Neuropeptide Y neurons of the locus coeruleus inhibit noradrenergic system activity to reduce anxiety

Abstract / Summary Adaptive responses to challenging environments depend on optimal function of the locus coeruleus (LC), the brain’s main source of noradrenaline and primary mediator of the initial stress response. Built-in systems that exert regulatory control over the LC are largely unidentified. A good candidate system is neuropeptide Y (NPY), which is traditionally linked to anxiety-relief. Currently, the endogenous source of NPY to the LC, and how NPY-expressing neurons modulate the noradrenergic system to regulate anxiety remain unclear. We here identify, in mice, a novel NPY-expressing neuronal population (peri-LC NPY ) neighboring LC noradrenergic neurons that locally innervates the pericoerulean space. Moreover, we demonstrate that stress engages peri-LC NPY neurons, increasing their excitability. Mimicking peri-LC NPY neuronal activation using ex vivo chemogenetics suppresses LC noradrenergic neuron activity, via an NPY Y1 receptor-mediated mechanism. Furthermore, in vivo chemogenetic stimulation of peri-LC NPY neurons results in Y1R-dependent anxiety-relief. Conversely, inhibiting peri-LC NPY neurons increases anxiety-like behaviors. Together, we establish a causal role for peri-LC NPY -mediated neuromodulation of the LC in the regulation of anxiety, providing novel insights in the endogenous mechanisms underlying adaptive responses to adversity.