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

在发育过程中，引导信号受体DCC引导生长的轴突朝向Netrin-1分泌靶点。然而，DCC受体也决定了突触连接的精细组织，一旦生长的轴突已经达到其最终目标，通过控制轴突树枝化，树突生长和突触形成。这些轴突后寻路过程继续发生在成年期，并密切参与经验诱导的突触可塑性。我们实验室最近的工作表明，成年雄性小鼠暴露于慢性社交失败压力导致内侧前额叶皮层（mPFC）锥体神经元DCC受体表达上调，这导致易患社交回避，快感缺乏和焦虑样行为。在压力暴露之前敲除这些神经元中的DCC受体会诱导对这些效应的恢复。成年锥体神经元中DCC介导的Netrin-1信号如何介导应激诱导的行为变化仍有待确定。该提案旨在通过调查是否涉及（i）树突结构/组织和棘形态的DCC依赖性重组以及（ii）特定神经元回路受到影响来解决这个问题，即mPFC向丘脑核的投射和/或mPFC向杏仁核的投射，这两个边缘系统区域涉及动机和情绪信息的处理。为了验证这些想法，我们将继续使用成年雄性小鼠的慢性社会压力模型和一系列行为测试来衡量社会互动，动机和奖励。我们将联合收割机这些行为的方法与国家的最先进的解剖，分子和神经记录策略。在这些实验中，我们还将在雌性小鼠中实施一个社会压力消除模型，以开始解决雌性小鼠中的类似问题。这项研究将首次提供有关引导线索在压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.