Gq/5-HT2c 受体信号激活局部 GABA 能抑制性反馈回路，调节小鼠的 5-羟色胺能放电和焦虑。
Gq/5-HT2c receptor signals activate a local GABAergic inhibitory feedback circuit to modulate serotonergic firing and anxiety in mice.
机构信息
Department of General Zoology and Neurobiology, Ruhr University Bochum, D-44780 Bochum, Germany.
出版信息
Proc Natl Acad Sci U S A. 2014 Apr 29;111(17):6479-84. doi: 10.1073/pnas.1321576111. Epub 2014 Apr 14.
Abstract
Serotonin 2c receptors (5-HT2c-Rs) are drug targets for certain mental disorders, including schizophrenia, depression, and anxiety. 5-HT2c-Rs are expressed throughout the brain, making it difficult to link behavioral changes to circuit specific receptor expression. Various 5-HT-Rs, including 5-HT2c-Rs, are found in the dorsal raphe nucleus (DRN); however, the function of 5-HT2c-Rs and their influence on the serotonergic signals mediating mood disorders remain unclear. To investigate the role of 5-HT2c-Rs in the DRN in mice, we developed a melanopsin-based optogenetic probe for activation of Gq signals in cellular domains, where 5-HT2c-Rs are localized. Our results demonstrate that precise temporal control of Gq signals in 5-HT2c-R domains in GABAergic neurons upstream of 5-HT neurons provides negative feedback regulation of serotonergic firing to modulate anxiety-like behavior in mice.
摘要
5-羟色胺 2c 受体（5-HT2c-Rs）是某些精神疾病的药物靶点，包括精神分裂症、抑郁症和焦虑症。5-HT2c-Rs 在整个大脑中表达，这使得将行为变化与特定回路的受体表达联系起来变得困难。各种 5-HT-Rs，包括 5-HT2c-Rs，都存在于中缝背核（DRN）中；然而，5-HT2c-Rs 的功能及其对调节情绪障碍的血清素信号的影响仍不清楚。为了研究 5-HT2c-Rs 在 DRN 中的作用，我们开发了一种基于黑视蛋白的光遗传学探针，用于激活细胞区域中的 Gq 信号，5-HT2c-Rs 定位于该区域。我们的结果表明，在 5-HT 神经元上游的 GABA 能神经元中，5-HT2c-R 域内 Gq 信号的精确时间控制为调节 5-HT 神经元的放电提供了负反馈调节，从而调节小鼠的焦虑样行为。
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J Neurosci. 2013 Aug 28;33(35):13978-88, 13988a. doi: 10.1523/JNEUROSCI.2383-13.2013.
2
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Neurosci Res. 2013 Jan;75(1):23-8. doi: 10.1016/j.neures.2012.07.005. Epub 2012 Jul 31.
3
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Neuropharmacology. 2011 Sep;61(3):524-43. doi: 10.1016/j.neuropharm.2011.04.008. Epub 2011 Apr 16.
4
Functional topography of midbrain and pontine serotonergic systems: implications for synaptic regulation of serotonergic circuits.中脑和脑桥 5-羟色胺能系统的功能拓扑：对 5-羟色胺能回路的突触调节的意义。
Psychopharmacology (Berl). 2011 Feb;213(2-3):243-64. doi: 10.1007/s00213-010-2089-z. Epub 2010 Nov 19.
5
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Neuroscience. 2010 Dec 15;171(3):734-46. doi: 10.1016/j.neuroscience.2010.08.060. Epub 2010 Sep 24.
6
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J Biol Chem. 2010 Oct 1;285(40):30825-36. doi: 10.1074/jbc.M110.147298. Epub 2010 Jul 19.
7
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Br J Pharmacol. 2009 Nov;158(6):1477-85. doi: 10.1111/j.1476-5381.2009.00406.x. Epub 2009 Oct 20.
8
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