Progress in Neuro-Psychopharmacology and Biological Psychiatry
In animal models, psychosocial stress-induced (neuro)inflammation, apoptosis and reduced neurogenesis are associated to the onset of depression
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.
Section snippets
IO&NS pathways in depression
There is now evidence that pro-inflammatory cytokines, produced by monocytes, macrophages and brain microglia, and by activated T lymphocytes, play an important role as mediators of external and internal stress responses (Maes, 1995, Maes, 2010). Based on various findings in clinical depression and animal models, the cytokine hypothesis was formulated, i.e. depression may be caused by an increased production of pro-inflammatory cytokines that are caused by external or internal stressors (Maes,
External stress models
In this paper we will review the data obtained in two external stress-induced models of depression, i.e. CMS and LH. The CMS paradigm involves the exposure of animals to a series of mild and unpredictable stressors such as isolation, crowded housing, alterations of dark–light cycle, restricted food access etc. for up to 3 months. After CMS, the animals show a variety of symptoms resembling human depression, such as long-lasting changes of locomotor activity, weight loss, altered diurnal rhythms,
Effect of antidepressants on IO&NS pathways
In this section we will discuss the effects of antidepressants on the IO&NS and neurogenic pathways that play a role in the external stress-related animal models of depression. Since peripheral cytokines directly or indirectly affect brain function (Kronfol and Remick, 2000), the effects of antidepressants on plasma cytokine concentrations or their production by isolated splenocytes, lymphocytes or by whole blood cultures were examined. In the CMS model, the antidepressant effect of imipramine
Conclusions
External stress, which is widely acknowledged as a predisposing and precipitating factor in depression, causes an increased expression of pro-inflammatory cytokines and activation of various inflammation-related pathways in the CNS. External stress models of depression show that depression-like behaviors are accompanied by peripheral and central activation of IO&NS pathways, including increased IL-1β, IL-6 and TNFα levels. External stress-induced increases in IL-1β are sufficient to explain the
Acknowledgment
This study was partly supported by research grants POIG.01.01.02-12-004/09-00 and N 401c130 31/2871 from the Ministry of Sciences and High Education Warszawa, Poland.
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