Siopi Eleni, Galerne Mathieu, Rivagorda Manon, Saha Soham, Moigneu Carine, Moriceau Stéphanie, Bigot Mathilde, Oury Franck, Lledo Pierre-Marie
Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Perception and Memory Unit, 75015, Paris, France.
Université Paris Cité, CNRS, INSERM, Institut Necker Enfants Malades-INEM, 75015, Paris, France.
Mol Psychiatry. 2023 Jul;28(7):3002-3012. doi: 10.1038/s41380-023-02071-6. Epub 2023 May 2.
Chronic stress constitutes a major risk factor for depression that can disrupt various aspects of homeostasis, including the gut microbiome (GM). We have recently shown that GM imbalance affects adult hippocampal (HPC) neurogenesis and induces depression-like behaviors, with the exact mechanisms being under active investigation. Here we hypothesized that the vagus nerve (VN), a key bidirectional route of communication between the gut and the brain, could relay the effects of stress-induced GM changes on HPC plasticity and behavior. We used fecal samples derived from mice that sustained unpredictable chronic mild stress (UCMS) to inoculate healthy mice and assess standard behavioral readouts for anxiety- and depressive-like behavior, conduct histological and molecular analyses for adult HPC neurogenesis and evaluate neurotransmission pathways and neuroinflammation. To study the potential role of the VN in mediating the effects of GM changes on brain functions and behavior, we used mice that sustained subdiaphragmatic vagotomy (Vx) prior the GM transfer. We found that inoculation of healthy mice with GM from UCMS mice activates the VN and induces early and sustained changes in both serotonin and dopamine neurotransmission pathways in the brainstem and HPC. These changes are associated with prompt and persistent deficits in adult HPC neurogenesis and induce early and sustained neuroinflammatory responses in the HPC. Remarkably, Vx abrogates adult HPC neurogenesis deficits, neuroinflammation and depressive-like behavior, suggesting that vagal afferent pathways are necessary to drive GM-mediated effects on the brain.
慢性应激是抑郁症的一个主要风险因素，它会破坏体内平衡的各个方面，包括肠道微生物群（GM）。我们最近发现，GM失衡会影响成年海马体（HPC）神经发生并诱发类似抑郁的行为，具体机制正在积极研究中。在这里，我们假设迷走神经（VN）作为肠道与大脑之间双向通信的关键途径，可能传递应激诱导的GM变化对HPC可塑性和行为的影响。我们使用来自遭受不可预测慢性轻度应激（UCMS）的小鼠的粪便样本接种健康小鼠，并评估焦虑和抑郁样行为的标准行为读数，对成年HPC神经发生进行组织学和分子分析，并评估神经传递途径和神经炎症。为了研究VN在介导GM变化对脑功能和行为影响中的潜在作用，我们使用在GM转移前进行了膈下迷走神经切断术（Vx）的小鼠。我们发现，用来自UCMS小鼠的GM接种健康小鼠会激活VN，并在脑干和HPC中诱导血清素和多巴胺神经传递途径的早期和持续变化。这些变化与成年HPC神经发生的迅速和持续缺陷相关，并在HPC中诱导早期和持续的神经炎症反应。值得注意的是，Vx消除了成年HPC神经发生缺陷、神经炎症和抑郁样行为，这表明迷走传入途径对于驱动GM对大脑的介导作用是必要的。
