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Cortical control of aggression: GABA signalling in the anterior cingulate cortex
European Neuropsychopharmacology ( IF 6.1 ) Pub Date : 2020-01-01 , DOI: 10.1016/j.euroneuro.2017.12.007
Amanda Jager 1 , Houshang Amiri 2 , Natalia Bielczyk 1 , Sabrina van Heukelum 1 , Arend Heerschap 3 , Armaz Aschrafi 4 , Geert Poelmans 5 , Jan K Buitelaar 1 , Tamas Kozicz 6 , Jeffrey C Glennon 1
Affiliation  

Reduced top-down control by cortical areas is assumed to underlie pathological forms of aggression. While the precise underlying molecular mechanisms are still elusive, it seems that balancing the excitatory and inhibitory tones of cortical brain areas has a role in aggression control. The molecular mechanisms underpinning aggression control were examined in the BALB/cJ mouse model. First, these mice were extensively phenotyped for aggression and anxiety in comparison to BALB/cByJ controls. Microarray data was then used to construct a molecular landscape, based on the mRNAs that were differentially expressed in the brains of BALB/cJ mice. Subsequently, we provided corroborating evidence for the key findings from the landscape through 1H-magnetic resonance imaging and quantitative polymerase chain reactions, specifically in the anterior cingulate cortex (ACC). The molecular landscape predicted that altered GABA signalling may underlie the observed increased aggression and anxiety in BALB/cJ mice. This was supported by a 40% reduction of 1H-MRS GABA levels and a 20-fold increase of the GABA-degrading enzyme Abat in the ventral ACC. As a possible compensation, Kcc2, a potassium-chloride channel involved in GABA-A receptor signalling, was found increased. Moreover, we observed aggressive behaviour that could be linked to altered expression of neuroligin-2, a membrane-bound cell adhesion protein that mediates synaptogenesis of mainly inhibitory synapses. In conclusion, Abat and Kcc2 seem to be involved in modulating aggressive and anxious behaviours observed in BALB/cJ mice through affecting GABA signalling in the ACC.

中文翻译:

攻击的皮层控制:前扣带回皮层中的 GABA 信号

皮质区域自上而下的控制减少被认为是病理形式的侵略的基础。虽然确切的潜在分子机制仍然难以捉摸,但平衡大脑皮层区域的兴奋和抑制音调似乎在攻击控制中起作用。在 BALB/cJ 小鼠模型中检查了支持攻击性控制的分子机制。首先,与 BALB/cByJ 对照相比,对这些小鼠的攻击性和焦虑性进行了广泛的表型分析。然后,基于 BALB/cJ 小鼠大脑中差异表达的 mRNA,使用微阵列数据构建分子图谱。随后,我们通过 1H 磁共振成像和定量聚合酶链反应为景观中的关键发现提供了确凿的证据,特别是在前扣带皮层(ACC)。分子景观预测,改变的 GABA 信号可能是观察到的 BALB/cJ 小鼠攻击性和焦虑增加的基础。这得到 1H-MRS GABA 水平降低 40% 和腹侧 ACC 中 GABA 降解酶 Abat 增加 20 倍的支持。作为一种可能的补偿,发现 Kcc2(一种参与 GABA-A 受体信号传导的氯化钾通道)增加。此外,我们观察到攻击行为可能与neuroligin-2 的表达改变有关,neuroligin-2 是一种膜结合细胞粘附蛋白,主要介导抑制性突触的突触发生。总之,Abat 和 Kcc2 似乎通过影响 ACC 中的 GABA 信号传导,参与调节在 BALB/cJ 小鼠中观察到的攻击性和焦虑行为。分子景观预测,改变的 GABA 信号可能是观察到的 BALB/cJ 小鼠攻击性和焦虑增加的基础。这得到 1H-MRS GABA 水平降低 40% 和腹侧 ACC 中 GABA 降解酶 Abat 增加 20 倍的支持。作为一种可能的补偿,发现 Kcc2(一种参与 GABA-A 受体信号传导的氯化钾通道)增加。此外,我们观察到攻击行为可能与neuroligin-2 的表达改变有关,neuroligin-2 是一种膜结合细胞粘附蛋白,主要介导抑制性突触的突触发生。总之,Abat 和 Kcc2 似乎通过影响 ACC 中的 GABA 信号传导,参与调节在 BALB/cJ 小鼠中观察到的攻击性和焦虑行为。分子景观预测,改变的 GABA 信号可能是观察到的 BALB/cJ 小鼠攻击性和焦虑增加的基础。这得到 1H-MRS GABA 水平降低 40% 和腹侧 ACC 中 GABA 降解酶 Abat 增加 20 倍的支持。作为一种可能的补偿,发现 Kcc2(一种参与 GABA-A 受体信号传导的氯化钾通道)增加。此外,我们观察到攻击行为可能与neuroligin-2 的表达改变有关,neuroligin-2 是一种膜结合细胞粘附蛋白,主要介导抑制性突触的突触发生。总之,Abat 和 Kcc2 似乎通过影响 ACC 中的 GABA 信号传导,参与调节在 BALB/cJ 小鼠中观察到的攻击性和焦虑行为。
更新日期:2020-01-01
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