# Spatiotemporal dynamics of locus coeruleus norepinephrine release in a learned behavior

> **NIH NIH F31** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2022 · $46,752

## Abstract

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. ...

## Key facts

- **NIH application ID:** 10463122
- **Project number:** 1F31MH129112-01A1
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Gabrielle Drummond
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-03-15 → 2024-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463122

## Citation

> US National Institutes of Health, RePORTER application 10463122, Spatiotemporal dynamics of locus coeruleus norepinephrine release in a learned behavior (1F31MH129112-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10463122. Licensed CC0.

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