Unravelling the role of locus coeruleus Neuropeptide Y in stress-induced anxiety

Abstract

The pathological anxiety that underlies anxiety disorders is commonly triggered by stress. Upon encountering a stressor, the locus coeruleus-norepinephrine system (LC-NE system) is activated. However, excessive activation of the LC-NE system results in a maladaptive stress response. The endogenous systems regulating LC-NE activity, thus modulating the stress response, are currently unknown. Neuropeptide Y (NPY) is the most abundant peptide of the mammalian brain, and global administration of the peptide has an anxiolytic, i.e., stress-reducing, effect. A population of NPY-expressing (NPY+) neurons that surround and terminate within the LC are thus perfectly positioned to modulate LC-NE system activity. Using chemogenetic tools in a mouse model, we tested whether peri-LC NPY function is causally linked to foot shock stress–induced anxiety. Contrary to our expectations, increasing peri-LC NPY+ activity had no effect on anxiety-like behaviour in the elevated plus maze and open field test after stress. Decreasing peri-LC NPY function did have an anxiolytic effect in the EPM in unstressed animals, however, this effect did not remain after stress. Additionally, after stress, mice with elevated NPY+ activity had a larger intake of palatable food than animals with decreased NPY+ activity and control animals. Altogether, our results indicate that the effect of NPY on the LC-NE system and stress-induced anxiety is not as one-sided as the anxiolytic effect attributed to the peptide in previous literature. These findings contribute to further elucidating the nuanced role of NPY in the response of the LC-NE system to stress, which brings us one step closer to understanding and treating stress and anxiety disorders.