Neuroinflammatory alterations in trait anxiety: modulatory effects of minocycline

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 neuroinflammatory system of genetically determined pathological anxiety or high trait anxiety individuals. We report microglial alterations in various brain regions in a mouse model of high trait anxiety (HAB). In particular, the dentate gyrus (DG) of the hippocampus of HABs exhibited enhanced density and average cell area of Iba1+, and density of phagocytic (CD68+/Iba1+) microglia compared to normal anxiety (NAB) controls. Minocycline was used to assess the capacity of a putative microglia 'inhibitor' in modulating hyperanxiety behavior of HABs. Chronic oral minocycline indeed reduced HAB hyperanxiety, which was associated with significant decreases in Iba1+ and CD68+Iba1+ cell densities in the DG. Addressing causality, it was demonstrated that longer (10 days), but not shorter (5 days), periods of minocycline microinfusions locally into the DG of HAB reduced Iba-1+ cell density and attenuated hyperanxietyrelated behavior, indicating that neuroinflammation in the DG is at least partially involved in the maintenance of pathological anxiety. The present data reveal evidence of disturbances in the microglial system of individuals with high trait anxiety. Minocycline attenuated HAB hyperanxiety, likely by modulation of microglial activity within the DG. Thus, the present data suggest that drugs with microglia-targeted anti-inflammatory properties could be promising as novel alternative or complimentary anxiolytic therapeutic approaches in specific subgroups of individuals genetically predisposed to hyperanxiety.

Hippocampal Activated Microglia May Contribute to Blood-brain Barrier Impairment and Cognitive Dysfunction in Post-traumatic Stress Disorder-like Rats

“…In this experiment, intraperitoneal injection of minocycline not only mitigated working memory impairment and improved the hippocampal BBB damage in SPS condition. Consistent with our studies, minocycline also attenuated hippocampal microglia activation and PTSD related behavioral changes including cognition, anxiety, and pain related parameters in other studies (Sun et al 2016;Wang et al 2018;Rooney et al 2020) Of course, there are some limitations to the study. Firstly, considering the potential hippocampal injury through local minocycline delivery, systemic administration was used in the study.…”

Prenatal alcohol-induced sex differences in immune, metabolic and neurobehavioral outcomes in adult rats

“…In rodents, PAE is an established cause of inflammation in the neonatal brain ( Kane et al, 2011 , Tiwari and Chopra, 2011 , Noor and Milligan, 2018 ) and that pro-inflammatory state persists in the adult brain ( Drew et al, 2015 , Cantacorps et al, 2017 ). Increased brain inflammation in turn is associated with adverse neurobehavioral outcomes including anxiety and depression ( Calcia et al, 2016 , Kim and Won, 2017 , Michopoulos et al, 2017 , Rooney et al, 2020 ), which are significantly more prevalent in persons with FASD than in the general population ( Himmelreich et al, 2020 ). Although these studies illustrate the adverse effects of developmental alcohol exposure on the neuroimmune response, the allostatic adaptations of peripheral immune organs to PAE and their relation to neurobehavioral outcomes in adult offspring are unclear.…”

Minocycline Pretreatment Prevents Blood–Brain Barrier Disruption in Septic Rats

“…Animal experiments have shown that minocycline can improve the prognosis of stroke and spinal cord injury. [24][25][26] Michels et al 10 showed that the intracerebroventricular injection of minocycline could improve BBB permeability, reduce EB extravasation in the hippocampus, reduce oxidative damage and the inflammatory response in the acute phase, and improve cognitive dysfunction in septic animals.…”