The Oxytocin Neurons in the Paraventricular Nucleus Are Essential for Chronic Sleep Deprivation‐Mediated Anxiety‐Related Behaviors

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 (PVNOXT neurons) in regulating anxiety-related behaviors following chronic sleep deprivation (cSD). In vivo optogenetic stimulation was used to regulate the activity of PVNOXT 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. 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 PVNOXT neurons. Instant optogenetic activation of PVNOXT 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 PVNOXT neurons promoted a prolonged inhibition of PVNOXT neurons and increased anxiety-like behaviors. Interestingly, short-term high-frequency stimulation (HFS) of PVNOXT neurons displayed a long-term potentiation of AMPAR-mediated synaptic transmission of PVNOXT neurons and could reverse cSD-induced anxiety by promoting the OXT-mediated inhibitory transmission of the mPFC. Our findings provide key mechanisms and promising deep brain stimulation strategies associated with synaptic plasticity for cSD-induced obsessive anxiety.