Gene expression patterns in the hippocampus and amygdala of endogenous depression and chronic stress models

Abstract

The etiology of depression is still poorly understood, but two major causative hypotheses have been put forth: the monoamine deficiency and the stress hypotheses of depression. We evaluate these hypotheses using animal models of endogenous depression and chronic stress. The endogenously depressed rat and its control strain were developed by bidirectional selective breeding from the Wistar–Kyoto (WKY) rat, an accepted model of major depressive disorder (MDD). The WKY More Immobile (WMI) substrain shows high immobility/despair-like behavior in the forced swim test (FST), while the control substrain, WKY Less Immobile (WLI), shows no depressive behavior in the FST. Chronic stress responses were investigated by using Brown Norway, Fischer 344, Lewis and WKY, genetically and behaviorally distinct strains of rats. Animals were either not stressed (NS) or exposed to chronic restraint stress (CRS). Genome-wide microarray analyses identified differentially expressed genes in hippocampi and amygdalae of the endogenous depression and the chronic stress models. No significant difference was observed in the expression of monoaminergic transmission-related genes in either model. Furthermore, very few genes showed overlapping changes in the WMI vs WLI and CRS vs NS comparisons, strongly suggesting divergence between endogenous depressive behavior- and chronic stress-related molecular mechanisms. Taken together, these results posit that although chronic stress may induce depressive behavior, its molecular underpinnings differ from those of endogenous depression in animals and possibly in humans, suggesting the need for different treatments. The identification of novel endogenous depression-related and chronic stress response genes suggests that unexplored molecular mechanisms could be targeted for the development of novel therapeutic agents.

Differential and Converging Molecular Mechanisms of Antidepressants’ Action in the Hippocampal Dentate Gyrus

“…Such approaches have been previously used to investigate the molecular alterations induced by ADs in the hippocampus and other brain regions of naive animals (Conti et al, 2007;Gaska et al, 2012;Korostynski et al, 2013;Landgrebe et al, 2002;Lee et al, 2010;Sillaber et al, 2008;Surget et al, 2009;Takahashi et al, 2006); interpretation of these studies is, however, limited by the fact that treatment of individuals who do not display signs of depressive-like behavior is not comparable to a pathological context (Cryan and Slattery, 2007). Previous comparable studies relied on measures of a single behavioral index measurement (Drigues et al, 2003;Nakatani et al, 2004), while others using multidimensional animal models of depression focused on a single class of AD (Andrus et al, 2012;Datson et al, 2012;Lisowski et al, 2013;Surget et al, 2009) or two monoaminergic ADs (Malki et al, 2012).…”

Forkhead box O transcription factors as possible mediators in the development of major depression

“…FoxOs have been linked to skeletal muscle atrophy and control of cardiomyocyte size in numerous models (Sandri et al, 2004;Skurk et al, 2005) observed in major depression most commonly occur in the raphe nuclei, nucleus accumbens, anterior cingulated cortex, amygdala and hippocampus (Goffer et al, 2013;Tripp et al, 2011;Underwood et al, 1999;Andrus et al, 2012), but we still need to elucidate whether the change of FoxOs and their related signal pathways could be altered in region specific manner.…”

The Neurobiology of Resilience

“…In a related study, Vidal et al (2011) found that better coping strategies might make Sprague Dawley rats more resilient to social defeat stress than Wistar rats as measured in fear-and anxiety-based domains 31 . Strain-dependent responses to other physical stressors such as restraint or CMS have been shown, underscoring the role of complex genetics in regulating risk and resilience to chronic stress [32][33][34] .…”