Microglia/myleoid system in anxiety and depression

Despite a wide variety of medications available to treat depression, chronic treatment resistant depression is a major problem affecting approximately 30 percent of patients. Research to develop more efficacious treatments needs novel targets and improved animal models which simulate the enhanced anxiety/depression behavior in human patients as well as the underlying neurobiology. Furthermore, an additional reason for the limited success in depression research could be accounted for relatively few studies focusing on glial cells. It has become evident that glial cells are involved in all brain functions including synaptic plasticity. In particular in the diseased brain, microglial cells (a type of glial cell that acts as the first and main form of active immune defense in the central nervous system) have a strong impact on the pathologic process. In addition, previous preclinical and clinical studies have shown the involvement of the peripheral nervous system such as the myeloid system in depression. Using the inborn high anxiety/depression mouse model_ENREF_5 we have recently observed that genetic predisposition to hyperanxiety and comorbid depression is associated with signs of increased microglial activation/ neuroinflammation. However, it is yet to be investigated, whether inborn anxiety and comorbid depression-like behavior i) involves activation of the myeloid or neuroinflammatory 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 at an early and/or later life stage can prevent the aberrant behavior and reduced neurogenesis. In an effort to reveal the 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 the neuroinflammatory system. We will use an animal model of genetic predisposition to hyperanxiety/depression in which pharmacological and non-pharmacological approaches such as deep brain stimulation and environmental enrichment approaches lead to long-lasting remission from aberrant anxiety/depressive behavior. We will analyze whether such interventions causally 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 predisposition to later life hyperanxiety/depression. Moreover we will investigate whether and how microglial/myeloid inhibitors/stimulators could act as antidepressants thereby providing novel alternatives for therapeutic intervention. Finally, results could aid in characterizing whether different components within the myeloid/microglial system can be used as a biomarker to predict treatment success.

Anxiety disorders are the most prevalent psychiatric disorders contributing significantly to global disability. Current treatment outcomes are suboptimal, particularly when comorbidities such as depression are present, calling for additional novel treatment options. Targeting the immune system has recently garnered attention in the treatment of psychiatric disorders. While such mechanisms have been studied in considerable detail in depression, the role of (neuro)inflammation in anxiety disorders is much less clear. Within the DACH framework, we show for the first time that a mouse model of heightened trait anxiety (HAB) displays signs of central neuroinflammation, such as enhanced microglial density and phagocytic activity and increase of proinflammatory cytokines in key regions of anxiety circuits, as compared to normal-anxiety controls (NAB). These findings were associated with signs of reduced neuroplasticity, e.g. reduced hippocampal neurogenesis. Low dose lipopolysaccharide challenge elicited an enhanced response of a wide range of cytokines in plasma indicating a primed capacity for stimulus-induced inflammation in HABs, which could be a potential biomarker approach to identify (and stratify for) "inflamed" anxiety patient sub-groups . We could show that both, chronic systemic or intra brain application of a drug that reduces microglial activation attenuates hyperanxiety in HABs, providing causal evidence that neuroinflammation is indeed linked to pathological anxiety. Anti-inflammatory interventions early in development however, could not prevent the development of hyperanxiety in HABs. Since also positive psychological attributes are thought to modulate inflammatory responses, we tested holding of mice in a particularly enriched environment and found that the attenuation of anxiety in HABs under these conditions was largely associated with the normalization of neuro-inammatory imbalances including microglial morphology and activation. To investigate microglia in more detail we implemented deep learning enabled bioimage analysis (in collaboration with Robert Blum, Würzburg, Germany) and revealed altered spatio-temporal distribution of different microglia morphotypes (clusters) in HABs vs NABs. Finally, using single cell sequencing approaches we found evidence of sexual dimorphism in microglial synaptic pruning in HABs (in collaboration with our DACH partners in Germany). These data suggest that sex dependent treatment approaches need to be considered when targeting the inflammatory system in trait anxiety. Taken together, pharmacological and/or environmental approaches triggering microglia-targeted anti-inammatory effects could be promising as novel alternative or complimentary anxiolytic therapeutic options in specic ("inflamed") subgroups of individuals with pathological anxiety.