Xing Lingyan, Son Jong-Hyun, Stevenson Tamara J, Lillesaar Christina, Bally-Cuif Laure, Dahl Tiffanie, Bonkowsky Joshua L
Interdepartmental Program in Neurosciences, Department of Pediatrics, and Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah 84108.
Department of Pediatrics, and Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah 84108.
J Neurosci. 2015 Nov 4;35(44):14794-808. doi: 10.1523/JNEUROSCI.1295-15.2015.
Modulation of connectivity formation in the developing brain in response to external stimuli is poorly understood. Here, we show that the raphe nucleus and its serotonergic projections regulate pathfinding of commissural axons in zebrafish. We found that the raphe neurons extend projections toward midline-crossing axons and that when serotonergic signaling is blocked by pharmacological inhibition or by raphe neuron ablation, commissural pathfinding is disrupted. We demonstrate that the serotonin receptor htr2a is expressed on these commissural axons and that genetic knock-down of htr2a disrupts crossing. We further show that knock-down of htr2a or ablation of the raphe neurons increases ephrinB2a protein levels in commissural axons. An ephrinB2a mutant can rescue midline crossing when serotonergic signaling is blocked. Furthermore, we found that regulation of serotonin expression in the raphe neurons is modulated in response to the developmental environment. Hypoxia causes the raphe to decrease serotonin levels, leading to a reduction in midline crossing. Increasing serotonin in the setting of hypoxia restored midline crossing. Our findings demonstrate an instructive role for serotonin in axon guidance acting through ephrinB2a and reveal a novel mechanism for developmental interpretation of the environmental milieu in the generation of mature neural circuitry.
We show here that serotonin has a novel role in regulating connectivity in response to the developmental environment. We demonstrate that serotonergic projections from raphe neurons regulate pathfinding of crossing axons. The neurons modulate their serotonin levels, and thus alter crossing, in response to the developmental environment including hypoxia. The findings suggest that modification of the serotonergic system by early exposures may contribute to permanent CNS connectivity alterations. This has important ramifications because of the association between premature birth and accompanying hypoxia, and increased risk of autism and evidence associating in utero exposure to some antidepressants and neurodevelopmental disorders. Finally, this work demonstrates that the vertebrate CNS can modulate its connectivity in response to the external environment.
人们对发育中的大脑中连接形成如何响应外部刺激的调节了解甚少。在此，我们表明中缝核及其5-羟色胺能投射调节斑马鱼连合轴突的路径寻找。我们发现中缝神经元向穿过中线的轴突延伸投射，并且当5-羟色胺能信号通过药理学抑制或中缝神经元消融被阻断时，连合路径寻找会被破坏。我们证明5-羟色胺受体htr2a在这些连合轴突上表达，并且htr2a的基因敲低会破坏交叉。我们进一步表明htr2a的敲低或中缝神经元的消融会增加连合轴突中ephrinB2a蛋白水平。一个ephrinB2a突变体在5-羟色胺能信号被阻断时可以挽救中线交叉。此外，我们发现中缝神经元中5-羟色胺表达的调节会响应发育环境而被调节。缺氧导致中缝降低5-羟色胺水平，导致中线交叉减少。在缺氧情况下增加5-羟色胺可恢复中线交叉。我们的发现证明了5-羟色胺在通过ephrinB2a起作用的轴突导向中具有指导作用，并揭示了在成熟神经回路生成中对环境背景进行发育解释的一种新机制。
我们在此表明5-羟色胺在响应发育环境调节连接性方面具有新作用。我们证明从中缝神经元发出的5-羟色胺能投射调节交叉轴突的路径寻找。这些神经元响应包括缺氧在内的发育环境调节其5-羟色胺水平，从而改变交叉。这些发现表明早期暴露对5-羟色胺能系统进行修饰可能导致中枢神经系统连接性的永久性改变。这具有重要影响，因为早产与伴随的缺氧之间存在关联，以及自闭症风险增加，还有子宫内接触某些抗抑郁药与神经发育障碍相关的证据。最后，这项工作证明脊椎动物中枢神经系统可以响应外部环境调节其连接性。
