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

Netrin-1 介导应激诱导的成年锥体神经元可塑性

• 批准号: RGPIN-2020-04703
• 负责人: Flores, Cecilia
• 金额: $ 4.74万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=763660
• 关键词: Netrin; mediates; stress; induced; plasticity

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.

在开发过程中，DCC引导提示受体指导轴突将轴突延伸到Netrin-1分泌靶标。但是，DCC受体还通过控制轴突植物，树突生长和突触形成，一旦生长轴突达到最终目标，就决定了突触连通性的良好组织。这些轴后探路过程在成年期继续进行，并与经验引起的突触可塑性密切相关。我们实验室的最新工作表明，成年雄性小鼠中慢性社会失败压力的暴露导致内侧前额叶皮层（MPFC）锥体神经元中DCC受体表达的上调，这会导致发展社会避免，ANHEDONIA和焦虑症状的敏感性。在压力暴露之前，在这些神经元中敲出DCC受体会引起对这些作用的弹性。 DCC介导的成年锥体神经元中的Netrin-1信号如何介导应力诱导的行为变化尚待确定。 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.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会压力模型和一系列行为测试来衡量社交互动，动机和回报。我们将将这些行为方法与最新的解剖学，分子和神经记录策略相结合。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，以开始解决女性中的类似问题。这项研究将首次提供有关指导线索在压力引起的可塑性中的作用的信息。它还将确定此过程中涉及的神经电路。