Riga Danai, Kooij Karlijn L, Rademakers Kelly, Wolterink-Donselaar Inge G, Basak Onur, Meye Frank J
Department of Translational Neuroscience, Brain Center, UMC Utrecht, Utrecht University, Utrecht, Netherlands.
Department of Human Genetics, Amsterdam University Medical Center, Amsterdam, Netherlands.
Sci Adv. 2025 Jul 25;11(30):eadq0011. doi: 10.1126/sciadv.adq0011. Epub 2025 Jul 23.
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 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 neurons, leading to local NPY release in vivo, whereas enhanced peri-LC neuronal activity curbs anxiety after stress. Together, we establish a causal role for peri-LC-mediated neuromodulation of the LC in the regulation of anxiety, providing mechanistic insights into the endogenous systems underlying adaptive responses to adversity.
对具有挑战性环境的适应性反应取决于蓝斑（LC）的最佳功能，蓝斑是大脑中去甲肾上腺素的主要来源以及初始应激反应的主要介质。结合对小鼠的功能电路剖析和因果体内干预，我们在此研究一种限制LC去甲肾上腺素能输出的内在肽能调节系统。特别是，我们对围绕LC去甲肾上腺素能细胞的表达神经肽Y（NPY）的神经元群体进行了表征。我们表明，这个LC周围群体通过NPY-Y1R信号传导对LC施加神经调节性抑制控制。在未受刺激的条件下，这导致对焦虑样行为的双向控制。应激经历会募集LC周围神经元，导致体内局部NPY释放，而增强的LC周围神经元活动会在应激后抑制焦虑。总之，我们确立了LC周围介导的对LC的神经调节在焦虑调节中的因果作用，为对逆境的适应性反应的内源性系统提供了机制性见解。
