The endogenous and reactive depression subtypes revisited: integrative animal and human studies implicate multiple distinct molecular mechanisms underlying major depressive disorder

Abstract

Background: Traditional diagnoses of major depressive disorder (MDD) suggested that the presence or absence of stress prior to onset results in either 'reactive' or 'endogenous' subtypes of the disorder, respectively. Several lines of research suggest that the biological underpinnings of 'reactive' or 'endogenous' subtypes may also differ, resulting in differential response to treatment. We investigated this hypothesis by comparing the gene-expression profiles of three animal models of 'reactive' and 'endogenous' depression. We then translated these findings to clinical samples using a human post-mortem mRNA study. Methods: Affymetrix mouse whole-genome oligonucleotide arrays were used to measure gene expression from hippocampal tissues of 144 mice from the Genome-based Therapeutic Drugs for Depression (GENDEP) project. The study used four inbred mouse strains and two depressogenic 'stress' protocols (maternal separation and Unpredictable Chronic Mild Stress) to model 'reactive' depression. Stress-related mRNA differences in mouse were compared with a parallel mRNA study using Flinders Sensitive and Resistant rat lines as a model of 'endogenous' depression. Convergent genes differentially expressed across the animal studies were used to inform candidate gene selection in a human mRNA post-mortem case control study from the Stanley Brain Consortium.

Fuzzy Logic and S‐Lagrangian Dynamics of Living Systems: Theory of Homeostasis

“…This prediction is supported by the recent experimental data, which show that both in human and in animal models, the expression of many genes changed in response to early and to late stresses [21]. …”

“…In the last type of behavior, the system cannot achieve any stable state, level of stress dramatically increases, system variables leave the life-compatible region, and the system moves toward death ( Figure 2). It should be noted that there is a critical value of injure, which leads to fatal instability of a system by violation of the condition (21). Apparently, there is a critical value of the stress as well, so if S-index exceeds this value, an organism inevitably moves toward death.…”

Genes and Gene Networks Implicated in Aggression Related Behaviour

“…The method uses the correlation patterns among genes across microarray samples as opposed to the association between each probe set and outcome [27,28]. WGCNA has been previously used to analyse gene expression data for a range of applications including mouse genetics [28][29][30]. In this study, we used WGCNA as an unsupervised, hypothesis-free method to uncover gene modules correlated with aggressive behaviour across all three genetic models of aggression.…”

Understanding the genetic architectonics of complex CNS traits: Lost by the association, but found in the interaction?

“…For example, applied to complex neuropsychiatric disorders, recent sophisticated omics-based analyses of clinical samples (Chang et al, 2015;Li et al, 2014) and preclinical data (Heinzmann et al, 2014;Malki et al, 2013Malki et al, , 2014 may become a particularly powerful tool in dissecting such additional layers of their genetic architectonics. Specifically, focusing on networks of molecules interacting with protein products of known/established endophenotype-specific genes, may help "connect the dots" and reveal novel cross-talk mechanisms (Kalueff et al, 2014).…”