Ablation of neurons expressing agouti-related protein activates fos and gliosis in postsynaptic target regions.
Ablation of neurons expressing agouti-related protein activates fos and gliosis in postsynaptic target regions.
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DOI：
10.1523/jneurosci.2449-08.2008
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发表时间：
2008-09-10
期刊：
影响因子：
--
通讯作者：
Palmiter RD
中科院分区：
文献类型：
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作者：
Wu Q;Howell MP;Palmiter RD
我们已经开发了一种小鼠模型，其中一个特定的群体的抑制性神经元可以选择性地消融的白喉毒素（DT）的行动。该模型涉及将人白喉毒素受体（DTR）靶向刺豚鼠相关蛋白（Agrp）位点，以便全身给予DT杀死所有表达AgRP的神经元，导致小鼠饥饿。AgRP神经元的消融导致在由AgRP神经元支配的许多脑区域中Fos基因表达的稳健（5至10倍）激活，所述脑区域包括弓状核（ARC）、室旁核、内侧视前区、外侧隔和孤束核。正如预期的那样，ARC中的GFAP染色（星形胶质细胞）以及IBA1和CD11b染色（小胶质细胞）响应于AgRP神经元消融而显著增加。这些标记物在大多数（但不是全部）AgRP轴突的突触后靶点中也显着增加。我们使用了一种遗传方法来减少黑皮质素信号，这减弱了AgRP神经元消融后某些脑区的Fos激活。我们认为，目标神经元上的抑制性信号的损失导致无对抗的兴奋，这是负责激活Fos和这些神经元回路的失调是负责饥饿。此外，AgRP神经元的靶区域中的胶质细胞活化似乎是由于兴奋性毒性。
We have developed a mouse model in which a specific population of inhibitory neurons can be selectively ablated by the action of diphtheria toxin (DT). The model involves targeting the human diphtheria toxin receptor (DTR) to the agouti-related protein (Agrp) locus so that systemic administration of DT kills all of the AgRP-expressing neurons resulting in starvation of the mice. Ablation of AgRP neurons results in robust (5 to 10 fold) activation of Fos gene expression in many brain regions that are innervated by AgRP neurons, including the arcuate nucleus (ARC), paraventricular nucleus, the medial pre-optic area, lateral septum and nucleus of the solitary tract. As expected, there is robust increase in GFAP staining (astrocytes) as well as IBA1 and CD11b staining (microglia) in the ARC in response to AgRP neuron ablation. There is also dramatic increase of these markers in most, but not all, post-synaptic targets of AgRP axons. We used a genetic approach to reduce melanocortin signaling, which attenuated Fos activation in some brain regions after ablation of AgRP neurons. We suggest that loss of inhibitory signaling onto target neurons results in unopposed excitation that is responsible for the activation of Fos and that dysregulation of these neuronal circuits is responsible for starvation. Furthermore, glial cell activation in target areas of AgRP neurons appears to be due to excitotoxicity.