Dynamic Microglial Activation is Associated with LPS-induced Depressive-like Behavior in Mice: An [18F] DPA-714 PET Imaging Study

Abstract

Major depressive disorder (MDD) 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. In this study 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 via positron emission tomography (PET) imaging. Animals were assessed at three time points, including 24 h prior to LPS injection, 24 h post-LPS injection, and 72 h 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 (Iba-1) and translocator protein (TSPO). Moreover, NOD-like receptor protein 3 (NLRP3) inflammasome activity and interleukin-1β (IL-1β) levels were assessed at 24 h post-LPS injection. We found that LPS treatment was associated with a marked increase in depressive-like behavior at 24 h post-injection time point, and that it was less pronounced at the 72 h 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 h 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 h 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.

Neuropsychiatric Symptoms and Microglial Activation in Patients with Alzheimer Disease

“…However, animal studies support a deleterious effect of microglial activation on NPS, such as anxiety and depression symptoms. 37 , 38 Altogether, these results support the notion that AD clinical trials testing drugs targeting microglial activation could use NPS, such as irritability and agitation, as secondary outcomes.…”

“…However, animal studies support a deleterious effect of microglial activation on NPS, such as anxiety and depression symptoms. 37,38 Altogether, these results support the notion that AD clinical trials testing drugs targeting microglial activation could use NPS, such as irritability and agitation, as secondary outcomes. The association between microglial activation and NPS was identified predominantly in the posterior cingulate, precuneus, inferior temporal, and anterior cingulate cortices.…”

“…Our data also suggest that mood symptoms (depression and anxiety) could potentially be associated with factors other than microglial activation in the AD clinical spectrum. However, animal studies support a deleterious effect of microglial activation on NPS, such as anxiety and depression symptoms . Altogether, these results support the notion that AD clinical trials testing drugs targeting microglial activation could use NPS, such as irritability and agitation, as secondary outcomes.…”

Prospective study on Maresin-1 and cytokine levels in medication-naïve adolescents with first-episode major depressive disorder

“…The peripheral levels of IL-1β were investigated in this study, but its concentration in the central nervous system could not be accessed. Nevertheless, animal studies have demonstrated that intraperitoneal LPS administration increased the inflammatory factor IL-1β in the hippocampus of mice and induced time-dependent microglia activation and depression-like behavior ( 55 ). In a study on sepsis mice with a cognitive impairment model, the importance of the NLRP3-IL-1β pathway in the transition from acute peripheral inflammation to chronic central neuritis was reported ( 56 ).…”

Chronic infection by atypical Toxoplasma gondii strain induces disturbance in microglia population and altered behaviour in mice

“…Disturbances in microglial functioning, combined with persistent neuroinflammation, can play major roles in the development of neuropsychiatric disorders, such as depression and anxiety ( Li et al, 2022 ). Recently, depressive-like behaviour induced by LPS intracerebral injection in C57BL/6 mice was found to be associated with increased microglial activation and enhanced hippocampal inflammation via NLRP3 inflammasome activation and high IL-1β expression ( Qiu et al, 2022 ).…”