The pregnane xenobiotic receptor, a prominent liver factor, has actions in the midbrain for neurosteroid synthesis and behavioral/neural plasticity of female rats
The pregnane xenobiotic receptor, a prominent liver factor, has actions in the midbrain for neurosteroid synthesis and behavioral/neural plasticity of female rats
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DOI：
10.3389/fnsys.2014.00060
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发表时间：
2014-01-01
影响因子：
3
通讯作者：
Walf, Alicia A.
中科院分区：
文献类型：
--
作者：
Frye, Cheryl A.;Koonce, Carolyn J.;Walf, Alicia A.
孕烷外源性受体（PXR）是大脑生长/可塑性的一个新的重要因素。 PXR 是一种肝脏因子，因其在异生素清除和胆固醇代谢中的作用而闻名。它在大脑中表达，表明可塑性的潜在作用，特别是涉及基于胆固醇的类固醇和神经类固醇。交配会诱导雌性啮齿动物的中脑腹侧被盖区（VTA）以及大脑的其他“可塑”区域（包括海马体）合成神经类固醇，这些区域可能参与交配经历的巩固。减少VTA中的PXR会减弱交配诱导的神经类固醇5α-pregnan3α-ol-20-one（3α，5α-THP）的生物合成。 18 kDA 易位蛋白 (TSPO) 是 3α、5α-THP 神经类固醇生成的限速因子之一。测试的假设是，PXR 是 TSPO 的上游因子，用于 VTA 中 3 α、5 α-THP 的神经类固醇生成，导致脊柱前凸，独立于外周腺体。首先，在将 PXR 反义寡核苷酸 (AS-ODN) 或载体输注至 VTA 后，给发情前期大鼠施用 TSPO 阻滞剂 (PK11195) 和/或 3α、5α-THP。用 PK11195 抑制 TSPO 会降低中脑和脊柱前凸中的 3 α、5 α-THP 水平，这种效应可以通过 3 α、5 α-THP 给药逆转，但不能通过 AS-ODN+ 3 α、5 α-THP 逆转。其次，在 AS-ODN 或媒介物注入 VTA 后，对发情前期、卵巢切除 (OVX) 或卵巢切除/肾上腺切除 (OVX/ADX) 大鼠输注 TSPO 增强剂 (FGIN 1-27)。 PXR AS-ODN 阻断 FGIN 1-27 对前凸的作用以及在发情前期 > OVX > OVX/ADX 大鼠中的 3 α、5 α-THP 水平。因此，PXR可能是TSPO的上游，参与大脑中可塑性的3α、5α-THP的神经类固醇生成。肝脏因素与行为/神经可塑性相关的这一新发现证实了未来的研究，这些研究调查了那些在外周器官（例如肝脏）中具有显着作用的因素，以调节大脑功能及其增强。
A novel factor of interest for growth/ plasticity in the brain is pregnane xenobiotic receptor (PXR). PXR is a liver factor known for its role in xenobiotic clearance and cholesterol metabolism. It is expressed in the brain, suggesting a potential role for plasticity, particularly involving cholesterol-based steroids and neurosteroids. Mating induces synthesis of neurosteroids in the midbrain Ventral Tegmental Area (VTA) of female rodents, as well as other "plastic" regions of the brain, including the hippocampus, that may be involved in the consolidation of the mating experience. Reducing PXR in the VTA attenuates mating-induced biosynthesis of the neurosteroid, 5 alpha-pregnan3 alpha- ol-20-one (3 alpha, 5 alpha-THP). The 18 kDA translocator protein (TSPO) is one rate-limiting factor for 3 alpha, 5 alpha-THP neurosteroidogenesis. The hypothesis tested was that PXR is an upstream factor of TSPO for neurosteroidogenesis of 3 alpha, 5 alpha-THP in the VTA for lordosis, independent of peripheral glands. First, proestrous rats were administered a TSPO blocker (PK11195) and/or 3 alpha, 5 alpha-THP following infusions of PXR antisense oligonucleotides (AS-ODNs) or vehicle to the VTA. Inhibiting TSPO with PK11195 reduced 3 alpha, 5 alpha-THP levels in the midbrain and lordosis, an effect that could be reversed with 3 alpha, 5 alpha-THP administration, but not AS-ODN+ 3 alpha, 5 alpha-THP. Second, proestrous, ovariectomized (OVX), or ovariectomized/adrenalectomized (OVX/ADX) rats were infused with a TSPO enhancer (FGIN 1-27) subsequent to AS-ODNs or vehicle to the VTA. PXR AS-ODNs blocked actions of FGIN 1-27 for lordosis and 3 alpha, 5 alpha-THP levels among proestrous > OVX > OVX/ADX rats. Thus, PXR may be upstream of TSPO, involved in neurosteroidogenesis of 3 alpha, 5 alpha-THP in the brain for plasticity. This novel finding of a liver factor involved in behavioral/neural plasticity substantiates future studies investigating factors known for their prominent actions in the peripheral organs, such as the liver, for modulating brain function and its augmentation.