Intramural Research Program, National Institute on Drug Abuse-National Institutes of Health, Baltimore, Maryland 21224
Intramural Research Program, National Institute on Drug Abuse-National Institutes of Health, Baltimore, Maryland 21224.
J Neurosci. 2019 Mar 27;39(13):2482-2496. doi: 10.1523/JNEUROSCI.2409-18.2019. Epub 2019 Jan 17.
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 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 colocalized with and 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. Aggression is often comorbid with neuropsychiatric diseases, including drug addiction. One form, appetitive aggression, exhibits symptomatology that mimics that of drug addiction and is hypothesized to be due to dysregulation of addiction-related reward circuits. However, our mechanistic understanding of the circuitry modulating appetitive operant aggression is limited. Here we used a novel mouse model of aggression self-administration and relapse, in combination with immunohistochemistry, hybridization, and chemogenetic manipulations to examine how cell types in the nucleus accumbens are recruited for, and control, operant aggression self-administration and aggression seeking on abstinence Day 1. We found that one population, dopamine receptor 1-expressing neurons, act as a critical modulator of operant aggression reward and aggression seeking.
我们最近开发了一种有欲望的操作性攻击的小鼠模型，并报告说，成年雄性远交 CD-1 小鼠按压杠杆以获得攻击从属雄性小鼠的机会，并在禁欲期间重新寻求攻击。在这里，我们研究了伏隔核（NAc）多巴胺受体（Drd）1 和 Drd2 表达神经元在攻击自我给药和攻击寻求中的作用。我们训练 CD-1 小鼠对入侵者进行自我给药（9 天，每天 12 次），并在禁欲第 1 天测试它们的攻击自我给药和攻击寻求。我们使用免疫组织化学和杂交来测量 NAc 中的神经元活动标记物 Fos，并对 Fos 与 Drd1 和 Drd2 表达神经元的细胞类型特异性共定位进行了检测。为了测试 Drd1 和 Drd2 表达神经元的因果作用，我们验证了一种转基因杂交繁殖策略，即将近交 Drd1-Cre 和 Drd2-Cre 转基因小鼠与远交 CD-1 小鼠杂交，并使用细胞类型特异性 Cre-DREADD（hM4Di）抑制 NAc Drd1 和 Drd2 表达神经元的活性。我们发现，攻击自我给药和攻击寻求诱导 NAc 壳中比核心更高的 Fos 表达，与 和 共定位，并且 Drd1 表达神经元的化学遗传抑制，但不是 Drd2 表达神经元的抑制，减少了攻击自我给药和攻击寻求。结果表明，Drd1 表达神经元具有细胞类型特异性作用，对攻击自我给药和攻击寻求都很关键。我们的研究还验证了一种简单的繁殖策略，即将远交 CD-1 小鼠与基于近交 C57 的 Cre 系杂交，可用于研究攻击奖励和复发的细胞类型和回路机制。攻击行为通常与神经精神疾病共病，包括药物成瘾。一种形式的有欲望的攻击行为表现出类似于药物成瘾的症状，据推测是由于与成瘾相关的奖励回路失调所致。然而，我们对调节有欲望的操作性攻击的回路的机制理解有限。在这里，我们使用一种新的攻击自我给药和复发的小鼠模型，结合免疫组织化学、杂交和化学遗传操作，研究了伏隔核中的细胞类型如何被招募来进行操作性攻击自我给药和在禁欲第 1 天寻求攻击。我们发现，一种多巴胺受体 1 表达神经元群体作为操作性攻击奖励和攻击寻求的关键调节剂。
