Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety-like behavior.

Jordan G Mccall,Garret D Stuber,Edward R Siuda,Lamley A Lawson,Zoe A Mcelligott,Dionnet L Bhatti,Michael R Bruchas

doi:10.7554/elife.18247

Jordan G Mccall, Garret D Stuber + Show 5 more

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https://doi.org/10.7554/elife.18247

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Abstract

Increased tonic activity of locus coeruleus noradrenergic (LC-NE) neurons induces anxiety-like and aversive behavior. While some information is known about the afferent circuitry that endogenously drives this neural activity and behavior, the downstream receptors and anatomical projections that mediate these acute risk aversive behavioral states via the LC-NE system remain unresolved. Here we use a combination of retrograde tracing, fast-scan cyclic voltammetry, electrophysiology, and in vivo optogenetics with localized pharmacology to identify neural substrates downstream of increased tonic LC-NE activity in mice. We demonstrate that photostimulation of LC-NE fibers in the BLA evokes norepinephrine release in the basolateral amygdala (BLA), alters BLA neuronal activity, conditions aversion, and increases anxiety-like behavior. Additionally, we report that β-adrenergic receptors mediate the anxiety-like phenotype of increased NE release in the BLA. These studies begin to illustrate how the complex efferent system of the LC-NE system selectively mediates behavior through distinct receptor and projection-selective mechanisms.

Highlights

The locus coeruleus noradrenergic system (LC-NE) comprises a widespread projection network throughout the central nervous system capable of modulating a diverse range of behaviors including arousal, learning, pain modulation, and stress-induced negative affective states (Berridge and Waterhouse, 2003; Sara, 2009)
Our previous work demonstrated that increased tonic LC-NE activity induces anxiety-like and aversive behavioral responses (McCall et al, 2015; Siuda et al, 2015a), we sought to test whether these same behaviors can be generated by stimulating LC-NE fibers at localized projections in the basolateral amygdala (BLA)
To assess whether the cFos+ BLA neurons resulting from LC-NE terminal activation were biased toward a particular class of BLA projection neurons we repeated the experiment with the retrograde tracer Cholera toxin subunit B (CTB) injected into BLA projection regions. These immunohistochemistry studies reveal that the cFos present following LC-NE terminal activation in the BLA, overlaps significantly more with ventral hippocampus (vHPC)- and central amygdala (CeA)-targeted compared to nucleus accumbens (NAc)-targeted CTB in the BLA (Figure 4C–G; Figure 4—figure supplement 1F–H). These results suggest that LC-NE terminals in the BLA preferentially activate vHPC- and CeA- projecting BLA neurons thought to be involved in modulating negative valence and affective behaviors

Summary

Introduction

The locus coeruleus noradrenergic system (LC-NE) comprises a widespread projection network throughout the central nervous system capable of modulating a diverse range of behaviors including arousal, learning, pain modulation, and stress-induced negative affective states (Berridge and Waterhouse, 2003; Sara, 2009). Understanding the neural circuit basis for how this nearly ubiquitous neuromodulatory network exerts influence on negative affect is a critical step towards therapeutically targeting stress-induced neuropsychiatric disorders (Schwarz and Luo, 2015; Schwarz et al, 2015; Reyes et al, 2015; McCall et al, 2015; Arnsten et al, 2015; Kebschull et al, 2016). One particular efferent projection from the LC is to the basolateral amygdala (BLA).

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