Hypothalamic-pituitary-adrenal axis abnormalities in response to deletion of 11beta-HSD1 is strain-dependent.
Hypothalamic-pituitary-adrenal axis abnormalities in response to deletion of 11beta-HSD1 is strain-dependent.
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下丘脑 - 垂体 - 肾上腺轴异常，响应于11BETA-HSD1的缺失是应变依赖性的。
DOI：
10.1111/j.1365-2826.2009.01899.x
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发表时间：
2009-11
影响因子：
3.2
通讯作者：
Holmes MC
中科院分区：
文献类型：
--
作者：
Carter RN;Paterson JM;Tworowska U;Stenvers DJ;Mullins JJ;Seckl JR;Holmes MC
下丘脑-垂体-肾上腺（HPA）轴活动的个体间差异是神经精神和代谢紊乱的不同易感性的基础，尽管这种差异的基础尚不清楚。11β-羟基类固醇脱氢酶1型（11β-HSD1）先前已被证明影响HPA轴活性。11β-HSD1缺失的129/MF1小鼠（129/MF1 HSD1−/−）肾上腺大小显著增加，HPA活性改变，与糖皮质激素负反馈减少一致。在此背景下，无应激小鼠血浆皮质酮和促肾上腺皮质激素（ACTH）浓度升高，与相同背景的遗传对照相比，hsd1缺失小鼠应激后对外源性糖皮质激素反馈的敏感性降低，并显示延迟恢复到基线水平。在目前的研究中，我们报告了遗传背景可以显著改变这种模式。与具有129/MF1基因背景的HSD1 - / -小鼠相比，具有C57Bl/6J基因背景的HSD1 - / -小鼠具有正常的基础血浆皮质酮和ACTH浓度，应激后血浆皮质酮和ACTH浓度恢复到正常基线水平。此外，与129/MF1 HSD1 - / -小鼠相比，C57Bl/6J HSD1 - / -小鼠在参与糖皮质激素负反馈的大脑区域（海马和室旁核）中糖皮质激素受体表达增加，这表明这可能是对HPA轴反馈控制正常化的代偿反应。为了支持这一假设，C57Bl/6J HSD1 - / -小鼠对地塞米松介导的皮质酮峰值抑制表现出更高的敏感性。因此，尽管11β-HSD1似乎有助于调节HPA轴，但遗传背景在控制对其丢失的反应（及其后果）方面至关重要。类似的可塑性变化可能是HPA轴失调相关疾病易感性的个体间差异的基础。他们还表明，11β-HSD1抑制并不一定会激活HPA轴。
Inter-individual differences in hypothalamic-pituitary-adrenal (HPA) axis activity underlie differential vulnerability to neuropsychiatric and metabolic disorders, although the basis of this variation is poorly understood. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has previously been shown to influence HPA axis activity. 129/MF1 mice null for 11β-HSD1 (129/MF1 HSD1−/−) have greatly increased adrenal gland size and altered HPA activity, consistent with reduced glucocorticoid negative feedback. On this background, concentrations of plasma corticosterone and adrenocorticotrophic hormone (ACTH) were elevated in unstressed mice, and showed a delayed return to baseline after stress in HSD1-null mice with reduced sensitivity to exogenous glucocorticoid feedback compared to same-background genetic controls. In the present study, we report that the genetic background can dramatically alter this pattern. By contrast to HSD1−/− mice on a 129/MF1 background, HSD1−/− mice congenic on a C57Bl/6J background have normal basal plasma corticosterone and ACTH concentrations and exhibit normal return to baseline of plasma corticosterone and ACTH concentrations after stress. Furthermore, in contrast to 129/MF1 HSD1−/− mice, C57Bl/6J HSD1−/− mice have increased glucocorticoid receptor expression in areas of the brain involved in glucocorticoid negative feedback (hippocampus and paraventricular nucleus), suggesting this may be a compensatory response to normalise feedback control of the HPA axis. In support of this hypothesis, C57Bl/6J HSD1−/− mice show increased sensitivity to dexamethasone-mediated suppression of peak corticosterone. Thus, although 11β-HSD1 appears to contribute to regulation of the HPA axis, the genetic background is crucial in governing the response to (and hence the consequences of) its loss. Similar variations in plasticity may underpin inter-individual differences in vulnerability to disorders associated with HPA axis dysregulation. They also indicate that 11β-HSD1 inhibition does not inevitably activate the HPA axis.
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影响因子：
1.6
作者：
Hagenbuch, Niels;Feldon, Joram;Yee, Benjamin K.
通讯作者：
Yee, Benjamin K.
影响因子：
4.8
作者：
LAKSHMI, V;SAKAI, RR;MONDER, C
通讯作者：
MONDER, C
影响因子：
3.4
作者：
McCutcheon, J. E.;Fisher, A. S.;Hunt, S. P.
通讯作者：
Hunt, S. P.
影响因子：
4.8
作者：
Peinado, JR;Laurent, V;Lindberg, I
通讯作者：
Lindberg, I
DOI：
10.1523/jneurosci.4464-05.2006
发表时间：
2006-04-05
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Holmes MC;Abrahamsen CT;French KL;Paterson JM;Mullins JJ;Seckl JR
通讯作者：
Seckl JR