Gargus Makenna, Ben-Azu Benneth, Landwehr Antonia, Dunn Jaclyn, Errico Joseph P, Tremblay Marie-Ève
Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
Department of Pharmacology, Faculty of Basic Medical Sciences, Delta State University, Abraka, Nigeria.
Front Neurosci. 2025 Jan 15;18:1527842. doi: 10.3389/fnins.2024.1527842. eCollection 2024.
The vagus nerve (VN) is the primary parasympathetic nerve, providing two-way communication between the body and brain through a network of afferent and efferent fibers. Evidence suggests that altered VN signaling is linked to changes in the neuroimmune system, including microglia. Dysfunction of microglia, the resident innate immune cells of the brain, is associated with various neurodevelopmental disorders, including schizophrenia, attention deficit hyperactive disorder (ADHD), autism spectrum disorder (ASD), and epilepsy. While the mechanistic understanding linking the VN, microglia, and neurodevelopmental disorders remains incomplete, vagus nerve stimulation (VNS) may provide a better understanding of the VN's mechanisms and act as a possible treatment modality. In this review we examine the VN's important role in modulating the immune system through the inflammatory reflex, which involves the cholinergic anti-inflammatory pathway, which releases acetylcholine. Within the central nervous system (CNS), the direct release of acetylcholine can also be triggered by VNS. Homeostatic balance in the CNS is notably maintained by microglia. Microglia facilitate neurogenesis, oligodendrogenesis, and astrogenesis, and promote neuronal survival via trophic factor release. These cells also monitor the CNS microenvironment through a complex sensome, including groups of receptors and proteins enabling microglia to modify neuroimmune health and CNS neurochemistry. Given the limitations of pharmacological interventions for the treatment of neurodevelopmental disorders, this review seeks to explore the application of VNS as an intervention for neurodevelopmental conditions. Accordingly, we review the established mechanisms of VNS action, e.g., modulation of microglia and various neurotransmitter pathways, as well as emerging preclinical and clinical evidence supporting VNS's impact on symptoms associated with neurodevelopmental disorders, such as those related to CNS inflammation induced by infections. We also discuss the potential of adapting non-invasive VNS for the prevention and treatment of these conditions. Overall, this review is intended to increase the understanding of VN's potential for alleviating microglial dysfunction involved in schizophrenia, ADHD, ASD, and epilepsy. Additionally, we aim to reveal new concepts in the field of CNS inflammation and microglia, which could serve to understand the mechanisms of VNS in the development of new therapies for neurodevelopmental disorders.
迷走神经（VN）是主要的副交感神经，通过传入和传出纤维网络在身体和大脑之间提供双向通信。有证据表明，VN信号改变与神经免疫系统的变化有关，包括小胶质细胞。小胶质细胞是大脑中固有的先天免疫细胞，其功能障碍与多种神经发育障碍有关，包括精神分裂症、注意力缺陷多动障碍（ADHD）、自闭症谱系障碍（ASD）和癫痫。虽然将VN、小胶质细胞和神经发育障碍联系起来的机制理解仍不完整，但迷走神经刺激（VNS）可能有助于更好地理解VN的机制，并作为一种可能的治疗方式。在这篇综述中，我们研究了VN在通过炎症反射调节免疫系统中的重要作用，炎症反射涉及胆碱能抗炎途径，该途径释放乙酰胆碱。在中枢神经系统（CNS）内，VNS也可触发乙酰胆碱的直接释放。CNS中的稳态平衡主要由小胶质细胞维持。小胶质细胞促进神经发生、少突胶质细胞生成和星形胶质细胞生成，并通过释放营养因子促进神经元存活。这些细胞还通过一个复杂的传感组监测CNS微环境，该传感组包括一组受体和蛋白质，使小胶质细胞能够改变神经免疫健康和CNS神经化学。鉴于治疗神经发育障碍的药物干预存在局限性，本综述旨在探讨VNS作为神经发育疾病干预措施的应用。因此，我们回顾了VNS作用的既定机制，例如对小胶质细胞和各种神经递质途径的调节，以及支持VNS对与神经发育障碍相关症状影响的新出现的临床前和临床证据，例如与感染引起的CNS炎症相关的症状。我们还讨论了采用非侵入性VNS预防和治疗这些疾病的潜力。总体而言，本综述旨在增进对VN在减轻精神分裂症、ADHD、ASD和癫痫中涉及的小胶质细胞功能障碍方面潜力的理解。此外，我们旨在揭示CNS炎症和小胶质细胞领域的新概念，这有助于理解VNS在神经发育障碍新疗法开发中的机制。
