# Maresin-1 Ameliorates Chronic Unpredictable Stress-Induced Depressive-like Behaviors Associated with Dynamic Modulation of Hippocampal Microglial Activity and TSPO PET Signals

## TL;DR

Maresin-1, a compound from omega-3 fatty acids, reduces depression-like behaviors in stressed mice by modulating brain immune cells and PET signals.

## Contribution

This study demonstrates Maresin-1's novel therapeutic potential in depression via dynamic modulation of hippocampal microglial activity and TSPO PET signals.

## Key findings

- MaR1 reversed chronic stress-induced anhedonia and improved locomotor activity in mice.
- Longitudinal PET imaging showed biphasic changes in neuroinflammation with MaR1 treatment.
- MaR1 normalized microglial and astrocytic activation and upregulated pro-resolving markers like IL-4 and TSPO.

## Abstract

Background/Objectives: Maresin-1 (MaR1), a specialized pro-resolving mediator (SPM) derived from omega-3 fatty acids, has demonstrated potent anti-inflammatory and pro-resolving properties. However, its effects on depression-like behaviors and the associated dynamics of neuroinflammation, particularly in the context of chronic stress, are not yet fully understood. This study aimed to investigate the therapeutic potential of MaR1 in a chronic unpredictable stress (CUS) model and to monitor its dynamic effects on neuroimmune activity using longitudinal in vivo imaging. Methods: Adolescent male C57BL/6J mice were subjected to a 5-week CUS protocol. Mice exhibiting stable anhedonia were randomized to receive intraperitoneal injections of either MaR1 (5 µg/kg) or vehicle every other day for 4 weeks. During this period, CUS procedures were maintained. Depression-like behaviors were assessed using the sucrose preference test (SPT), tail suspension test (TST), and open field test (OFT). Dynamic changes in neuroinflammation were monitored via longitudinal [18F]DPA-714 positron emission tomography (PET) scans at baseline and after 2 and 4 weeks of treatment. Ex vivo analyses included immunofluorescence quantification of hippocampal microglia (ionized calcium-binding adaptor molecule 1, Iba1), astrocytes (glial fibrillary acidic protein, GFAP), and 18 kDa translocator protein (TSPO) co-expression, alongside quantitative polymerase chain reaction (qPCR) and Western blotting for inflammatory markers (IL-1β, IL-4, TSPO). Results: MaR1 treatment selectively alleviated depression-like behaviors, significantly reversing CUS-induced anhedonia in the SPT and improving locomotor activity, while its effect on despair-like behavior (TST) was not statistically significant. Longitudinal PET imaging revealed a biphasic neuroimmune response, characterized by an initial increase in [18F]DPA-714 standardized uptake value (SUV) at 2 weeks, followed by a return toward baseline at 4 weeks. Histologically, MaR1 reversed CUS-induced hippocampal microglial loss, resulting in a rebound of microglial numbers, and normalized astrocytic activation. At the molecular level, MaR1 dynamically modulated cytokine expression, culminating in a significant upregulation of the pro-resolving marker IL-4 and TSPO at 4 weeks. Conclusions: These findings indicate that Maresin-1 treatment is associated with behavioral improvement and dynamic modulation of glial activity and TSPO PET signals in the hippocampus. This study highlights the value of TSPO PET imaging for monitoring dynamic glial changes during therapeutic intervention and provides supportive evidence for targeting neuroimmune pathways in depression.