5-HT 神经元中脂联素 AdipoR1 受体对抑郁相关行为的调节。,Molecular Psychiatry

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5-HT 神经元中脂联素 AdipoR1 受体对抑郁相关行为的调节。
Molecular Psychiatry ( IF 9.6 ) Pub Date : 2020-01-24 , DOI: 10.1038/s41380-020-0649-0
Chen Li _{1,

2} , Fantao Meng ₁ , Jacob C Garza _{2,

3} , Jing Liu ₁ , Yun Lei ₂ , Sergei A Kirov ₂ , Ming Guo _{1,

2} , Xin-Yun Lu ₂

Affiliation

脂肪细胞衍生的激素脂联素具有超越代谢控制的广泛功能。我们之前曾报道脂联素在大脑中起作用以调节与抑郁相关的行为。然而，尚未确定其潜在的神经底物。在这里，我们显示脂联素受体 1 (AdipoR1) 在中缝背核 (DRN) 中表达，并与色氨酸羟化酶 2 (TPH2)、血清素 (5-HT) 神经元的标记物共定位。5-HT 神经元中 AdipoR1 的选择性缺失会导致雄性小鼠快感缺失，这表现为雌性尿液嗅探时间和糖精偏好减少，雌性小鼠行为绝望以及两性对蔗糖偏好的压力诱导降低。在 5-HT 神经元中缺乏 AdipoR1 的雄性而非雌性小鼠中，TPH2 的表达水平下调，同时 DRN 及其两个主要投射区域海马和内侧前额叶皮层 (mPFC) 中的 5-HT 免疫反应性降低. 此外，5-羟色胺转运蛋白 (SERT) 表达在雄性小鼠的 DRN 投射区域中上调，但仅在雌性小鼠的 mPFC 中上调。这些变化可能导致 5-HT 合成减少和/或 5-HT 再摄取增加，从而减少 5-HT 传递。在条件性基因敲除雄性小鼠中观察到选择性5-羟色胺再摄取抑制剂氟西汀而不是选择性去甲肾上腺素再摄取抑制剂地昔帕明的增强行为反应支持抑郁症相关表型的5-HT传递缺陷。

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Modulation of depression-related behaviors by adiponectin AdipoR1 receptors in 5-HT neurons.

The adipocyte-derived hormone adiponectin has a broad spectrum of functions beyond metabolic control. We previously reported that adiponectin acts in the brain to regulate depression-related behaviors. However, its underlying neural substrates have not been identified. Here we show that adiponectin receptor 1 (AdipoR1) is expressed in the dorsal raphe nucleus (DRN) and colocalized with tryptophan hydroxylase 2 (TPH2), a marker of serotonin (5-HT) neurons. Selective deletion of AdipoR1 in 5-HT neurons induced anhedonia in male mice, as indicated by reduced female urine sniffing time and saccharin preference, and behavioral despair in female mice and enhanced stress-induced decrease in sucrose preference in both sexes. The expression levels of TPH2 were downregulated with a concurrent reduction of 5-HT-immunoreactivity in the DRN and its two major projection regions, the hippocampus and medial prefrontal cortex (mPFC), in male but not female mice lacking AdipoR1 in 5-HT neurons. In addition, serotonin transporter (SERT) expression was upregulated in both DRN projection fields of male mice but only in the mPFC of female mice. These changes presumably lead to decreased 5-HT synthesis and/or increased 5-HT reuptake, thereby reducing 5-HT transmission. The augmented behavioral responses to the selective serotonin reuptake inhibitor fluoxetine but not desipramine, a selective norepinephrine reuptake inhibitor, observed in conditional knockout male mice supports deficient 5-HT transmission underlying depression-related phenotypes. Our results indicate that adiponectin acts on 5-HT neurons through AdipoR1 receptors to regulate depression-related behaviors in a sex-dependent manner.

更新日期：2020-01-26

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