Microglia/Myeloid System in Anxiety and Depression

以往的研究主要集中在神经元功能障碍上，对重性抑郁症的病理生理认识有限。最近，神经胶质细胞参与了包括突触可塑性在内的所有脑功能，特别是在患病的大脑中，这一点已经变得很明显；小胶质细胞对不同的病理过程有很强的影响。利用先天高焦虑/抑郁小鼠模型，我们最近观察到，过度焦虑和共病抑郁的遗传易感性与神经炎症/小胶质细胞激活增加和海马神经发生减少的迹象有关。与此同时，先前的临床前和临床研究表明，髓系系统（CCR2+ Ly6Chi细胞）参与抑郁症。然而，先天焦虑和共病抑郁样行为是否与外周髓系或早期大脑免疫系统的改变有关，还有待研究。随后介导或支持异常行为ii)使用小胶质/髓细胞刺激/抑制剂调节外周和神经炎症机制是否可以分别在早期和/或晚期给予异常行为和诱导神经发生。为了揭示潜在的神经机制，我们将确定小胶质细胞激活与神经元兴奋性变化相关的大脑区域，为我们提供介导过度焦虑/抑郁与神经炎症系统改变之间关联的候选大脑区域。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，如深部脑刺激和环境富集，而不是标准的药物治疗，可以导致异常焦虑/抑郁行为的长期缓解。我们将分析这些干预是否涉及骨髓和/或小胶质系统。这些发现将提供第一个直接证据，证明早期发育阶段的髓细胞/小胶质细胞功能紊乱是否在以后的生活中过度焦虑/抑郁的发展中起作用。此外，我们将研究小胶质细胞/髓系抑制剂/刺激剂是否以及如何作为抗抑郁药，从而为治疗和可能的预防策略提供新的选择。最后，研究结果可以帮助确定骨髓/小胶质系统内的不同成分是否可以用作预测治疗成功的生物标志物。

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.