Abnormal neuronal morphological features, such as dendrite branching, axonal branching, and spine density, are thought to contribute to the symptoms of depression and anxiety. However, the role and molecular mechanisms of aberrant neuronal morphology in the regulation of mood disorders remain poorly characterized. Here, we show that neuritin, an activity-dependent protein, regulates the axonal morphology of serotonin neurons. Male neuritin knock-out (KO) mice harbored impaired axonal branches of serotonin neurons in the medial prefrontal cortex and basolateral region of the amygdala (BLA), and male neuritin KO mice exhibited depressive and anxiety-like behaviors. We also observed that the expression of neuritin was decreased by unpredictable chronic stress in the male mouse brain and that decreased expression of neuritin was associated with reduced axonal branching of serotonin neurons in the brain and with depressive and anxiety behaviors in mice. Furthermore, the stress-mediated impairments in axonal branching and depressive behaviors were reversed by the overexpression of neuritin in the BLA. The ability of neuritin to increase axonal branching in serotonin neurons involves fibroblast growth factor (FGF) signaling, and neuritin contributes to FGF-2-mediated axonal branching regulation in vitro. Finally, the oral administration of an FGF inhibitor reduced the axonal branching of serotonin neurons in the brain and caused depressive and anxiety behaviors in male mice. Our results support the involvement of neuritin in models of stress-induced depression and suggest that neuronal morphological plasticity may play a role in controlling animal behavior.

异常的神经元形态特征，如树突分支、轴突分支和脊柱密度，被认为会导致抑郁和焦虑的症状。然而，异常神经元形态在调节情绪障碍中的作用和分子机制仍然难以表征。在这里，我们表明神经素是一种活性依赖性蛋白，可调节血清素神经元的轴突形态。雄性神经蛋白敲除 （KO） 小鼠在杏仁核 （BLA） 的内侧前额叶皮层和基底外侧区域 5-羟色胺神经元的轴突分支受损，雄性神经蛋白 KO 小鼠表现出抑郁和焦虑样行为。我们还观察到，雄性小鼠大脑中不可预测的慢性应激降低了神经炎的表达，并且神经炎表达的减少与大脑中 5-羟色胺神经元的轴突分支减少以及小鼠的抑郁和焦虑行为有关。此外，BLA 中神经蛋白的过表达逆转了应力介导的轴突分支和抑郁行为损伤。神经素增加 5-羟色胺神经元轴突分支的能力涉及成纤维细胞生长因子 （FGF） 信号传导，神经素有助于体外 FGF-2 介导的轴突分支调节。最后，口服 FGF 抑制剂减少了大脑中 5-羟色胺神经元的轴突分支，并导致雄性小鼠出现抑郁和焦虑行为。我们的研究结果支持神经炎参与压力诱导的抑郁症模型，并表明神经元形态可塑性可能在控制动物行为中发挥作用。