Microglia/Myeloid System in Anxiety and Depression

• Applicant: Privatdozentin Dr. Susanne A. Wolf
• Subject Area: Biological Psychiatry
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407530837

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.

• DFG Programme: Research Grants
• International Connection: Austria
• Cooperation Partner: Professor Dr. Nicolas A. Singewald