Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides
Introduction
Major depressive disorder (MDD) affects approximately 350 million people worldwide and is ranked as one of the main causes of disability (World Health Organization [WHO], 2012). This severe condition, characterized by depressed mood and/or loss of interest, too often results in suicide completion. Suicide ranks among the top ten causes of death for individuals of all ages and is the leading cause of death in most developed countries for subjects younger than 35 years (WHO, 2006). Psychological autopsy studies indicate that at least 50% of all adult suicides have had a previous diagnosis of depression (Kim et al., 2003). Furthermore, up to 15% of individuals with a lifetime diagnosis of MDD admit having attempted suicide at some point in their lives (Chen and Dilsaver, 1996). This serious societal problem has given rise to an increasingly multidisciplinary research field aimed at understanding the biological causes underlying depression and suicide. The inflammatory theory of depression stands as one of the main hypotheses having emerged from this research (Dantzer et al., 2008, Miller et al., 2009). It has at its roots a number of independent clinical studies showing that the expression of some peripheral inflammatory markers is increased in depressed patients (Dowlati et al., 2010). In fact, increased expression of circulating pro-inflammatory cytokines has even been proposed as a biomarker of depression (Lichtblau et al., 2013, Maes et al., 2009). Further supporting this hypothesis, the peripheral administration of pro-inflammatory cytokines such as IFN-α for the treatment of hepatitis C leads to depressive symptoms in about half of the patients (Capuron and Miller, 2004, Malaguarnera et al., 1998). This treatment was also reported to activate the dorsal anterior cingulate cortex (dACC) (Capuron et al., 2005), a region that has been shown to display reduced volume and activity in magnetic resonance imaging studies of MDD patients (Chana et al., 2003, Ebert and Ebmeier, 1996) and associated with behavioral response to peripheral inflammation (Miller et al., 2013). These data strongly suggest that circulating pro-inflammatory cytokines may affect mood states through a functional alteration of limbic brain circuits. Further indication that immune activation may have a significant influence on mood comes from the increased incidence of depression in patients suffering from chronic inflammatory illnesses such as coronary artery disease (Frasure-Smith and Lesperance, 2006). Animal studies have also supported this hypothesis, namely by providing strong evidence of a positive correlation between increased circulating pro-inflammatory cytokines and depressive-like behaviors (Goshen et al., 2008, Merali et al., 2003). Despite these converging lines of evidence, less than a handful of studies have examined the expression of cerebral cytokines in individuals having suffered from depression (Dean, 2011, Pandey et al., 2012, Tonelli et al., 2008).
At the cellular echelon, central immune responses are mainly modulated by microglia, but also by astrocytes, which generally play inflammatory and anti-inflammatory roles, respectively (McNally et al., 2008). Perivascular macrophages, which share many features with microglia, are also implicated by mediating the brain’s physiological responses to circulating pro-inflammatory cytokines (Serrats et al., 2010). In a murine model of social stress, Wohleb and colleagues recently described that social defeat is accompanied by the priming of monocytes and the recruitment of peripheral macrophages into cerebral perivascular space. This trafficking of myeloid cells in the brain coincides with the activation of resident microglia, the production of pro-inflammatory cytokines and the appearance of anxiety-like behaviours (Wohleb et al., 2012, Wohleb et al., 2013). There currently exists a knowledge gap with regards to these cells in regions implicated in depression and suicide. In fact, little is known about macrophages in the human brain (Guillemin and Brew, 2004), let alone in mood disorders. Interestingly, Steiner and colleagues have reported immunohistological evidence of increased cerebral gray matter HLA-DR-immunoreactive microglial densities in suicide victims, irrespective of psychiatric diagnosis (Steiner et al., 2008). However, the distribution and morphological phenotypes of white matter macrophages remains to be investigated, particularly in the dACC, a region that has been repeatedly implicated in mood disorders and in the behavioral response to inflammation (Capuron et al., 2005, Haroon et al., 2014, Miller et al., 2013). Furthermore, white matter astrocytes in the dACC of depressed suicides display a hypertrophic phenotype suggestive of mild astrogliosis (Torres-Platas et al., 2011). The aim of the present study was to examine the distribution and morphology of macrophages in well-characterized dACC white matter samples from depressed suicides and matched psychiatrically healthy controls.
Section snippets
Brain samples
This study was approved by the Douglas Hospital Research Ethics Board, and informed consent from next-of-kin was obtained for each subject. Postmortem brain samples from depressed suicides and matched sudden-death controls were provided by the Suicide section of the Douglas-Bell Canada Brain Bank. All psychiatric subjects committed suicide in the context of a major depressive episode, and controls died suddenly without psychiatric, neurological or inflammatory illnesses (Table 1). Seven
Microglia
As described previously, four major microglial phenotypes were observed in IBA1-immunostained sections of human dACC white matter (Torres-Platas et al., 2014). Total densities of IBA1-IR microglia (individual and combined phenotypes) did not differ between depressed suicides and controls. A finer analysis examining relative proportions of microglial phenotypes revealed that the ratio of primed over ramified microglia was significantly increased (t(19) 2.3 p = 0.03) in depressed suicides compared
Discussion
This study provides the first evidence of increased microglial priming in postmortem brain samples from individuals having suffered from MDD. Microglial cells can adopt different morphologies that are generally related to their functional status. Although intermediate stages are recognized, four main phenotypes have been described in rodents (Karperien et al., 2013, Kettenmann et al., 2011, Soltys et al., 2001, Stence et al., 2001) and in humans (Torres-Platas et al., 2014): ramified, primed,
Funding and disclosure
This work was supported by operating grants from CIHR (NM; grant number MOP-111022); FRQS (NM and GT; grant number 16425); as well as an infrastructure grant from CFI (NM) and an equipment grant from NSERC (NM). SGTP is the recipient of a CONACyT doctoral scholarship, and NM is the Bell Senior Fellow in Mental Health, as well as a FRQS chercheur-boursier and CIHR New Investigator.
Acknowledgments
We thank Quebec’s coroner office as well as the next-of-kin of the deceased for their support. We also thank the expert staff of the Douglas-Bell Canada Brain Bank (Maâmar Bouchouka, Josée Prud’homme, Danielle Cécyre, Kirsten Humbert and Lucie Ratelle), Dr. Giamal Luheshi for helpful discussions, and Dr. Joseph Rochford for his assistance with the statistical analyses.
References (50)
- et al.
Changes in behaviour and cytokine expression upon a peripheral immune challenge
Behav. Brain Res.
(2011) - et al.
Cytokines and psychopathology: lessons from interferon-alpha
Biol. Psychiatry
(2004) - et al.
Anterior cingulate activation and error processing during interferon-alpha treatment
Biol. Psychiatry
(2005) - et al.
Two-dimensional assessment of cytoarchitecture in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia: evidence for decreased neuronal somal size and increased neuronal density
Biol. Psychiatry
(2003) - et al.
Lifetime rates of suicide attempts among subjects with bipolar and unipolar disorders relative to subjects with other Axis I disorders
Biol. Psychiatry
(1996) - et al.
A meta-analysis of cytokines in major depression
Biol. Psychiatry
(2010) - et al.
The role of the cingulate gyrus in depression: from functional anatomy to neurochemistry
Biol. Psychiatry
(1996) - et al.
A quantitative morphometric study of the human anterior cingulate cortex
Brain Res.
(2004) - et al.
Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression
Biol. Psychiatry
(2009) - et al.
Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims
J. Psychiatric Res.
(2012)