Cheng Ziqian, Zhao Fangyi, Piao Jingjing, Yang Wei, Cui Ranji, Li Bingjin
Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, Second Hospital of Jilin University, Changchun, 130041, PR China.
Engineering Lab on Screening of Antidepressant Drugs, Jilin Province Development and Reform Commission, Changchun, 130041, PR China.
Mol Psychiatry. 2025 Feb;30(2):435-449. doi: 10.1038/s41380-024-02684-5. Epub 2024 Aug 3.
Depressive symptoms, such as anhedonia, decreased social interaction, and lack of motivation, implicate brain reward systems in the pathophysiology of depression. Exposure to chronic stress impairs the function of brain reward circuits and is well-known to be involved in the etiology of depression. A transcriptomic analysis found that stress alters the expression of Rasd2 in mice prefrontal cortex (PFC). Similarly, in our previous study, acute fasting decreased Rasd2 expression in mice PFC, and RASD2 modulated dopamine D2 receptor (DRD2)-mediated antidepressant-like effects in ovariectomized mice. This research suggests the role of RASD2 in stress-induced depression and its underlying neural mechanisms that require further investigation. Here, we show that 5-day unpredictable mild stress (5-d UMS) exposure reduces RASD2 expression in both the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) of mice, while overexpression (but not knock-down) of Rasd2 in the NAc core (NAcc) alleviates 5-d UMS-induced depression-like behaviors and activates the DRD2-cAMP-PKA-DARPP-32 signaling pathway. Further studies investigated neuronal projections between the mPFC (Cg1, PrL, and IL) and NAcc, labeled by the retrograde tracer Fluorogold. Depression-like behaviors induced by 5-d UMS were only related to inhibition of the PrL-NAcc circuit. DREADD (Designer receptors exclusively activated by designer drug) analysis found that the activation of PrL-NAcc glutaminergic projection alleviated depression-like behaviors and increased DRD2- and RASD2-positive neurons in the NAcc. Using Drd2-cre transgenic mice, we constructed mice with Rasd2 overexpression in DRD2 neurons, finding that Rasd2 overexpression ameliorated 5-d UMS-induced depression-like behaviors. These findings demonstrate a critical role for RASD2 modulation of DRD2 neurons in 5-d UMS-induced depression-like behaviors. In addition, the study identifies a new potential strategy for precision medical treatment of depression.
抑郁症状，如快感缺乏、社交互动减少和缺乏动力，表明大脑奖赏系统参与了抑郁症的病理生理过程。长期暴露于应激会损害大脑奖赏回路的功能，并且众所周知其与抑郁症的病因有关。一项转录组分析发现，应激会改变小鼠前额叶皮质（PFC）中Rasd2的表达。同样，在我们之前的研究中，急性禁食会降低小鼠PFC中Rasd2的表达，并且RASD2调节去卵巢小鼠中多巴胺D2受体（DRD2）介导的抗抑郁样作用。这项研究表明RASD2在应激诱导的抑郁症中的作用及其潜在的神经机制，需要进一步研究。在这里，我们表明，暴露于5天不可预测的轻度应激（5-d UMS）会降低小鼠伏隔核（NAc）和内侧前额叶皮质（mPFC）中RASD2的表达，而在伏隔核核心（NAcc）中过表达（而非敲低）Rasd2可减轻5-d UMS诱导的抑郁样行为，并激活DRD2-cAMP-PKA-DARPP-32信号通路。进一步的研究通过逆行示踪剂荧光金标记，研究了mPFC（Cg1、PrL和IL）与NAc之间的神经元投射。5-d UMS诱导的抑郁样行为仅与PrL-NAc回路的抑制有关。设计受体特异性激活药物（DREADD）分析发现，激活PrL-NAc谷氨酸能投射可减轻抑郁样行为，并增加NAc中DRD2和RASD2阳性神经元。使用Drd2-cre转基因小鼠，我们构建了在DRD2神经元中过表达Rasd2的小鼠，发现Rasd2过表达改善了5-d UMS诱导的抑郁样行为。这些发现证明了RASD2对DRD2神经元的调节在5-d UMS诱导的抑郁样行为中起关键作用。此外，该研究确定了一种抑郁症精准医疗的新潜在策略。
