In animal models, psychosocial stress-induced (neuro)inflammation, apoptosis and reduced neurogenesis are associated to the onset of depression

Abstract

Recently, the inflammatory and neurodegenerative (I&ND) hypothesis of depression was formulated (Maes et al., 2009), i.e. the neurodegeneration and reduced neurogenesis that characterize depression are caused by inflammation, cell-mediated immune activation and their long-term sequels. The aim of this paper is to review the body of evidence that external stressors may induce (neuro)inflammation, neurodegeneration and reduced neurogenesis; and that antidepressive treatments may impact on these pathways.

The chronic mild stress (CMS) and learned helplessness (LH) models show that depression-like behaviors are accompanied by peripheral and central inflammation, neuronal cell damage, decreased neurogenesis and apoptosis in the hippocampus. External stress-induced depression-like behaviors are associated with a) increased interleukin-(IL)1β, tumor necrosis factor-α, IL-6, nuclear factor κB, cyclooxygenase-2, expression of Toll-like receptors and lipid peroxidation; b) antineurogenic effects and reduced brain-derived neurotrophic factor (BDNF) levels; and c) apoptosis with reduced levels of Bcl-2 and BAG1 (Bcl-2 associated athanogene 1), and increased levels of caspase-3. Stress-induced inflammation, e.g. increased IL-1β, but not reduced neurogenesis, is sufficient to cause depression. Antidepressants a) reduce peripheral and central inflammatory pathways by decreasing IL-1β, TNFα and IL-6 levels; b) stimulate neuronal differentiation, synaptic plasticity, axonal growth and regeneration through stimulatory effects on the expression of different neurotrophic factors, e.g. trkB, the receptor for brain-derived neurotrophic factor; and c) attenuate apoptotic pathways by activating Bcl-2 and Bcl-xl proteins, and suppressing caspase-3.

It is concluded that external stressors may provoke depression-like behaviors through activation of inflammatory, oxidative, apoptotic and antineurogenic mechanisms. The clinical efficacity of antidepressants may be ascribed to their ability to reverse these different pathways.

Introduction

External stress is widely acknowledged as a predisposing and precipitating factor of depression especially in genetically predisposed persons. An enhanced responsivity to external stress is associated with the early phases of depression. Early life experiences modulate the development of appropriate/inappropriate responses to external stressors and thus the vulnerability for depressive episodes. The latter, in turn, may be triggered by external stressors, such as negative life events (Maes, 1999, Maes, 2001).

There is now evidence that depression is accompanied by activation of immune, inflammatory, oxidative and nitrosative stress (IO&NS) pathways (Maes, 1993, Maes, 2010, Maes et al., 1990). Review papers in this special issue summarize that different IO&NS pathways are key features of depression (Maes, 2010, Maes et al., 2010, Szewczyk et al., 2010, Zunszain et al., 2010, Song and Wang, 2010, Gardner and Boles, 2010). External stressors, like stressful life events, and/or internal stressors, e.g. inflammatory conditions, may induce the previously mentioned pathways and consequently are involved in the etiology of depression (Maes, 1995, Maes, 2008, Maes et al., 1995, Maes et al., 2009, Anisman, 2009, Miller et al., 2009).

There is also evidence that depression is accompanied by structural changes in the hippocampus, prefrontal cortex, amygdala, anterior cingulate and basal ganglia (Campbell and MacQueen, 2006). The selective loss of hippocampal volume is caused by a) hippocampal neuronal death, neuronal and glial cell modifications, and other cellular changes as well (Stockmeier et al., 2004); and b) decreased neurogenesis (Sapolsky, 2004). The inflammatory and (neuro)degenerative (I&ND) hypothesis of depression states that the abovementioned changes in depression are caused by IO&NS pathways (Maes et al., 2009). The reviews included in this special issue focus on the different IO&NS pathways that play a role in the I&ND hypothesis of depression (Maes et al., 2010, Szewczyk et al., 2010, Zunszain et al., 2010, Song and Wang, 2010, Gardner and Boles, 2010).

Translational research, including animal models of depression, is needed to decipher the exact pathways and molecular mechanisms by which external and internal stressors activate peripheral and central IO&NS pathways and cause neurodegeneration, which ultimately lead to depression-like behaviors. Findings from animal models can serve as templates for identifying targeted brain regions for further assessments in humans. Adequate animal models of depression should a) closely simulate the etiology, the symptomatology, and the course of depression and should respond to antidepressive treatments established in human depression; and b) have sufficient face and predictive validity and be reproducible between investigators.

The aim of this paper is to review the body of evidence that a) external stressors may cause systemic inflammation, neuroinflammation, neurodegeneration and reduced neurogenesis; and b) these stress-induced changes may be blocked by antidepressants. Toward this end, we will review well-validated, external stress-induced animal models of depression, such as the chronic mild stress model (CMS) and the learned helplessness (LH) paradigm. In this special issue, another review on animal models summarizes the pathways that link internal stressors, for example depressive-like behaviors induced by lipopolysaccharide (LPS), to microglial activation and neuroregression (Song and Wang, 2010). We will start with a brief review on the I&ND hypothesis of depression in humans and the pathways by which peripheral inflammatory pathways may drive central biochemical and inflammatory changes thereby causing depressive-like behaviors.