Hypothalamic oxytocin neurons produce pro-anxiety effects through glutamatergic projections to the lateral hypothalamus

Anxiety disorders represent the most prevalent class of psychiatric illnesses worldwide. Oxytocin (OXT), a well-known nonapeptide, has garnered attention for its therapeutic potential in affective disorders, including anxiety 1 , 2 . Direct infusion of OXT into emotion-related regions, such as central amygdala (CeA), anterior cingulate cortex (ACC), and dorsal raphe nucleus, has been shown to activate OXT receptors (OxtRs) and reduce anxiety and depression 3 , 4 , 5 . Endogenous OXT is primarily synthesized and released by neurons in the paraventricular nucleus of hypothalamus (PVN) and supraoptic nucleus (SON). Stimulating OXT axons within the CeA or ACC has also been shown to alleviate anxiety- and depression-like behaviors 3 , 4 , 6 . However, recent studies reported that chronic chemogenetic activation of PVN OXT neurons and chronic infusion of OXT promoted anxiety-like behaviors 7 , 8 , which contrasts with the anxiolytic effect of OXT. The contribution of OXT neuronal activity to anxiety remains to be elucidated. Neuronal functions critically depend on the released neuroactive molecules and circuit-specific projections. Some types of neurons are found to co-release multiple neurotransmitters or neuromodulators, which can even exert opposing functional effects 9 , 10 . PVN OXT neurons synthesize and co-release glutamate 11 . Although the functions of OXT released from PVN neurons have been extensively characterized 2 , 3 , 6 , 12 , the regions in which PVN OXT neurons release glutamate 13 , as well as the functional implications of this co-release, remain poorly understood.