PT - JOURNAL ARTICLE AU - Riga, Danai AU - Rademakers, Kelly AU - Wolterink-Donselaar, Inge G. AU - Meye, Frank J. TI - Neuropeptide Y neurons of the locus coeruleus inhibit noradrenergic system activity to reduce anxiety AID - 10.1101/2023.10.16.562534 DP - 2023 Jan 01 TA - bioRxiv PG - 2023.10.16.562534 4099 - http://biorxiv.org/content/early/2023/10/17/2023.10.16.562534.short 4100 - http://biorxiv.org/content/early/2023/10/17/2023.10.16.562534.full 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.