Hyperactivity of Hypothalamic-Pituitary-Adrenal Axis Due to Dysfunction of the Hypothalamic Glucocorticoid Receptor in Sigma-1 Receptor Knockout Mice.
Hyperactivity of Hypothalamic-Pituitary-Adrenal Axis Due to Dysfunction of the Hypothalamic Glucocorticoid Receptor in Sigma-1 Receptor Knockout Mice.
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Sigma-1 受体基因敲除小鼠下丘脑糖皮质激素受体功能障碍导致下丘脑-垂体-肾上腺轴过度活跃
DOI：
10.3389/fnmol.2017.00287
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发表时间：
2017
影响因子：
4.8
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Di T;Zhang S;Hong J;Zhang T;Chen L
Sigma-1受体敲除（σ1R-KO）小鼠表现出抑郁样表型。由于σ1R在下丘脑室旁核（PVN）神经元细胞中高表达，本研究探讨了σ1R缺乏对下丘脑-垂体-肾上腺皮质（HPA）轴调控的影响。本研究发现，成年雄性σ1R-KO小鼠与野生型（WT）小鼠的基础血清皮质酮（CORT）、促肾上腺皮质激素（ACTH）、促肾上腺皮质激素释放因子（CRF）水平及PVN中CRF mRNA水平无显著差异。急性轻度约束应激（AMRS）诱导σ1R-KO小鼠HPA轴活性和CRF表达的持续升高。在σ1R−/−小鼠中，地塞米松（Dex）诱导的CORT水平降低百分比明显减弱。σ1R- ko小鼠和σ1R拮抗剂ne100处理的WT小鼠PVN中糖皮质激素受体（GR）和蛋白激酶C （PKC）磷酸化水平降低。AMRS对σ1R-KO小鼠PVN camp反应元件结合蛋白（CREB）的磷酸化作用强于WT小鼠。在σ1R-KO小鼠脑室内注射PKC激活剂PMA 3 d，不仅恢复了GR磷酸化和dex减少的CORT百分比，而且纠正了amrs诱导的HPA轴高活性和CRF mRNA和CREB磷酸化的增强。此外，注射PMA （i.c.v）对σ1R-KO小鼠在强迫游泳试验（FST）和悬尾试验（TST）中不动时间的延长也有纠正作用。上述结果表明，σ1R缺失通过降低PKC磷酸化导致GR下调，从而减弱GR介导的对HPA轴的反馈抑制，促进HPA轴的应激反应，导致抑郁样行为的产生。
Sigma-1 receptor knockout (σ1R-KO) mice exhibit a depressive-like phenotype. Because σ1R is highly expressed in the neuronal cells of hypothalamic paraventricular nuclei (PVN), this study investigated the influence of σ1R deficiency on the regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Here, we show that the levels of basal serum corticosterone (CORT), adrenocorticotropic hormone (ACTH) and corticotrophin releasing factor (CRF) as well as the level of CRF mRNA in PVN did not significantly differ between adult male σ1R-KO mice and wild-type (WT) mice. Acute mild restraint stress (AMRS) induced a higher and more sustainable increase in activity of HPA axis and CRF expression in σ1R-KO mice. Percentage of dexamethasone (Dex)-induced reduction in level of CORT was markedly attenuated in σ1R−/− mice. The levels of glucocorticoid receptor (GR) and protein kinase C (PKC) phosphorylation were reduced in the PVN of σ1R-KO mice and σ1R antagonist NE100-treated WT mice. The exposure to AMRS in σ1R-KO mice induced a stronger phosphorylation of cAMP-response element binding protein (CREB) in PVN than that in WT mice. Intracerebroventricular (i.c.v.) injection of PKC activator PMA for 3 days in σ1R-KO mice not only recovered the GR phosphorylation and the percentage of Dex-reduced CORT but also corrected the AMRS-induced hyperactivity of HPA axis and enhancement of CRF mRNA and CREB phosphorylation. Furthermore, the injection (i.c.v.) of PMA in σ1R-KO mice corrected the prolongation of immobility time in forced swim test (FST) and tail suspension test (TST). These results indicate that σ1R deficiency causes down-regulation of GR by reducing PKC phosphorylation, which attenuates GR-mediated feedback inhibition of HPA axis and facilitates the stress response of HPA axis leading to the production of depressive-like behaviors.
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影响因子：
3.6
作者：
Bertarello Zeni, Ana Lucia;Elpo Zomkowski, Andrea Dias;Tasca, Carla Ines
通讯作者：
Tasca, Carla Ines
影响因子：
3.5
作者：
Brossaud, Julie;Roumes, Helene;Corcuff, Jean-Benoit
通讯作者：
Corcuff, Jean-Benoit
影响因子：
4.4
作者：
Cote-Velez, Antonieta;Perez-Martinez, Leonor;Joseph-Bravo, Patricia
通讯作者：
Joseph-Bravo, Patricia
影响因子：
6.1
作者：
Hayashi, T;Su, TP
通讯作者：
Su, TP
影响因子：
4.8
作者：
John, C;Cover, P;Buckingham, J
通讯作者：
Buckingham, J