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

在发育过程中，引导线索受体，DCC，引导生长轴突向分泌netrin -1的目标。然而，当生长的轴突到达最终目标时，DCC受体也通过控制轴突树突生长、树突生长和突触形成来决定突触连接的精细组织。这些轴突后寻路过程在成年期继续发生，并与经验诱导的突触可塑性密切相关。我们实验室最近的研究表明，成年雄性小鼠暴露于慢性社会失败压力下，会导致内侧前额叶皮层（mPFC）锥体神经元中DCC受体表达上调，从而导致社交回避、快感缺乏和焦虑样行为的易感性。在压力暴露之前，敲除这些神经元中的DCC受体会诱导对这些影响的恢复能力。成人锥体神经元中dcc介导的Netrin-1信号如何介导应激诱导的行为改变仍有待确定。本研究旨在通过研究(i)树突结构/组织和脊柱形态的dcc依赖性重组是否参与，以及（ii）特定神经元回路是否受到影响，即向伏隔核的mPFC投影和/或向杏仁核的mPFC投影，这两个边缘区域涉及动机和情绪信息的处理，从而解决这个问题。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模型，开始在雌性小鼠中解决类似的问题。这项研究将首次提供关于引导线索在应力诱导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.