CSF1R-Mediated Microglial Engagement Is Required for Stress-Induced MMP-2/9 Activity
Stress is a major risk factor for numerous neuropsychiatric disorders and induces enduring synaptic plasticity within the nucleus accumbens core (NAcore), a key brain region involved in reward and stress-related behaviors. Previous studies from our laboratory demonstrated that stress-induced plasticity depends on matrix metalloproteinase (MMP)-2/9-mediated extracellular matrix (ECM) remodeling; however, the upstream cellular mechanisms regulating MMP activation remain unclear. Because microglia regulate neuroimmune signaling, ECM dynamics, and synaptic plasticity, we tested the hypothesis that microglial colony-stimulating factor 1 receptor (CSF1R) signaling contributes to stress-induced MMP-2/9 activation within the NAcore. Male rats received the CSF1R inhibitor PLX3397 prior to acute restraint stress. In vivo fluorescent zymography, immunohistochemistry, and quantitative PCR were used to assess MMP activity, microglial signaling, and inflammatory gene expression. Acute stress increased MMP-2/9 activity enhanced microglial CD68-associated phagocytic signaling, and elevated expression of Csf1r, Tnfa, Cnr2, and Mmp16 within the NAcore. Importantly, CSF1R inhibition attenuated stress-induced increases in MMP-2/9 activity and CD68 immunoreactivity. Combined, these findings identify microglial CSF1R signaling as an upstream regulator of stress-induced ECM remodeling within the NAcore and provide mechanistic insight into how acute stress recruits neuroimmune pathways to remodel reward circuitry.