Microglial activation contributes to depressive-like behavior in dopamine D3 receptor knockout mice
Microglial activation contributes to depressive-like behavior in dopamine D3 receptor knockout mice
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小胶质细胞激活导致多巴胺 D3 受体敲除小鼠的抑郁样行为
DOI：
10.1016/j.bbi.2019.10.016
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发表时间：
2020-01
期刊：
影响因子：
--
通讯作者：
Yanjiong Chen
中科院分区：
文献类型：
--
作者：
Jing Wang;Simin Lai;Guodong Li;Ting Zhou;Biao Wang;Fang Cao;Teng Chen;Xia Zhang;Yanjiong Chen
我们先前证明，多巴胺D3受体(D3R)抑制剂NGB2904增加了小鼠抑郁样症状的易感性，提高了促炎细胞因子的表达，并改变了小鼠中脑边缘多巴胺能区域的脑源性神经营养因子(BDNF)水平，包括内侧前额叶皮质(MPFC)、伏隔核(NAC)和腹侧被盖区(VTA)。D3R抑制影响神经炎症和抑郁症发病的机制尚不清楚。在这里，我们利用D3R基因敲除(D3RKO)和同源野生型C56BL/6(WT)小鼠，证明D3RKO小鼠表现出抑郁样行为，肿瘤坏死因子-α(肿瘤坏死因子-α)、白细胞介素1β(IL-1β)和IL-6水平升高，并改变了选定的中边缘多巴胺能区脑源性神经营养因子的表达。D3R表达定位于WT小鼠mPFC、NAC和VTA的星形胶质细胞或小胶质细胞。D3RKO小鼠在中脑边缘多巴胺能区没有胶质纤维酸性蛋白(GFAP)标记的星形胶质细胞的情况下，显示大量Iba1标记的小胶质细胞。用米诺环素(25 mg/kg和50 mg/kg)或PLX3397(40 mg/kg)抑制或消融小胶质细胞可改善D3RKO小鼠抑郁样症状、促炎细胞因子水平和脑组织神经营养因子的表达。二甲胺四环素治疗可减轻D3RKO小鼠NAc区突触密度的增加。这些发现表明，小胶质细胞在选定的中脑边缘奖赏区域的激活影响D3R缺乏诱导的抑郁样行为。
We previously demonstrated that the dopamine D3 receptor (D3R) inhibitor, NGB2904, increases susceptibility to depressive-like symptoms, elevates pro-inflammatory cytokine expression, and alters brain-derived neurotrophic factor (BDNF) levels in mesolimbic dopaminergic regions, including the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and ventral tegmental area (VTA) in mice. The mechanisms by which D3R inhibition affects neuroinflammation and onset of depression remain unclear. Here, using D3R-knockout (D3RKO) and congenic wild-type C56BL/6 (WT) mice, we demonstrated that D3RKO mice displayed depressive-like behaviors, increased tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 levels, and altered BDNF expression in selected mesolimbic dopaminergic regions. D3R expression was localized to astrocytes or microglia in the mPFC, NAc, and VTA in WT mice. D3RKO mice exhibited a large number of Iba1-labelled microglia in the absence of glial fibrillary acidic protein (GFAP)-labelled astrocytes in mesolimbic dopaminergic brain areas. Inhibition or ablation of microglia by minocycline (25 mg/kg and 50 mg/kg) or PLX3397 (40 mg/kg) treatment ameliorated depressive-like symptoms, alterations in pro-inflammatory cytokine levels, and BDNF expression in the indicated brain regions in D3RKO mice. Minocycline therapy alleviated the increase in synaptic density in the NAc in D3RKO mice. These findings suggest that microglial activation in selected mesolimbic reward regions affects depressive-like behaviors induced by D3R deficiency.
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影响因子：
5.8
作者：
Newman, Amy Hauck;Blaylock, Brandi L.;Nader, Michael A.;Bergman, Jack;Sibley, David R.;Skolnick, Phil
通讯作者：
Skolnick, Phil
影响因子：
2.9
作者：
S. Tsuchimine;N. Yasui‐Furukori;T. Nakagami;Yasushi Sato;S. Kaneko
通讯作者：
S. Tsuchimine;N. Yasui‐Furukori;T. Nakagami;Yasushi Sato;S. Kaneko
影响因子：
4.2
作者：
Zhu, Jie;Chen, Yanjiong;Zhao, Na;Cao, Guofen;Dang, Yonghui;Han, Wei;Xu, Ming;Chen, Teng
通讯作者：
Chen, Teng
影响因子：
64.8
作者：
Shao, Wei;Zhang, Shu-zhen;Zhou, Jia-wei
通讯作者：
Zhou, Jia-wei
影响因子：
5
作者：
Bergamini G;Mechtersheimer J;Azzinnari D;Sigrist H;Buerge M;Dallmann R;Freije R;Kouraki A;Opacka-Juffry J;Seifritz E;Ferger B;Suter T;Pryce CR
通讯作者：
Pryce CR