MENINGEAL IMMUNITY AS A MODULATOR OF NEUROINFLAMMATION INDUCED BY PSYCHOSTIMULANT EXPOSURE

Exposure to Methamphetamine (Meth), a highly addictive psychostimulant, is used in our lab as model to study the role of microglia reactivity in the neurotoxicity of psychostimulant drugs. We have previously shown that binge Meth increases microglia activation through astrocytic TNF and glutamate and that IL-10 has a protective effect in Meth-induced neuroinflammation. More recently, we established a model of chronic Meth exposure to investigate neuroimmune regulation and found that it leads to microgliosis and decreased microglial arborization in the hippocampus. Recent studies implicate meningeal immunity modulating the brain parenchyma and influencing behavior, which sparked our interest. Furthermore, opioid exposure has been shown to drive brain infiltration of T cells with enhanced IFNg expression, contributing to withdrawal symptoms. Interestingly in our model we found a peak in meningeal IFNg production after 3 doses of Meth in gamma-delta T cells, and a significant decrease in IFNg levels, as well as reduced CD4+ and CD8+ populations, after 10 days of Meth exposure. In the brain parenchyma, we found that chronic Meth leads to an increase in CD8+ T-cells and an increase in IFNg production exclusively in gamma-delta-T cells. Furthermore, resorting to IFNgKO mice, we saw that in the absence of IFNg Meth microglial effects are substantially reduced. Currently, we want to understand the link between meningeal immune alterations and brain neuroinflammation aiming to modulate the brain’s neuroinflammatory response through modulation of meningeal immunity. This could represent a novel outside-in modulation approach to mitigate the brain’s neuroinflammatory response to psychostimulants.