Mice selected for extremes in stress reactivity reveal key endophenotypes of major depression: A translational approach

Abstract

Clear evidence has linked dysregulated hypothalamus-pituitary-adrenocortical (HPA) axis function to the aetiology and pathophysiology of major depression (MD), as observed in the majority of patients. Increased stress reactivity and hyperactivity of the HPA axis seem characteristic for psychotic/melancholic depression, while the atypical subtype of depression has been connected with the opposing phenotypes. However, the underlying molecular-genetic mechanisms are poorly understood. In the present study, mouse lines selectively bred for extremes in stress reactivity (SR), i.e. presenting high (HR) or low (LR) corticosterone secretion in response to stressors, were used to characterise the molecular alterations on all levels of the HPA axis. Results were contrasted with clinical phenotypes of MD patients from the Munich Antidepressant Response Signature project, stratified according to their cortisol response in the Dex/CRH test. Distinct differences between HR and LR mice were found in the expression of HPA axis-related genes in the adrenals, pituitary and selected brain areas. Moreover, HR animals presented an enhanced adrenal sensitivity, increased stress-induced neuronal activation in the PVN and an overshooting Dex/CRH test response, whereas LR animals showed a blunted response in these paradigms. Interestingly, analogous neuroendocrine, morphometric, psychopathological and behavioural differences were observed between the respective high and low HPA axis responder groups of MD patients. Our findings suggests that (i) the SR mouse model can serve as a valuable tool to elucidate HPA axis-related mechanisms underlying affective disorders and (ii) a stratification of MD patients according to their HPA axis-related neuroendocrine function should be considered for clinical research and treatment.

Late-Onset Cognitive Impairments after Early-Life Stress Are Shaped by Inherited Differences in Stress Reactivity

“…When animals were tested during early adulthood, the total distance traveled in the OF arena revealed a main effect of mouse line ( F 2,54 = 23.371, p < 0.001). Specifically, LR mice traveled shorter distances than HR and IR mice ( post hoc tests: HR vs. IR: p = 0.409, HR vs. LR: p < 0.001, IR vs. LR: p < 0.001) ( McIlwrick et al, 2016 , also shown in Figure 2A ), confirming previous findings in the SR mouse model ( Touma et al, 2008 ; Heinzmann et al, 2014 ). ELS exposure had no effect on the animals’ locomotor activity in the OFT at this time point.…”

“…In the HR line, these include a reduced bodyweight, increased locomotor activity, hyperactive stress-coping behavior, altered sleep architecture with increased rapid eye movement (REM) sleep, and impaired cognition, akin to endophenotypes of melancholic/psychotic depression. On the other hand, LR animals show an increased bodyweight, reduced locomotor activity, passive stress-coping behavior, and intact sleep and cognitive function, in line with endophenotypes of the atypical depression subtype ( Touma et al, 2008 , 2009 ; Knapman et al, 2010a , b , 2012 ; Fenzl et al, 2011 ; Pillai et al, 2012 ; Heinzmann et al, 2014 ).…”

“…The brains were sectioned into 200 μm thick coronal slices and mounted onto glass slides. Tissue punches of the dorsal (-1.2 to -2,0 mm from Bregma) and ventral (-3.0 to -3,80 mm from Bregma) hippocampus (dHip and vHip) were collected via micropuncture (for further details see Heinzmann et al, 2014 ). Total mRNA was extracted using RNeasy columns (RNeasy Micro Kit, Qiagen, Hilden, Germany) and 200 ng of the extracted mRNA was reverse transcribed to cDNA using high-capacity transcription kits (High-Capacity cDNA Reverse Transcription Kit, Applied Biosystems, Foster City, CA, USA).…”

“…This stratification of MDD patients by HPA axis function suggests that different genetic predispositions may be underlying the divergent endophenotypes ( Antonijevic, 2006 ; Heinzmann et al, 2014 ). The stress reactivity (SR) mouse model is a genetic animal model, which recapitulates several of the key endophenotypes of the two MDD subtypes described above ( Touma et al, 2008 ; Heinzmann et al, 2014 ), including associated changes in bodyweight ( Touma et al, 2009 ), sleep architecture ( Touma et al, 2009 ; Fenzl et al, 2011 ), stress hormone profiles ( Touma et al, 2008 , 2009 ; Heinzmann et al, 2014 ), and cognitive performance ( Knapman et al, 2010a , b , 2012 ). Using this animal model, our group recently showed that an inherited predisposition for extremes in stress reactivity (high or low) interacts with ELS to shape short-term, as well as lasting consequences at the level of stress-coping behavior, neuroendocrine function, and gene expression ( McIlwrick et al, 2016 ).…”

Social stress shortens lifespan in mice

“…This technique of glucocorticoid metabolite quantification in fecal samples has been established in an increasing number of species and has been extensively validated for laboratory mice (Touma, Palme & Sachser, 2004). Fecal samples were collected 2 months after the end of the CPS and were analyzed for immunoreactive corticosterone metabolites using a 5α‐pregnane‐3β,11β,21‐triol‐20‐one enzyme immunoassay (EIA) according to published methods (Heinzmann et al., 2014). Before EIA analysis, the fecal samples were dried (2 hr at 80°C), homogenized, and aliquots of 0.05 g of powdered feces were extracted with 1 ml of 80% methanol.…”