Aims: Sleep disorders increase the risk of anxiety disorders. The underlying mechanisms and potential targets remain poorly understood. Our research aimed to discover the essential role of oxytocin neurons in the paraventricular nucleus (PVN^OXT neurons) in regulating anxiety-related behaviors following chronic sleep deprivation (cSD).

Methods: In vivo optogenetic stimulation was used to regulate the activity of PVN^OXT neurons, and meanwhile, anxiety-related behavioral tests were performed. Electrophysiological analysis was used to test neuronal synaptic transmission. In vivo fiber photometry was used to assess OXT release.

Results: Through c-Fos staining of the whole brain, we found that cSD decreased c-Fos expression in the PVN and increased c-Fos expression in the medial prefrontal cortex (mPFC). cSD promoted anxiety-related behaviors mainly through inhibiting AMPAR-mediated postsynaptic excitability of PVN^OXT neurons. Instant optogenetic activation of PVN^OXT neurons decreased anxiety-like behaviors and promoted fear memory extinction by promoting oxytocin release into the mPFC. Similar to cSD, optogenetic long-term low-frequency (LTF) stimulation of PVN^OXT neurons promoted a prolonged inhibition of PVN^OXT neurons and increased anxiety-like behaviors. Interestingly, short-term high-frequency stimulation (HFS) of PVN^OXT neurons displayed a long-term potentiation of AMPAR-mediated synaptic transmission of PVN^OXT neurons and could reverse cSD-induced anxiety by promoting the OXT-mediated inhibitory transmission of the mPFC.

Conclusion: Our findings provide key mechanisms and promising deep brain stimulation strategies associated with synaptic plasticity for cSD-induced obsessive anxiety.

Keywords: anxiety; chronic sleep deprivation; oxytocin neurons; the paraventricular nucleus.

© 2025 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.

目的： 睡眠障碍增加焦虑障碍的风险。其潜在机制和目标尚不明确。我们的研究旨在发现下视丘室周核（PVN^OXT神经元）中的催产素神经元在调节慢性睡眠剥夺（cSD）后与焦虑相关的行为中所起的关键作用。

方法： 采用在体光遗传学刺激来调控PVN^OXT神经元的活性，并同时进行与焦虑相关的行为测试。使用电生理分析来检测神经突触传递。采用在体光纤光度测定法评估催产素释放。

结果： 通过全脑c-Fos染色，我们发现慢性睡眠剥夺减少了PVN中的c-Fos表达并增加了前扣带皮层（mPFC）中的c-Fos表达。慢性睡眠剥夺主要通过抑制PVN^OXT神经元的AMPAR介导的突触后兴奋性来促进与焦虑相关的行为。瞬时光遗传学激活PVN^OXT神经元可以减少类似焦虑的行为，并通过将催产素释放到mPFC中来促进恐惧记忆消退。类似于慢性睡眠剥夺，对PVN^OXT神经元进行长时间的低频（LTF）光遗传学刺激会延长抑制PVN^OXT神经元的时间并增加类似焦虑的行为。有趣的是，对PVN^OXT神经元进行短期高频（HFS）刺激可以增强AMPAR介导的突触传递，并通过促进mPFC中的催产素介导的抑制性传递来逆转慢性睡眠剥夺引起的焦虑。

结论： 我们的发现提供了与慢性睡眠剥夺诱发的强迫焦虑相关的突触可塑性的关键机制和有前景的大脑深部刺激策略。

关键词： 焦虑；慢性睡眠剥夺；催产素神经元；下视丘室周核