Nucleus Accumbens Drd1-Expressing Neurons Control Aggression Self-Administration and Aggression Seeking in Mice
Nucleus Accumbens Drd1-Expressing Neurons Control Aggression Self-Administration and Aggression Seeking in Mice
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DOI：
10.1523/jneurosci.2409-18.2019
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发表时间：
2019-03-27
影响因子：
5.3
通讯作者：
Shaham, Yavin
中科院分区：
文献类型：
--
作者：
Golden, Sam A.;Jin, Michelle;Shaham, Yavin
我们最近开发了一种小鼠模型的食欲操作性攻击，并报告说，成年雄性远交CD-1小鼠的压力，为机会攻击下属的雄性小鼠和复发的攻击寻求禁欲期间。本研究探讨了多巴胺受体1和2在攻击性自我管理和攻击寻求中的作用。我们训练CD-1小鼠自我管理入侵者（9天，12次试验/天），并在禁欲第1天测试它们的攻击自我管理和攻击寻求。我们使用免疫组织化学和原位杂交来测量NAc中的神经元活性标记物Fos，以及Fos与表达Drd 1和Drd 2的神经元的细胞类型特异性共定位。为了测试Drd 1和Drd 2表达神经元的因果作用，我们验证了一种转基因杂交育种策略，将近交系Drd 1-Cre和Drd 2-Cre转基因小鼠与远交系CD-1小鼠杂交，并使用细胞类型特异性Cre-DREADD（hM 4Di）抑制NAc Drd 1和Drd 2表达神经元的活性。我们发现，侵略自我管理和侵略寻求诱导更高的Fos表达在NAC壳比在核心，Fos共定位与Drd 1和Drd 2在这两个亚区，和Drd 1-，但不是Drd 2-，表达神经元的化学发生抑制减少侵略自我管理和侵略寻求。结果表明，细胞类型的特定作用的Drd 1表达的神经元，这是至关重要的侵略自我管理和侵略寻求。我们的研究还验证了远交CD-1小鼠和基于C57的近交Cre系之间的简单育种策略，该策略可用于研究攻击性奖励和复发的细胞类型和电路机制。
We recently developed a mouse model of appetitive operant aggression and reported that adult male outbred CD-1 mice lever-press for the opportunity to attack subordinate male mice and relapse to aggression seeking during abstinence. Here we studied the role of nucleus accumbens (NAc) dopamine receptor (Drd)1- and Drd2-expressing neurons in aggression self-administration and aggression seeking. We trained CD-1 mice to self-administer intruders (9 d, 12 trials/d) and tested them for aggression self-administration and aggression seeking on abstinence Day 1. We used immunohistochemistry and in situ hybridization to measure the neuronal activity marker Fos in the NAc, and cell-type-specific colocalization of Fos with Drd1- and Drd2-expressing neurons. To test the causal role of Drd1- and Drd2-expressing neurons, we validated a transgenic hybrid breeding strategy crossing inbred Drd1-Cre and Drd2-Cre transgenic mice with outbred CD-1 mice and used cell-type-specific Cre-DREADD (hM4Di) to inhibit NAc Drd1- and Drd2-expressing neuron activity. We found that aggression self-administration and aggression seeking induced higher Fos expression in NAc shell than in core, that Fos colocalized with Drd1 and Drd2 in both subregions, and that chemogenetic inhibition of Drd1-, but not Drd2-, expressing neurons decreased aggression self-administration and aggression seeking. Results indicate a cell-type-specific role of Drd1-expressing neurons that is critical for both aggression self-administration and aggression seeking. Our study also validates a simple breeding strategy between outbred CD-1 mice and inbred C57-based Cre lines that can be used to study cell-type and circuit mechanisms of aggression reward and relapse.