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

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. Combining functional circuit dissection and causal in vivo interventions in mice, we here investigate a built-in peptidergic regulatory system that restricts LC noradrenergic output. In particular, we characterize a population of neuropeptide Y (NPY)–expressing neurons surrounding LC noradrenergic cells. We show that this peri-LC NPY population exerts neuromodulatory inhibitory control over the LC via NPY-Y1R signaling. Under naïve conditions, this results in bidirectional control of anxiety-like behaviors. Stressful experiences recruit peri-LC NPY neurons, leading to local NPY release in vivo, whereas enhanced peri-LC NPY neuronal activity curbs anxiety after stress. Together, we establish a causal role for peri-LC NPY –mediated neuromodulation of the LC in the regulation of anxiety, providing mechanistic insights into the endogenous systems underlying adaptive responses to adversity.