Enhanced innate fear and altered stress axis regulation in VGluT3 knockout mice
Enhanced innate fear and altered stress axis regulation in VGluT3 knockout mice
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DOI：
10.1080/10253890.2017.1423053
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发表时间：
2018-01-01
影响因子：
2.3
通讯作者：
Zelena, Dora
中科院分区：
文献类型：
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作者：
Balazsfi, Diana;Fodor, Anna;Zelena, Dora
以囊泡谷氨酸转运体（VGluT 1 -3）为特征的谷氨酸能神经元提供脑中的主要兴奋。他们的紊乱与各种大脑疾病有关，这也可以通过啮齿动物的情境恐惧测试来建模。我们的目的是表征参与VGluT 3的发展背景下的恐惧，通过其贡献下丘脑-垂体-肾上腺皮质轴（HPA）的调节基因敲除（KO）小鼠。通过足部电击诱导情境性恐惧条件反射，并在相同环境中比较野生型与KO 1天和7天后检查小鼠。足部电击增加不动时间，无上下文特异性。此外，足部电击减少了高架十字迷宫（高架十字迷宫）测试中的开放臂时间，以及旷场（OF）测试中的行进距离，这代表了恐惧的泛化。此外，KO小鼠在情境恐惧测试期间花费更多的时间进行冻结，在开放臂中的时间较少，并且在OF中行进的距离较小，进入中央区域的次数较少。然而，没有足部电击和基因型相互作用，表明VGluT 3不影响恐惧条件反射，而是决定了小鼠的焦虑样特征。KO小鼠的静息下丘脑CRH mRNA较高，应激诱导的皮质酮升高降低。免疫组化结果显示，VGluT 3阳性纤维的存在下丘脑室旁核，但不是在垂体。结论VGluT 3基因敲除小鼠存在先天性恐惧，但对恐惧记忆和泛化能力无显著影响，可能与其室旁核CRH mRNA水平升高和应激反应性降低有关。
Glutamatergic neurons, characterized by vesicular glutamate transporters (VGluT1-3) provide the main excitation in the brain. Their disturbances have been linked to various brain disorders, which could be also modeled by the contextual fear test in rodents. We aimed to characterize the participation of VGluT3 in the development of contextual fear through its contribution to hypothalamic-pituitary-adrenocortical axis (HPA) regulation using knockout (KO) mice. Contextual fear conditioning was induced by foot shock and mice were examined 1 and 7d later in the same environment comparing wild type with KO. Foot shock increased the immobility time without context specificity. Additionally, foot shock reduced open arm time in the elevated plus maze (EPM) test, and distance traveled in the open field (OF) test, representing the generalization of fear. Moreover, KO mice spent more time with freezing during the contextual fear test, less time in the open arm of the EPM, and traveled a smaller distance in the OF, with less entries into the central area. However, there was no foot shock and genotype interaction suggesting that VGluT3 does not influence the fear conditioning, rather determines anxiety-like characteristic of the mice. The resting hypothalamic CRH mRNA was higher in KO mice with reduced stressor-induced corticosterone elevations. Immunohistochemistry revealed the presence of VGluT3 positive fibers in the paraventricular nucleus of hypothalamus, but not on the hypophysis. As a summary, we confirmed the involvement of VGluT3 in innate fear, but not in the development of fear memory and generalization, with a significant contribution to HPA alterations.HighlightsVGluT3 KO mice show innate fear without significant influence on fear memory and generalization.A putative background is the higher resting CRH mRNA level in their PVN and reduced stress-reactivity.