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

• Final Report Year: 2023

Final Report Abstract

High trait anxiety is a substantial risk factor for developing anxiety disorders and depression. While neuroinflammation has been identified to contribute to stress-induced anxiety, little is known about potential dysregulation in the (neuro)inflammatory system of genetically determined pathological anxiety or high trait anxiety individuals. Within the DACH framework, we show for the first time that a mouse model of heightened trait anxiety (HAB) displays enhanced microglial density and phagocytic activity in key regions of anxiety circuits compared to normal-anxiety controls (NAB). Using single cell sequencing approaches we found evidence of sexual dimorphism in microglial synaptic pruning in high trait anxiety. These data suggest that sex dependent treatment approaches need to be considered when targeting inflammatory systems in trait anxiety. Taken together, the results obtained using the DACH funding support the role of inflammation in high trait anxiety and its risk for adulthood pathologies. It is hypothesized that a pro-inflammatory bias or ‘priming’ of the neuro-immune axis may be a mechanism underlying the increased risk for stressrelated disorders exhibited by high trait anxiety individuals. Pharmacological and/or positive behavioral therapies triggering microglia-targeted anti-inflammatory effects could be promising as novel alternatives or complimentary anxiolytic therapeutic approaches in specific subgroups of individuals predisposed to trait anxiety.

Publications

• Microglial ablation in rats disrupts the circadian system. The FASEB Journal, 35(2).
  Sominsky, Luba; Dangel, Tamara; Malik, Sajida; De Luca Simone, N.; Singewald, Nicolas & Spencer, Sarah J.
  
• Neuroinflammatory alterations in trait anxiety: modulatory effects of minocycline. Translational Psychiatry, 10(1).
  Rooney, Sinead; Sah, Anupam; Unger, Michael S.; Kharitonova, Maria; Sartori, Simone B.; Schwarzer, Christoph; Aigner, Ludwig; Kettenmann, Helmut; Wolf, Susanne A. & Singewald, Nicolas
  
• On the objectivity, reliability, and validity of deep learning enabled bioimage analyses. eLife, 9.
  Segebarth, Dennis; Griebel, Matthias; Stein, Nikolai; von Collenberg, Cora R.; Martin, Corinna; Fiedler, Dominik; Comeras, Lucas B.; Sah, Anupam; Schoeffler, Victoria; Lüffe, Teresa; Dürr, Alexander; Gupta, Rohini; Sasi, Manju; Lillesaar, Christina; Lange, Maren D.; Tasan, Ramon O.; Singewald, Nicolas; Pape, Hans-Christian; Flath, Christoph M. & Blum, Robert
  
• Brain-derived neurotrophic factor expression in serotonergic neurons improves stress resilience and promotes adult hippocampal neurogenesis. Progress in Neurobiology, 217, 102333.
  Leschik, Julia; Gentile, Antonietta; Cicek, Cigdem; Péron, Sophie; Tevosian, Margaryta; Beer, Annika; Radyushkin, Konstantin; Bludau, Anna; Ebner, Karl; Neumann, Inga; Singewald, Nicolas; Berninger, Benedikt; Lessmann, Volkmar & Lutz, Beat
  
• Enriched Environment Attenuates Enhanced Trait Anxiety in Association with Normalization of Aberrant Neuro-Inflammatory Events. International Journal of Molecular Sciences, 23(21), 13052.
  Sah, Anupam; Rooney, Sinead; Kharitonova, Maria; Sartori, Simone B.; Wolf, Susanne A. & Singewald, Nicolas