BACKGROUND Dopaminergic input to the prefrontal cortex (PFC) increases throughout adolescence and, by establishing precisely localized synapses, calibrates cognitive function. However, why and how mesocortical dopamine axon density increases across adolescence remains unknown. METHODS We used a developmental application of axon-initiated recombination to label and track the growth of dopamine axons across adolescence in mice. We then paired this recombination with cell-specific knockdown of the netrin-1 receptor DCC to determine its role in adolescent dopamine axon growth. We then assessed how altering adolescent PFC dopamine axon growth changes the structural and functional development of the PFC by quantifying pyramidal neuron morphology and cognitive performance. RESULTS We show, for the first time, that dopamine axons continue to grow from the striatum to the PFC during adolescence. Importantly, we discover that DCC, a guidance cue receptor, controls the extent of this protracted growth by determining where and when dopamine axons recognize their final target. When DCC-dependent adolescent targeting events are disrupted, dopamine axons continue to grow ectopically from the nucleus accumbens to the PFC and profoundly change PFC structural and functional development. This leads to alterations in cognitive processes known to be impaired across psychiatric conditions. CONCLUSIONS The prolonged growth of dopamine axons represents an extraordinary period for experience to influence their adolescent trajectory and predispose to or protect against psychopathology. DCC receptor signaling in dopamine neurons is a molecular link where genetic and environmental factors may interact in adolescence to influence the development and function of the prefrontal cortex.

中文翻译：

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DCC 受体通过确定青春期多巴胺轴突靶向来驱动前额叶皮层成熟

背景 前额叶皮层 (PFC) 的多巴胺能输入在整个青春期都会增加，并且通过建立精确定位的突触，校准认知功能。然而，中皮层多巴胺轴突密度在青春期增加的原因和方式仍然未知。方法我们使用轴突启动重组的发育应用来标记和跟踪小鼠整个青春期多巴胺轴突的生长。然后，我们将这种重组与 netrin-1 受体 DCC 的细胞特异性敲低配对，以确定其在青少年多巴胺轴突生长中的作用。然后，我们通过量化锥体神经元形态和认知表现来评估改变青少年 PFC 多巴胺轴突生长如何改变 PFC 的结构和功能发育。结果我们第一次表明，多巴胺轴突在青春期继续从纹状体生长到 PFC。重要的是，我们发现 DCC（一种引导提示受体）通过确定多巴胺轴突识别其最终目标的位置和时间来控制这种长期生长的程度。当依赖 DCC 的青少年靶向事件被破坏时，多巴胺轴突继续从伏隔核到 PFC 异位生长，并深刻改变 PFC 的结构和功能发育。这会导致已知在精神疾病中受损的认知过程发生改变。结论 多巴胺轴突的长期生长代表了一个非凡的时期，可以影响他们的青少年发展轨迹并导致或预防精神病理学。