Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action.
Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action.
复制标题
大脑奖励回路中的中脑边缘多巴胺神经元介导对社交失败和抗抑郁作用的敏感性
DOI：
10.1523/jneurosci.3177-10.2010
复制
发表时间：
2010-12-08
期刊：
影响因子：
--
通讯作者：
Han MH
中科院分区：
文献类型：
--
作者：
Cao JL;Covington HE 3rd;Friedman AK;Wilkinson MB;Walsh JJ;Cooper DC;Nestler EJ;Han MH
我们以前曾报道，腹侧被盖区(VTA)的中脑边缘多巴胺神经元的活性是行为易感性与对慢性社会失败应激的韧性的关键决定因素。然而，这完全是基于体外测量，在易感和有弹性的小鼠中，VTA多巴胺神经元的体内放电特性以及抗抑郁治疗的效果仍然完全未知。在这里，我们表明，慢性(10d)社会失败应激显著增加了易感小鼠体内的自发放电率和爆发事件，但在有弹性的亚组中没有。被试的开机率和突发事件与社交回避行为呈显著负相关，而社交回避行为是慢性社会失败应激引起的关键行为异常。此外，抗抑郁药物氟西汀(20 mg/kg)的慢性(2周)而非急性(单次剂量)治疗可完全逆转易感小鼠增加的放电率、爆发事件和回避行为。慢性社会失败应激增加了VTA多巴胺神经元的超极化激活阳离子电流(Ih)，这一效应也被氟西汀慢性治疗正常化。局部注射IH抑制剂ZD72 88(0.1μg)或DK-AH2 6 9(0.6μg)也可产生抗抑郁药样的行为效应。综上所述，这些数据表明，体内中脑边缘多巴胺神经元的放电模式调节了个体对慢性应激和抗抑郁作用的反应。
We previously reported that the activity of mesolimbic dopamine neurons of the ventral tegmental area (VTA) is a key determinant of behavioral susceptibility vs resilience to chronic social defeat stress. However, this was based solely on ex vivo measurements, and the in vivo firing properties of VTA dopamine neurons in susceptible and resilient mice, as well as the effects of antidepressant treatments, remain completely unknown. Here, we show that chronic (10 d) social defeat stress significantly increased the in vivo spontaneous firing rates and bursting events in susceptible mice but not in the resilient subgroup. Both the firing rates and bursting events were significantly negatively correlated with social avoidance behavior, a key behavioral abnormality induced by chronic social defeat stress. Moreover, the increased firing rates, bursting events, and avoidance behavior in susceptible mice were completely reversed by chronic (2 week), but not acute (single dose), treatments with the antidepressant medication fluoxetine (20 mg/kg). Chronic social defeat stress increased hyperpolarization-activated cation current (Ih) in VTA dopamine neurons, an effect that was also normalized by chronic treatment with fluoxetine. As well, local infusion of Ih inhibitors ZD7288 (0.1 μg) or DK-AH 269 (0.6 μg) into the VTA exerted antidepressant-like behavioral effects. Together, these data suggest that the firing patterns of mesolimbic dopamine neurons in vivo mediate an individual's responses to chronic stress and antidepressant action.