The impact of repeated opioid withdrawal on mouse behavior and microglia

Abstract

Microglia are specialized cells of the central nervous system (CNS), often mentioned as the resident myeloid population or the resident immune cells of the CNS. Microglia, as well as astrocytes and oligodendrocytes, contribute to drug induced changes in CNS function, which can be investigated using powerful new omics techniques. Microglia have been shown to play a role in opioid withdrawal by modulating the actions of various signaling molecules and by releasing inflammatory agents, leading to alterations in animal behavior. We hypothesized that microglia may contribute to the behavioral signs of opioid withdrawal when an individual experiences withdrawal several times in succession. Here we present work studying the impact of multiple withdrawal experiences on mouse behavior, as well as changes to microglia morphology and microglia RNA translation, specific to the mouse striatum. We find that five withdrawal experiences lead to more intense and protracted withdrawal signs in mice. Additionally, the impact of multiple cycles of withdrawal changes microglia cells to adopt a more ameboid and inflammatory-like state, perhaps proliferating specifically in the striatum of female mice. Our RNA sequencing results also indicate that multiple cycles of withdrawal induce an inflammatory signature in the microglia translatome, and support our finding that microglia are shifted to a proliferative state in the mouse striatum.