Disruption of 5-HT1A function in adolescence but not early adulthood leads to sustained increases of anxiety.
Disruption of 5-HT1A function in adolescence but not early adulthood leads to sustained increases of anxiety.
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DOI：
10.1016/j.neuroscience.2015.05.076
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发表时间：
2016-05-03
期刊：
影响因子：
3.3
通讯作者：
Leonardo ED
中科院分区：
文献类型：
--
作者：
Garcia-Garcia AL;Meng Q;Richardson-Jones J;Dranovsky A;Leonardo ED
目前的证据表明，焦虑症与发育有关。早期对辅助情绪调节的回路的侮辱被认为会在以后的生活中导致疾病。来自小鼠的研究证据表明，一般情况下，5-羟色胺能系统，特别是5-HT1A受体，在出生后早期对于帮助焦虑行为的回路的正常发展至关重要。然而，关于5-羟色胺通过5-HT1a受体在断奶后正常焦虑行为的出现和成熟的成年表型之间的作用，人们知之甚少。在这里，我们在雄性小鼠身上使用转基因和药理学方法，以确定5-HT1A功能在青春期调节焦虑行为的回路稳定中的敏感期。使用转基因方法，我们发现在青春期早期开始抑制5-HT1A受体的表达会导致在旷场测试中出现焦虑样的表型。我们进一步证明，在出生后35天和50天之间使用5-HT1A拮抗剂方法100,635，而不是在以后的时间点进行治疗，会导致基于行为学的冲突测试(如开场测试和高架加迷宫)中焦虑的改变。焦虑行为的这种变化在更多与抑郁有关的蔗糖偏好测试或强迫游泳测试中没有影响行为。Way 100,635的治疗不影响成年5-HT1A的表达水平，但导致中缝5-羟色胺转运体的表达增加，以及与成年小鼠观察到的行为变化相关的前额叶皮质和中缝5-羟色胺水平的增加。这项工作表明，在青春期(出现病理性焦虑的时期)，而不是成年早期，通过5-HT1a受体发出的信号在调节焦虑设定点方面是至关重要的。这些数据表明，在青春期对5-羟色胺能系统进行短暂干预可能会导致生理和行为的深刻和持久的变化。
Current evidence suggests that anxiety disorders have developmental origins. Early insults to the circuits that sub-serve emotional regulation are thought to cause disease later in life. Evidence from studies in mice demonstrate that the serotonergic system in general, and 5-HT1A receptors in particular, are critical during the early postnatal period for the normal development of circuits that subserve anxious behavior. However, little is known about the role of serotonin signaling through 5-HT1A receptors between the emergence of normal anxiety behavior after weaning, and the mature adult phenotype. Here, we use both transgenic and pharmacological approaches in male mice, to identify a sensitive period for 5-HT1A function in the stabilization of circuits mediating anxious behavior during adolescence. Using a transgenic approach we show that suppression of 5-HT1A receptor expression beginning in early adolescence results in an anxiety-like phenotype in the open field test. We further demonstrate that treatment with the 5-HT1A antagonist WAY 100,635 between postnatal day (P)35 and P50 but not at later timepoints, results in altered anxiety in ethologically based conflict tests like the open field test and elevated plus maze. This change in anxiety behavior occurs without impacting behavior in the more depression related sucrose preference test or forced swim test. The treatment with WAY 100,635 does not affect adult 5-HT1A expression levels, but leads to increased expression of the serotonin transporter in the raphe, along with enhanced serotonin levels in both the prefrontal cortex and raphe that correlate with the behavioral changes observed in adult mice. This work demonstrates that signaling through 5-HT1A receptors during adolescence (a time when pathological anxiety emerges), but not early adulthood, is critical in regulating anxiety setpoints. These data suggest the possibility that brief interventions in the serotonergic system during adolescence could lead to profound and enduring changes in physiology and behavior.