Netrin-1 mediates stress-induced plasticity of adult pyramidal neurons

在发育过程中，引导线索受体DCC引导生长的轴突朝向Netrin-1分泌靶点。然而，DCC受体也通过控制轴突的分枝、树突的生长和突触的形成，在生长的轴突达到最终目标后决定突触连接的精细组织。这些轴突后寻路过程在成年后继续发生，并与经验诱导的突触可塑性密切相关。我们实验室最近的工作表明，成年雄性小鼠暴露在慢性社会失败应激下，会导致内侧前额叶皮质(MPFC)锥体神经元DCC受体表达上调，从而导致容易出现社交回避、快感缺失和焦虑样行为。在应激暴露前敲除这些神经元中的DCC受体可以诱导对这些影响的弹性。DCC介导的成年锥体神经元Netrin-1信号如何介导应激诱导的行为改变仍有待确定。这一建议旨在通过研究是否涉及(I)依赖于DCC的树突结构/组织和脊椎形态的重组以及(Ii)特定的神经元回路是否受到影响，即mPFC投射到伏隔核和/或mPFC投射到杏仁核，这两个边缘区域参与动机和情绪信息的处理。为了测试这些想法，我们将继续使用成年雄性小鼠的慢性社交压力模型和一系列行为测试来衡量社交互动、动机和奖励。我们将把这些行为方法与最先进的解剖学、分子和神经记录策略结合起来。在这些实验中，我们还将在雌性小鼠中实施社会压力失败的模型，以开始在雌性小鼠中解决类似的问题。这项研究将首次提供有关指导线索在应力诱导的可塑性中的作用的信息。它还将识别参与这一过程的神经回路。

During development, the guidance cue receptor, DCC, guides growing axons towards Netrin-1-secreting targets. However, DCC receptors also dictate the fine organization of synaptic connectivity once growing axons have reached their final targets, by controlling axon arborization, dendritic growth and synapse formation. These post-axonal pathfinding processes continue to occur in adulthood and are intimately involved in experience-induced synaptic plasticity. Recent work from our laboratory shows that exposure to chronic social defeat stress in adult male mice results in upregulation of DCC receptor expression in medial prefrontal cortex (mPFC) pyramidal neurons and that this causes susceptibility to develop social avoidance, anhedonia, and anxiety-like behaviors. Knocking out DCC receptors in these neurons prior to stress exposure induces resilience to these effects. How DCC-mediated Netrin-1 signaling in adult pyramidal neurons mediate stress-induced behavioral changes remains to be determined. This proposal is aimed at addressing this question by investigating whether (i) DCC-dependent reorganization of dendritic structure/organization and of spine morphology are involved and (ii) specific neuronal circuits are affected, namely mPFC projections to the nucleus accumbens and/or mPFC projections to the amygdala, two limbic regions involved in motivation and processing of emotional information. To test these ideas, we will continue using a model of chronic social stress in adult male mice and a battery of behavioral tests to measure social interaction, motivation and reward. We will combine these behavioral methods with state-of-the-art anatomical, molecular, and neural recording strategies. In these experiments we will also implement a model of social stress defeat in female mice to begin addressing similar questions in females. This research will provide information, for the first time, about the role of guidance cues in stress-induced plasticity. It will also identify the neural circuitries that are involved in this process.