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 分泌目标。然而，一旦生长的轴突达到最终目标，DCC 受体也会通过控制轴突树枝化、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。我们实验室最近的研究表明，成年雄性小鼠暴露于慢性社交失败压力会导致内侧前额叶皮层 (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 受体可以诱导对这些影响的恢复。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) DCC 依赖的树突结构/组织和脊柱形态的重组以及 (ii) 特定神经元回路受到影响，即 mPFC 投射到伏隔核和/或 mPFC 来解决这个问题投射到杏仁核，这两个边缘区域涉及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会压力模型和一系列行为测试来测量社会互动、动机和奖励。我们将把这些行为方法与最先进的解剖、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交压力失败模型，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指导线索在压力诱导的可塑性中的作用的信息。它还将识别参与此过程的神经回路。