NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing 400016, China; Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Neurology Department of the First affiliated hospital of Kunming Medical University, Kunming, China.
Pharmacol Res. 2023 May;191:106717. doi: 10.1016/j.phrs.2023.106717. Epub 2023 Mar 21.
Neuroinflammation is tightly associated with onset of depression. The nuclear receptor related 1 protein (Nurr1, also called Nr4a2), its roles in dopaminergic neurons is well understood, which can alleviate inflammation. Nevertheless, potential effects of Nr4a2 on neuroinflammation associated with depression still remains unclear. Chronic lipopolysaccharides (LPS) stress induced depressive-behaviors were confirmed via behavioral tests. Differentially expressed genes were detected by using RNA-sequencing. The anterior cingulate cortex (ACC) tissues were collected for biochemical experiments. The Golgi-Cox staining and virus labeling were used to evaluate the dendritic spines. We applied fluoxetine (FLX) and amodiaquine dihydrochloride (AQ, a highly selective agonist of Nr4a2) in mice. Overexpression experiments were performed by injecting with AAV-Nr4a2-EGFP into ACC. Chemogenetic activation of CamkII neurons via injecting the hM3Dq virus. Mice treated with LPS displayed depressive- and anxiety-like behaviors. The reduction of Nr4a2 and FosB induced by LPS were rescued by pretreatment with FLX or AQ. More importantly, LPS-induced behavior deficits in mice were also alleviated via fluoxetine treatment and pharmacological activation the expression of Nr4a2. Meanwhile, enhancing the level of Nr4a2 could improve dendritic spines loss of neuron and morphological changes in microglia. Overexpression of Nr4a2 in ACC reversed the depressive- and anxiety-like behaviors caused by LPS administration. Activation of CamkII neurons in ACC could robustly increase the expression of Nr4a2 and improve LPS-induced behavior deficits. Our findings demonstrate that the Nr4a2 may regulate depressive-like behaviors via alleviating the impairment of morphology and function on microglia and CamkII neurons induced by chronic neuroinflammation.
神经炎症与抑郁症的发病密切相关。核受体相关 1 蛋白（Nurr1，也称为 Nr4a2）在多巴胺能神经元中的作用已得到充分证实，它可以减轻炎症。然而，Nr4a2 对与抑郁症相关的神经炎症的潜在影响仍不清楚。通过行为测试证实慢性脂多糖（LPS）应激诱导的抑郁样行为。通过 RNA 测序检测差异表达基因。采集前扣带皮层（ACC）组织进行生化实验。应用高尔基-考克斯染色和病毒标记评估树突棘。我们在小鼠中应用氟西汀（FLX）和盐酸阿莫地喹（AQ，一种高度选择性的 Nr4a2 激动剂）。通过向 ACC 注射 AAV-Nr4a2-EGFP 进行过表达实验。通过注射 hM3Dq 病毒对 CamkII 神经元进行化学遗传激活。LPS 处理的小鼠表现出抑郁和焦虑样行为。FLX 或 AQ 预处理可挽救 LPS 诱导的 Nr4a2 和 FosB 减少。更重要的是，通过氟西汀治疗和药理激活 Nr4a2 的表达，也减轻了 LPS 诱导的小鼠行为缺陷。同时，增强 Nr4a2 的水平可以改善神经元树突棘丢失和小胶质细胞的形态变化。ACC 中 Nr4a2 的过表达逆转了 LPS 给药引起的抑郁和焦虑样行为。ACC 中 CamkII 神经元的激活可以显著增加 Nr4a2 的表达并改善 LPS 诱导的行为缺陷。我们的研究结果表明，Nr4a2 可能通过减轻慢性神经炎症引起的小胶质细胞和 CamkII 神经元形态和功能损伤来调节抑郁样行为。
