Acute pharmacogenetic activation of medial prefrontal cortex excitatory neurons regulates anxiety-like behaviour
Acute pharmacogenetic activation of medial prefrontal cortex excitatory neurons regulates anxiety-like behaviour
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DOI：
10.1007/s12038-018-9732-y
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发表时间：
2018-03-01
影响因子：
2.9
通讯作者：
Vaidya, Vidita A.
中科院分区：
文献类型：
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作者：
Pati, Sthitapranjya;Sood, Ankit;Vaidya, Vidita A.
内侧前额叶皮层（mPFC）与焦虑样行为有关。在啮齿类动物模型中，通过药理学操作、mPFC神经元的光遗传学激活或生长抑素中间神经元的细胞类型特异性药理学抑制对mPFC神经元活动的扰动表明，对焦虑样行为的影响是相互矛盾的。在本研究中，我们研究了Ca2+/钙调素依赖性蛋白激酶α (CamKII α)阳性兴奋性神经元的药物遗传学激活对焦虑样行为的影响。我们使用氯氮平- n -氧化物（CNO）在药药学上激活病毒传递的CamKII α - hm3dq - dreadd在mPFC兴奋性神经元。在CamKII α - hm3dq - dreadd或CamKII α - gfp病毒感染的大鼠中，研究急性CNO或车辆治疗对开放场地和升高迷宫试验中焦虑样行为的影响。此外，利用免疫组织化学方法检测急性CNO治疗对mPFC以及下游靶神经元回路中神经元活性标记物c-Fos表达的影响。急性药理学激活的mPFC兴奋性神经元可选择性地诱发焦虑样行为的显著减少，但在开放场试验中则没有。急性CNO治疗导致mPFC边缘下、边缘前和扣带区c- fos免疫阳性细胞数量增加。这也伴随着cno处理hM3Dq动物mPFC多个下游回路中c- fos免疫阳性细胞数量的增加。mPFC兴奋性神经元的急性药理学激活以任务特异性方式减少焦虑样行为，同时mPFC和涉及焦虑样行为调节的多个目标回路中c-Fos表达增强。
The medial prefrontal cortex (mPFC) is implicated in anxiety-like behaviour. In rodent models, perturbations of mPFC neuronal activity through pharmacological manipulations, optogenetic activation of mPFC neurons or cell-type specific pharmacogenetic inhibition of somatostatin interneurons indicate conflicting effects on anxiety-like behaviour. In the present study we examined the effects of pharmacogenetic activation of Ca2+/calmodulin-dependent protein kinase alpha (CamKII alpha)-positive excitatory neurons on anxiety-like behaviour. We used clozapine-N-oxide (CNO) to pharmacogenetically activate virally delivered CamKII alpha-hM3Dq-DREADD in mPFC excitatory neurons. The effects of acute CNO or vehicle treatment on anxiety-like behaviour in the open field and elevated plus maze tests were examined in rats virally infected with either CamKII alpha-hM3Dq-DREADD or CamKII alpha-GFP. In addition, the effects of acute CNO treatment on the expression of the neuronal activity marker c-Fos were examined in the mPFC as well as downstream target neuronal circuits using immunohistochemistry. Acute pharmacogenetic activation of mPFC excitatory neurons evoked a significant decrease in anxiety-like behaviour selectively on the elevated plus maze task, but not the open field test. Acute CNO treatment resulted in enhanced c-Fos-immunopositive cell number in the infralimbic, prelimbic and cingulate subdivisions of the mPFC. This was also accompanied by enhanced c-Fos-immunopositive cell number in multiple downstream circuits of the mPFC in CNO-treated hM3Dq animals. Acute pharmacogenetic activation of mPFC excitatory neurons reduces anxiety-like behaviour in a task-specific fashion accompanied by enhanced c-Fos expression in the mPFC and multiple target circuits implicated in the regulation of anxiety-like behaviour.