during well-controlled behavioral tasks in mice, will enable testing these three hypotheses. Understanding the spatial and temporal dynamics of NE release in cortex will be necessary for understanding flexible decision making in general, and disorders of attention, arousal, and mood that rely on its function.

NARRATIVE Flexible decision making requires learning from experience over multiple timescales: reinforcement can drive future behavior over tens of seconds to minutes, while sensory feedback can drive changes in ongoing movements over hundreds of milliseconds. Norepinephrine is a neuromodulator hypothesized to adjust activity throughout the neocortex to learn from experience over multiple timescales. The work in this proposal tests this hypothesis using multiple techniques to understand the functions of norepinephrine-releasing neurons in locus coeruleus and their targets in neocortex, using dynamic behaviors in mice.