Evidence that Microglia Mediate the Neurobiological Effects of Chronic Psychological Stress on the Medial Prefrontal Cortex

Abstract

Psychological stress contributes to the development of clinical depression. This has prompted many preclinical studies to investigate the neurobiology of this relationship, however, the effects of stress on glia remain unclear. In this study, we wished to determine, first, how exposure to chronic psychological stress affects microglial activity within the prefrontal cortex (PFC) and, second, whether the observed changes were meaningfully related to corresponding changes in local neuronal activity and PFC-regulated behavior. Therefore, we examined markers of microglial activation, antigen presentation, apoptosis, and persistent neuronal activation within the PFC after exposure to repeated restraint stress. We also examined the effect of stress on spatial working memory, a PFC-dependent function. Finally, we tested the ability of a microglial activation inhibitor (minocycline) to alter the impact of chronic stress on all of these endpoints. Stressor exposure produced positively correlated increases in microglial and long-term neuronal activation in the PFC but not antigen presentation or apoptosis. As expected, it also impaired spatial working memory. Importantly, minocycline reduced the impact of stress on neuronal activation and working memory, as well as microglial activation. These results suggest a role for microglia in mediating the effects of stress on PFC neuronal function and PFC-regulated behavior.

Minocycline modulates neuropathic pain behaviour and cortical M1–M2 microglial gene expression in a rat model of depression

“…Antidepressant-like effects of minocycline have been demonstrated in several animal models (Henry et al, 2008, O'Connor et al, 2009, Hinwood et al, 2012, Arakawa et al, 2012, with recent data expanding this to include the OB rat. Specifically, chronic minocycline has been demonstrated to attenuate OB-related hyperactivity, behavioural despair (forced swim test) and spatial memory deficits (Borre et al, 2012, Rinwa andKumar, 2013).…”

“…Antidepressant efficacy of minocycline, a second-generation antibiotic that also inhibits microglial activation, has been reported both clinically (Miyaoka et al, 2012) and in animal models (Henry et al, 2008, O'Connor et al, 2009, Arakawa et al, 2012, Hinwood et al, 2012. Furthermore, minocycline has been shown to be beneficial in pain states such as rheumatoid arthritis (Langevitz et al, 2000) and sciatica (Sumracki et al, 2012).…”

Roles of Dopamine and Inflammation-Related Molecules in Behavioral Alterations Caused by Repeated Stress

“…Consistent with this notion, several groups including ours have suggested microglial activation with repeated stress. After repeated social defeat stress, microglia show histological markers for microglial activation, such as hyper-ramified morphology and increased Iba-1 immunoreactivity, in various brain areas such as the VTA, NAc, and the mPFC (9,11,12). In addition, stress exposure alters gene expression profiles of microglia and primes microglia for cytokine production upon subsequent stimulation (12,27).…”

“…For example, genetic deletion of IL-1 receptor type I abolishes histological changes associated with microglial activation as well as elevated anxiety induced by repeated social defeat stress (12). In addition, systemic treatment with minocycline, a drug that inhibits microglial activation by a yet-unknown mechanism, during stress exposure prevents repeated restraint stress from inducing working memory deficit (11).…”

“…This dopaminergic attenuation is mediated by prostaglandin (PG) E 2 , a bioactive lipid derived from arachidonic acid, and its receptor EP1 (9). Several lines of evidence suggest that microglia activated by repeated stress act as a cellular source of inflammation-related mediators, such as PGE 2 and IL-1β, in the brain and contribute to stress-induced behavioral changes (9,11,12). In this review, I will summarize these recent findings, which potentially contribute to pharmaceutical development for psychiatric disorders.…”