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The Hypothalamic Medial Preoptic Area-Paraventricular Nucleus Circuit Modulates Depressive-Like Behaviors in a Mouse
Ping Fu1, Cui-Ping Liu1, Cheng-Yi Liu1
1Department of Neurology and Medical Psychology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Institute for Brain Sciences, Chinese Academy of Medical Sciences Research Unit of Extracellular RNA, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Chemistry and Biomedicine Innovation Center, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.
Abstract:
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 PVNAVP 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 PVNAVP neurons. Moreover, in HW mice, chemogenetic inhibition of PVNAVP 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 PVNAVP neurons. Thus, our findings suggest that PVNAVP 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.
