Garcia-Garcia Alvaro L, Meng Qingyuan, Canetta Sarah, Gardier Alain M, Guiard Bruno P, Kellendonk Christoph, Dranovsky Alex, Leonardo E David
Dranovsky-Leonardo (ADL) Lab, Division of Integrative Neuroscience, Department of Psychiatry, Columbia University and the New York State Psychiatric Institute, 1051 Riverside Dr., Box 87, New York, NY 10032, USA.
Department of Psychiatry, Columbia University, New York, NY 10032, USA.
Cell Rep. 2017 Jan 31;18(5):1144-1156. doi: 10.1016/j.celrep.2017.01.021.
Lifelong homeostatic setpoints for mood-related behaviors emerge during adolescence. Serotonin (5-HT) plays an important role in refining the formation of brain circuits during sensitive developmental periods. In rodents, the role of 5-HT receptors in general and autoreceptors in particular has been characterized in anxiety. However, less is known about the role of 5-HT receptors in depression-related behavior. Here, we show that whole-life suppression of heteroreceptor expression results in a broad depression-like behavioral phenotype accompanied by physiological and cellular changes within medial prefrontal cortex-dorsal raphe proper (mPFC-DRN) circuitry. These changes include increased basal 5-HT in a mPFC that is hyporesponsive to stress and decreased basal 5-HT levels and firing rates in a DRN hyperactivated by the same stressor. Remarkably, loss of heteroreceptors in the PFC at adolescence is sufficient to recapitulate this depression-like behavioral syndrome. Our results suggest that targeting mPFC 5-HT heteroreceptors during adolescence in humans may have lifelong ramifications for depression and its treatment.
与情绪相关行为的终身稳态设定点在青春期出现。血清素（5-羟色胺，5-HT）在敏感发育阶段对脑回路形成的优化过程中发挥重要作用。在啮齿动物中，5-HT受体尤其是自身受体在焦虑方面的作用已得到明确。然而，5-HT受体在抑郁相关行为中的作用却鲜为人知。在此，我们表明，异受体表达的终身抑制会导致广泛的抑郁样行为表型，并伴有内侧前额叶皮质-中缝背核（mPFC-DRN）神经回路内的生理和细胞变化。这些变化包括对压力反应低下的mPFC中基础5-HT增加，以及被相同应激源过度激活的DRN中基础5-HT水平和放电频率降低。值得注意的是，青春期PFC中异受体的缺失足以重现这种抑郁样行为综合征。我们的研究结果表明，在人类青春期针对mPFC 5-HT异受体可能对抑郁症及其治疗产生终身影响。
