Microglia/Myeloid System in Anxiety and Depression

焦虑和抑郁中的小胶质细胞/骨髓系统

• 批准号: 407530837
• 负责人: Privatdozentin Dr. Susanne A. Wolf
• 金额: --
• 依托单位: Max-Delbrück-Centrum für Molekulare Medizin (MDC) in der Helmholtz-Gemeinschaft
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/407530837?language=en
• 关键词: Microglia; Myeloid; System; Anxiety; Depression

The limited success in understanding the pathophysiology of major depression may result from a main research focus on the dysfunction of neurons in the past. More recently, it has become evident that glial cells are involved in all brain functions including synaptic plasticity and that in particular in the diseased brain; microglial cells have a strong impact on different pathological processes. Using the inborn high anxiety/depression mouse model we have recently observed that genetic predisposition to hyperanxiety and comorbid depression is associated with signs of increased neuroinflammation/microglial activation and reduced hippocampal neurogenesis. In parallel, previous preclinical and clinical studies have shown the involvement of the myeloid system (CCR2+ Ly6Chi cells) in depression. However, it is yet to be investigated, whether inborn anxiety and comorbid depression-like behavior i) is associated with alteration of the peripheral myeloid or the brain’s immune system at an early life stage, which subsequently mediates or supports the aberrant behavior and ii) whether modulation of peripheral and neuro-inflammatory mechanisms using microglial/myeloid stimulators/inhibitors can prevent the aberrant behavior and induce neurogenesis when given at an early and/or later life stage, respectively.In an effort to reveal underlying neural mechanisms we will identify brain regions in which microglial activation goes along with changes in neuronal excitability, providing us with candidate brain regions mediating the association between hyperanxiety/depression and an altered neuroinflammatory system. We will use an animal model of genetic predisposition to hyperanxiety/depression in which non-pharmacological approaches such as deep brain stimulation and environmental enrichment but not standard pharmacological treatments lead to long-lasting remission from aberrant anxiety/depressive behavior. We will analyze whether such interventions involve the myeloid and/or microglial system. These findings will provide first direct evidences whether disturbances in myeloid/microglial functions at an early stage of development play a role in the development of hyperanxiety/depression later in life. Moreover we will investigate whether and how microglial/myeloid inhibitors/stimulators could act as antidepressants thereby providing novel alternatives for therapeutic and possibly preventive strategies. Finally, results could aid in characterizing whether different components within the myeloid/microglial system can be used as biomarkers to predict treatment success.

在理解抑郁症的病理生理学方面的有限成功可能是由于过去主要研究集中在神经元功能障碍上。最近，已经变得明显的是，神经胶质细胞参与所有的脑功能，包括突触可塑性，特别是在患病的大脑中;小神经胶质细胞对不同的病理过程有很大的影响。使用先天性高度焦虑/抑郁小鼠模型，我们最近观察到过度焦虑和共病抑郁症的遗传易感性与神经炎症/小胶质细胞活化增加和海马神经发生减少的迹象相关。与此同时，先前的临床前和临床研究已经显示了骨髓系统（CCR 2 + Ly 6Chi细胞）参与抑郁症。然而，还有待研究，先天性焦虑和共病抑郁样行为i）是否与生命早期外周骨髓或大脑免疫系统的改变有关，其随后介导或支持异常行为，以及ii）是否使用小胶质细胞/骨髓刺激物调节外周和神经炎症机制/当分别在生命早期和/或晚期给予抑制剂时，可以防止异常行为并诱导神经发生。为了揭示潜在的神经机制，我们将鉴定其中小胶质细胞活化沿着神经元兴奋性变化的脑区域，为我们提供了在过度焦虑/抑郁和改变的神经炎症系统之间介导联系的候选大脑区域。 我们将使用过度焦虑/抑郁遗传易感性的动物模型，其中非药物方法，如脑深部电刺激和环境富集，但不是标准的药物治疗，导致异常焦虑/抑郁行为的长期缓解。我们将分析这种干预是否涉及骨髓和/或小胶质细胞系统。这些研究结果将提供第一个直接证据，表明早期发育阶段的髓样/小胶质细胞功能障碍是否在以后的生活中过度焦虑/抑郁的发展中发挥作用。此外，我们将研究是否以及如何小胶质细胞/骨髓抑制剂/刺激剂可以作为抗抑郁药，从而提供新的替代治疗和可能的预防策略。最后，结果可以帮助表征骨髓/小胶质细胞系统中的不同成分是否可以用作预测治疗成功的生物标志物。