MC4R Signaling in Dorsal Raphe Nucleus Controls Feeding, Anxiety, and Depression
MC4R Signaling in Dorsal Raphe Nucleus Controls Feeding, Anxiety, and Depression
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DOI：
10.1016/j.celrep.2020.108267
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发表时间：
2020-10-13
期刊：
影响因子：
8.8
通讯作者：
Diano, Sabrina
中科院分区：
文献类型：
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作者：
Bruschetta, Giuseppe;Jin, Sungho;Diano, Sabrina
重度抑郁症与体重减轻和食欲下降有关；然而，连接这些条件的信号尚不清楚。在这里，我们发现中缝背核（DRN）中的MC4R信号影响进食、焦虑和抑郁。DRN输注α - msh降低DRN神经元的激活和摄食。DRN MC4R在gaba能产生prcp的神经元中表达。DRN选择性敲除PRCP (PRCP (DRNKD))，一种使α - msh失活的酶，可以减少进食和DRN神经元的激活。有趣的是，Prcp（DRNKD）小鼠表现出较低的DRN血清素水平和抑郁样行为。同样，Prcp消融的MC4R小鼠（Prcp(MC4RKO)）表现出与Prcp（DRNKD）小鼠相似的代谢和行为表型。PRCP （MC4RKO）小鼠DRN MC4R神经元选择性PRCP重表达部分逆转摄食，同时完全恢复情绪行为。DRN MC4R神经元的化学发生抑制会引起焦虑、抑郁和摄食减少，而化学发生激活会逆转这些影响。我们的研究结果表明，DRN中的MC4R信号在喂养、焦虑和抑郁中起作用。
Major depressive disorder is associated with weight loss and decreased appetite; however, the signaling that connects these conditions is unclear. Here, we show that MC4R signaling in the dorsal raphe nucleus (DRN) affects feeding, anxiety, and depression. DRN infusion of alpha-MSH decreases DRN neuronal activation and feeding. DRN MC4R is expressed in GABAergic PRCP-producing neurons. DRN selective knockdown of PRCP (Prcp(DRNKD)), an enzyme inactivating alpha-MSH, decreases feeding and DRN neuronal activation. Interestingly, Prcp(DRNKD) mice present lower DRN serotonin levels and depressive-like behavior. Similarly, PRCP-ablated MC4R mice (Prcp(MC4RKO)) show metabolic and behavioral phenotypes comparable to those of Prcp(DRNKD) mice. Selective PRCP re-expression in DRN MC4R neurons of Prcp(MC4RKO) mice partially reverses feeding, while fully restoring mood behaviors. Chemogenetic inhibition of DRN MC4R neurons induces anxiety, depression, and reduced feeding, whereas chemogenetic activation reverses these effects. Our results indicate that MC4R signaling in DRN plays a role in feeding, anxiety, and depression.