C57BL/6J小鼠强迫游泳应激后循环及边缘脑区（3α,5α）-3-羟基孕烷-20-酮（3α,5α-THP）水平降低。
Reduction of circulating and selective limbic brain levels of (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP) following forced swim stress in C57BL/6J mice.
作者信息
Maldonado-Devincci Antoniette M, Beattie Matthew C, Morrow Danielle H, McKinley Raechel E, Cook Jason B, O'Buckley Todd K, Morrow A Leslie
机构信息
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, 3027 Thurston Bowles Building, CB 7178, Chapel Hill, NC, 27599, USA.
出版信息
Psychopharmacology (Berl). 2014 Sep;231(17):3281-92. doi: 10.1007/s00213-014-3552-z. Epub 2014 Apr 18.
RATIONALE
Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, and GABAergic neuroactive steroids contribute to homeostatic regulation of this circuitry. Acute forced swim stress (FSS) increases plasma, cortical, and hypothalamic (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP) levels in rats. However, there have not been systemic investigations of acute stress on changes in plasma and brain levels of 3α,5α-THP in mouse models.
OBJECTIVES
The present experiments aimed to assess circulating and local brain levels of 3α,5α-THP following acute FSS in C57BL/6J mice.
METHODS
Mice were exposed to FSS (10 min), and 50 min later, blood and brains were collected. Circulating pregnenolone and 3α,5α-THP levels were assessed in serum. Free-floating brain sections (40 μm, four to five sections/region) were immunostained and analyzed in cortical and limbic brain structures.
RESULTS
FSS decreased circulating 3α,5α-THP (-41.6 ± 10.4 %) and reduced 3α,5α-THP immunolabeling in the paraventricular nucleus of the hypothalamus (-15.2 ± 5.7 %), lateral amygdala (LA, -31.1 ± 13.4 %), and nucleus accumbens (NAcc) shell (-31.9 ± 14.6). Within the LA, vesicular glutamate transporter 1 (VGLUT1) and vesicular GABA transporter were localized in 3α,5α-THP-positively stained cells, while in the NAcc shell, only VGLUT1 was localized in 3α,5α-THP-positively stained cells, suggesting that both glutamatergic and GABAergic cells within the LA are 3α,5α-THP-positive, while in the NAcc shell, 3α,5α-THP only localizes to glutamatergic cells.
CONCLUSIONS
The decrease in circulating and brain levels of 3α,5α-THP may be due to alterations in the biosynthesis/metabolism or changes in the regulation of the HPA axis following FSS. Changes in GABAergic neuroactive steroids in response to stress likely mediate functional adaptations in neuronal activity. This may provide a potential targeted therapeutic avenue to address maladaptive stress responsivity.
理论依据
应激激活下丘脑 - 垂体 - 肾上腺（HPA）轴，而γ-氨基丁酸能神经活性甾体有助于该神经回路的稳态调节。急性强迫游泳应激（FSS）会增加大鼠血浆、皮质和下丘脑的（3α，5α）-3 - 羟基孕烷 - 20 - 酮（3α，5α-THP）水平。然而，尚未在小鼠模型中对急性应激对血浆和脑内3α，5α-THP水平变化进行系统研究。
目的
本实验旨在评估C57BL/6J小鼠急性FSS后3α，5α-THP的循环水平和脑内局部水平。
方法
将小鼠暴露于FSS（10分钟），50分钟后，采集血液和脑组织。检测血清中循环的孕烯醇酮和3α，5α-THP水平。对游离脑切片（40μm，每个区域4至5片）进行免疫染色，并在皮质和边缘脑结构中进行分析。
结果
FSS使循环中的3α，5α-THP降低（-41.6±10.4%），并使下丘脑室旁核（-15.2±5.7%）、外侧杏仁核（LA，-31.1±13.4%）和伏隔核（NAcc）壳（-31.9±14.6）中的3α，5α-THP免疫标记减少。在LA内，囊泡型谷氨酸转运体1（VGLUT1）和囊泡型GABA转运体定位于3α，5α-THP阳性染色细胞中，而在NAcc壳中，只有VGLUT1定位于3α，5α-THP阳性染色细胞中，这表明LA内的谷氨酸能和GABA能细胞均为3α，5α-THP阳性，而在NAcc壳中，3α，5α-THP仅定位于谷氨酸能细胞。
结论
3α,5α-THP循环水平和脑内水平的降低可能是由于FSS后生物合成/代谢改变或HPA轴调节变化所致。应激反应中γ-氨基丁酸能神经活性甾体的变化可能介导神经元活动的功能适应性改变。这可能为解决适应不良的应激反应提供一条潜在的靶向治疗途径。
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