Zilkha Neurogenetic Institute and Center for Neural Circuits and Sensory Processing Disorders, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
Graduate Program in Biological and Biomedical Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
Nat Commun. 2024 Oct 3;15(1):8575. doi: 10.1038/s41467-024-52727-2.
Dysregulation of brain homeostasis is associated with neuropsychiatric conditions such as major depressive disorder. However, underlying neural-circuit mechanisms remain not well-understood. We show in mice that chronic restraint stress (CRS) and social defeat stress (SDS) are both associated with disruption of excitation (E)-inhibition (I) balance, with increased E/I ratios, in medial preoptic area (MPOA) circuits, but through affecting different neuronal types. CRS results in elevated activity in glutamatergic neurons, and their suppression mitigates CRS-induced depressive-like behaviors. Paraventricular hypothalamic input to these neurons contributes to induction but not expression of depressive-like behaviors. Their projections to ventral tegmental area and periaqueductal gray/dorsal raphe suppress midbrain dopaminergic and serotonergic activity, respectively, and mediate expression of divergent depressive-like symptoms. By contrast, SDS results in reduced activity of GABAergic neurons, and their activation alleviates SDS-induced depressive-like behaviors. Thus, E/I imbalance with relatively increased excitation in MPOA circuits may be a general mechanism underlying depression caused by different etiological factors.
大脑内环境稳态的失调与精神神经疾病相关，如重度抑郁症。然而，其潜在的神经回路机制仍不清楚。我们在小鼠中发现，慢性束缚应激（CRS）和社会挫败应激（SDS）均与中脑视前区（MPOA）回路中兴奋（E）-抑制（I）平衡的破坏相关，表现为 E/I 比值升高，但这是通过影响不同的神经元类型实现的。CRS 导致谷氨酸能神经元活性升高，而其抑制可减轻 CRS 诱导的抑郁样行为。室旁下丘脑对这些神经元的输入有助于诱导而非表达抑郁样行为。它们投射到腹侧被盖区和中脑导水管周围灰质/背侧中缝核分别抑制中脑多巴胺能和 5-羟色胺能活性，并介导不同抑郁样症状的表达。相比之下，SDS 导致 GABA 能神经元活性降低，而其激活可减轻 SDS 诱导的抑郁样行为。因此，MPOA 回路中 E/I 失衡伴相对兴奋增加可能是不同病因引起抑郁的一般机制。
