Dynamic microglial activation is associated with LPS-induced depressive-like behavior in mice: An [18F] DPA-714 PET imaging study.

Abstract

Major depressive disorder is a highly pervasive, severe psychological condition for which the precise underlying pathophysiology is incompletely understood, although microglial activation is known to play a role in this context. Here, we analyzed the association between neuroinflammation and depressive-like behaviors in a lipopolysaccharide (LPS)-induced mouse model system using 10–12-week-old male C57BL/6 mice. Microglial activation and associated neuroinflammatory activity were monitored through positron emission tomography (PET) imaging. Animals were assessed at 3 time points, including 24 hours prior to LPS injection, 24 hours post-LPS injection, and 72 hours post-LPS injection. Analyses of microglial activation and hippocampal neuroinflammation were conducted through [18]F DPA-714 PET imaging and immunohistochemical staining for ionized calcium-binding adapter molecule 1 and translocator protein. Moreover, NOD-like receptor protein 3 (NLRP3) inflammasome activity and interleukin-1β (IL-1β) levels were assessed at 24 hours post-LPS injection. We found that the LPS treatment was associated with a marked increase in depressive-like behavior at 24 hours post-injection that was less pronounced at the 72 hours post-injection time point. These changes coincided with enhanced [18F] DPA-714 PET uptake in the whole brain, hippocampus, cortex, and amygdala together with increased hippocampal microglial activation as evidenced by immunofluorescent staining. By 72 hours post-injection, however, these PET and immunofluorescence phenotypes had returned to baseline levels. Furthermore, increased NLRP3 inflammasome activation and IL-1β expression were evident at 24 hours post-LPS injection. These data demonstrate that dynamic microglial activation is associated with LPS-induced depressive-like behaviors and hippocampal neuroinflammation in a mouse model system.