The Hypothalamic Medial Preoptic Area-Paraventricular Nucleus Circuit Modulates Depressive-Like Behaviors in a Mouse Model of Postpartum Depression

Estrogen fluctuations have been implicated in various mood disorders, including perimenopausal and postpartum depression (PPD), likely through complex neural networks. γ-aminobutyric acid-ergic (GABAergic) neurons in the medial preoptic area (MPOA) that express Estrogen receptor 1 (ESR1) are essential for the development and expression of depressive-like behaviors in ovarian hormone withdrawal (HW) mice. However, the precise circuit mechanisms through which MPOA GABAergic neurons influence behavior remain incompletely understood. Here, we identified robust projections from MPOA GABAergic neurons to the paraventricular nucleus of the hypothalamus (PVN). In HW mice, chemogenetic activation of MPOA GABAergic neurons targeting PVN attenuated depressive-like behaviors. Conversely, in nonhormone withdrawal (NHW) control mice (which received continuous estrogen), suppression of MPOA GABAergic projections to PVN exacerbated depressive-like behaviors. Further analyses using quantitative polymerase chain reaction and immunostaining identified arginine vasopressin (AVP) as a key neuropeptide in this pathway in the HW mouse model. Chemogenetic inhibition of PVN^AVP neurons significantly alleviated depressive-like behaviors in HW mice, while their activation in NHW mice worsened depressive-like behaviors. These behaviors were dependent on AVP expression in PVN^AVP neurons. Moreover, in HW mice, chemogenetic inhibition of PVN^AVP neurons receiving MPOA input mitigated depressive-like behaviors. Conversely, in NHW mice, activation of these neurons exacerbated depressive-like behaviors. Electrophysiological recordings demonstrated that MPOA GABAergic neurons directly inhibit PVN^AVP neurons. Thus, our findings suggest that PVN^AVP neurons serve as downstream effectors of MPOA GABAergic neurons via monosynaptic inhibitory signaling to regulate depressive-like behaviors. Targeting this circuit may offer a novel therapeutic strategy for PPD.