妊娠相关孤儿受体，一种重要的肝因子，在中脑中具有促进神经甾体合成以及雌性大鼠行为/神经可塑性的作用。
The pregnane xenobiotic receptor, a prominent liver factor, has actions in the midbrain for neurosteroid synthesis and behavioral/neural plasticity of female rats.
机构信息
Department of Psychology, The University at Albany-SUNY Albany, NY, USA ; Department of Biological Sciences, The University at Albany-SUNY Albany, NY, USA ; The Center for Neuroscience Research, The University at Albany-SUNY Albany, NY, USA ; The Center for Life Sciences Research, The University at Albany-SUNY Albany, NY, USA ; Department of Chemistry and Biochemistry, The University of Alaska-Fairbanks Fairbanks, AK, USA ; Institute of Arctic Biology, The University of Alaska-Fairbanks Fairbanks, AK, USA ; IDeA Network of Biomedical Excellence (INBRE), The University of Alaska-Fairbanks Fairbanks, AK, USA.
Department of Psychology, The University at Albany-SUNY Albany, NY, USA ; Institute of Arctic Biology, The University of Alaska-Fairbanks Fairbanks, AK, USA ; IDeA Network of Biomedical Excellence (INBRE), The University of Alaska-Fairbanks Fairbanks, AK, USA.
出版信息
Front Syst Neurosci. 2014 Apr 21;8:60. doi: 10.3389/fnsys.2014.00060. eCollection 2014.
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, 5α-pregnan-3α-ol-20-one (3α,5α-THP). The 18 kDA translocator protein (TSPO) is one rate-limiting factor for 3α,5α-THP neurosteroidogenesis. The hypothesis tested was that PXR is an upstream factor of TSPO for neurosteroidogenesis of 3α,5α-THP in the VTA for lordosis, independent of peripheral glands. First, proestrous rats were administered a TSPO blocker (PK11195) and/or 3α,5α-THP following infusions of PXR antisense oligonucleotides (AS-ODNs) or vehicle to the VTA. Inhibiting TSPO with PK11195 reduced 3α,5α-THP levels in the midbrain and lordosis, an effect that could be reversed with 3α,5α-THP administration, but not AS-ODN+3α,5α-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 3α,5α-THP levels among proestrous > OVX > OVX/ADX rats. Thus, PXR may be upstream of TSPO, involved in neurosteroidogenesis of 3α,5α-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.
一种新的与大脑生长/可塑性相关的因素是孕烷 X 受体（PXR）。PXR 是一种肝脏因子，已知其在清除外源性物质和胆固醇代谢中发挥作用。它在大脑中表达，表明其可能在可塑性方面发挥作用，特别是涉及胆固醇衍生的甾体和神经甾体。交配会诱导雌性啮齿动物中脑腹侧被盖区（VTA）以及大脑其他“可塑性”区域的神经甾体合成，包括海马体，这些区域可能与交配体验的巩固有关。在 VTA 中减少 PXR 会减弱交配诱导的神经甾体 5α-孕烷-3α-醇-20-酮（3α,5α-THP）的生物合成。18kDa 转位蛋白（TSPO）是 3α,5α-THP 神经甾体生成的限速因素之一。测试的假设是，PXR 是 TSPO 的上游因子，用于 VTA 中 3α,5α-THP 的神经甾体生成，与外周腺体无关。首先，发情前期大鼠接受 TSPO 阻断剂（PK11195）和/或 VTA 中 PXR 反义寡核苷酸（AS-ODN）或载体输注后的 3α,5α-THP。用 PK11195 抑制 TSPO 会降低中脑中的 3α,5α-THP 水平和发情前期大鼠的弓状背屈反射，这种作用可以用 3α,5α-THP 给药逆转，但不能用 AS-ODN+3α,5α-THP 逆转。其次，发情前期、卵巢切除（OVX）或卵巢切除/肾上腺切除（OVX/ADX）大鼠在 VTA 中接受 TSPO 增强剂（FGIN 1-27）输注后，给予 AS-ODN 或载体。PXR AS-ODN 阻断了 FGIN 1-27 对发情前期>OVX>OVX/ADX 大鼠弓状背屈反射和 3α,5α-THP 水平的作用。因此，PXR 可能是 TSPO 的上游因子，参与大脑中 3α,5α-THP 的神经甾体生成，以实现可塑性。这个新发现的肝脏因子参与行为/神经可塑性，为未来研究提供了依据，这些研究旨在探索在外周器官（如肝脏）中以其突出作用而闻名的因子，以调节大脑功能及其增强。
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