Dissecting the role of locus coeruleus circuitry in anxiety-like behaviors

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): 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.