RT Journal Article SR Electronic T1 Neuropeptide Y neurons of the locus coeruleus inhibit noradrenergic system activity to reduce anxiety JF bioRxiv FD Cold Spring Harbor Laboratory SP 2023.10.16.562534 DO 10.1101/2023.10.16.562534 A1 Riga, Danai A1 Rademakers, Kelly A1 Wolterink-Donselaar, Inge G. A1 Meye, Frank J. YR 2023 UL http://biorxiv.org/content/early/2023/10/17/2023.10.16.562534.abstract AB 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-LCNPY) neighboring LC noradrenergic neurons that locally innervates the pericoerulean space. Moreover, we demonstrate that stress engages peri-LCNPY neurons, increasing their excitability. Mimicking peri-LCNPY 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-LCNPY neurons results in Y1R-dependent anxiety-relief. Conversely, inhibiting peri-LCNPY neurons increases anxiety-like behaviors. Together, we establish a causal role for peri-LCNPY-mediated neuromodulation of the LC in the regulation of anxiety, providing novel insights in the endogenous mechanisms underlying adaptive responses to adversity.Competing Interest StatementThe authors have declared no competing interest.