The overall goal of this research is to better understand the neurobiological basis of anxiety and other stress- induced behavioral disorders. This research focuses on the locus coeruleus noradrenergic (LC-NE) system, a major neurotransmitter system in the mammalian brain, and seeks to understand the circuit- and cellular-level mechanisms for increased tonic activity in the LC-NE system and how these changes in firing patterns contribute to stress-induced behaviors. LC-NE neurons exhibit three distinct activation profiles: low tonic, high tonic, and phasic activity, believed to function differently in determining behavioral flexibility in response to various environmental challenges. Stress and stress-related neuropeptide release (such as corticotrophin- releasing factor) is thought to shift LC activity towards a high tonic mode of firing while simultaneously decreasing phasic firing events, while endogenous opioid transmission is thought to return LC tonic firing to baseline. However, the receptor systems and specific circuitry that underlie these changes in activity and their behavioral implications are not known. Accordingly, the proposed research will use pharmacological, optogenetic, and electrophysiological techniques to determine the role of this high tonic activity in mediating anxiety-like and aversive behaviors.
The first aim of this proposal is to determine the sufficiency and necessity of the LC-NE system in driving these negative affective behaviors and will identify the downstream adrenergic receptor systems involved.
The second aim will determine how specific cells in the central amygdala (CeA) containing endogenous corticotrophin-releasing factor control this neuronal activity and the subsequent implications on behavior. The proposed experiments will be the first to specifically probe the endogenous LC- NE system and its CeA neuropeptidergic afferent inputs in models of stress-induced anxiety-like behaviors aimed at deciphering the underlying circuit dynamics that mediate these important behavioral responses. Results from these experiments will provide a basic understanding of how endogenous neuropeptide release modulates LC-NE neuronal activity and how these changes in activity contribute to anxiety-like behavioral phenotypes. Understanding the basic function of this brain system will be critical for effective pharmaceutical and behavioral therapies targeting anxiety and other neuropsychiatric disorders such as stress-induced anxiety and posttraumatic stress disorder.

Public Health Relevance

Anxiety affects nearly 20% of the United States population and has detrimental implications for both human health and the economy. Norepinephrine cells in the brain help maintain appropriate arousal and attention, and are essential to normal brain function. The goal of this research is to understand how these cells function in producing and protecting against anxiety.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31MH101956-01
Application #
8591594
Study Section
Special Emphasis Panel (ZRG1-F02A-J (20))
Program Officer
Rosemond, Erica K
Project Start
2013-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$28,498
Indirect Cost
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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