Decoding Locus Coeruleus Neural Circuits and Signaling In Negative Affect

Abstract: Acute stress and threat produce physiological anxiety to facilitate planning and allow for
organisms to tune behavior for exploration of the environment, thus serving to promote hyperarousal,
anxiogenic-like behavior and avoidance (i.e. aversive responses). Stress is also directly linked to numerous
mental health diseases and these disorders currently affect ~30% of the US population. The locus coeruleus
(LC) noradrenergic (NE) system and its related GPCRs have been implicated in numerous stress-related
affective disorders including, anxiety, hyperarousal and negative affect. The LC-NE system is a critical
component for integration of stress-induced avoidance. Our recent evidence and the literature suggests that
LC-NE neurons exhibit more molecular, cellular, circuit and functional diversity (i.e. are polymorphic) than
previously thought. It is hypothesized that through these various modes of LC-NE operation, output to
downstream circuits, GPCRs, and behavior are tightly regulated. We propose to isolate and define the unique
molecular-cellular, physiological and neuropharmacological mechanisms regulating LC-NE function in
response to salient stimuli and stress. Recent evidence from our group and others also suggests that LC-NE
soperational modes are tightly regulated by a local GABAergic neuron population alongside a host of unknown
molecular and neuropharmacological components. In the next five years we will focus on a comprehensive
alignment of molecular-cellular, neuropharmacological, imaging, and behavioral approaches to better define
converging characteristics of the LC-NE system in avoidance, arousal and “anxiety-like” responses. Here we
use a multi-disciplinary approach that includes molecular-cellular approaches, neuropharmacology, NE-
biosensors, optogenetics, and in vivo 2p/1p calcium imaging approaches to define the specific cells, circuits,
and receptors within the LC system that mediate stress-induced behavioral avoidance and “anxiety-like”
behaviors. Our central hypothesis to be tested is that the LC-NE system and it’s distinct neurons have diverse
stress/stimuli-responsive molecular and physiological modes in vivo. We predict that LC-NE neuron activity - in
part - determines release NE in BLA and HPC; and unique LC cell types, and discrete neuropeptide/GPCRs,
tightly regulate LC-NE operation and behavioral avoidance. We propose 3 aims: 1) To determine how stress-
induced activation of LC-NE neurons alters encoding and norepinephrine release in the hippocampus and BLA
2) To define the dynamic role of peri-LC GABAergic neurons in the control of LC-NE neuron activity during
acute stress and avoidance. 3) To utilize molecular profiling alongside electrophysiology, sensors, and
neuropharmacology, to decipher genetically defined LC cell types impacted by stress. This confluence of
molecular-cellular, neuropharmacological, physiological and behavioral analysis of LC-NE function will provide
a valuable framework for understanding the complexity of noradrenergic function at the intersection of negative
affect and stress.

Grant Number: 5R01MH112355-10
NIH Institute/Center: NIH
Principal Investigator: Michael Bruchas