Blockade of Indoleamine 2, 3-dioxygenase 1 ameliorates hippocampal neurogenesis and BOLD-fMRI signals in chronic stress precipitated depression.
Blockade of Indoleamine 2, 3-dioxygenase 1 ameliorates hippocampal neurogenesis and BOLD-fMRI signals in chronic stress precipitated depression.
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阻断吲哚胺 2, 3-双加氧酶 1 可改善慢性应激诱发抑郁症中的海马神经发生和 BOLD-fMRI 信号。
DOI：
10.18632/aging.202511
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发表时间：
2021-02-11
期刊：
影响因子：
--
通讯作者：
Lv Z
中科院分区：
文献类型：
--
作者：
Gao L;Gao T;Zeng T;Huang P;Wong NK;Dong Z;Li Y;Deng G;Wu Z;Lv Z
吲哚胺2，3-双加氧酶1(IDO1)与抑郁症的发病机制有关，但其分子机制尚不清楚。我们利用Ido1-/-小鼠和WT小鼠的慢性不可预测温和应激(CUMS)模型，研究了IDO1在抑郁症中的分子机制。采用功能磁共振成像(FMRI)技术采集小鼠脑血氧水平依赖(BOLD)信号。通过立体定向注射IDO1抑制剂INCB024360干预中缝背核(DRN)。发现CUMS小鼠血清IDO1活性升高，5-羟色胺含量降低，且血清IDO1活性与5-羟色胺水平呈负相关。在CUMS小鼠中，IDO1在海马区和DRN区持续增加，伴随着海马区BDNF水平的降低。具体地说，药物抑制DRN中的IDO1活性可以通过改善CUMS小鼠海马区BDNF的表达和神经发生来缓解抑郁样行为。此外，通过稳定的BOLD信号、脑源性神经营养因子的表达和海马区的神经发生，Ido1的消融对CUMS小鼠施加了应激抵抗，降低了抑郁的敏感性。因此，IDO1的过度活动在调节5-羟色胺代谢和脑源性神经营养因子功能中起着至关重要的作用，从而影响抑郁障碍患者海马神经发生和BOLD信号的转归。
Indoleamine 2, 3-dioxygenase 1 (IDO1) has been implicated in the pathogenesis of depression, though its molecular mechanism is still poorly understood. We investigated the molecular mechanism of IDO1 in depression by using the chronic unpredictable mild stress (CUMS) model in Ido1-/- mice and WT mice. The brain blood oxygen level dependent (BOLD) signals in mice were collected by functional magnetic resonance imaging (fMRI) technology. IDO1 inhibitor INCB024360 was intervened in dorsal raphe nucleus (DRN) through stereotactic injection. We found an elevation of serum IDO1 activity and decreased 5-HT in CUMS mice, and the serum IDO1 activity was negatively correlated with 5-HT level. Consistently, IDO1 was increased in hippocampus and DRN regions, accompanied by a reduction of hippocampal BDNF levels in mice with CUMS. Specifically, pharmacological inhibition of IDO1 activity in the DRN alleviated depressive-like behaviour with improving hippocampal BDNF expression and neurogenesis in CUMS mice. Furthermore, ablation of Ido1 exerted stress resistance and decreased the sensitivity of depression in CUMS mice with the stable BOLD signals, BDNF expression and neurogenesis in hippocampus. Thus, IDO1 hyperactivity played crucial roles in modulating 5-HT metabolism and BDNF function thereby impacting outcomes of hippocampal neurogenesis and BOLD signals in depressive disorder.
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影响因子：
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DOI：
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发表时间：
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影响因子：
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