Abstract
The chronic unpredictable stress (CUS) paradigm is extensively used in preclinical research. However, CUS exhibits translational inconsistencies, some of them resulting from the use of adult rodents, despite the evidence that vulnerability for many psychiatric disorders accumulates during early life. Here, we assessed the validity of the CUS model by including ethologically-relevant paradigms in juvenile rats. Thus, socially-isolated (SI) rats were submitted to CUS and compared with SI (experiment 1) and group-housed controls (experiment 1 and 2). We found that lower body-weight gain and hyperlocomotion, instead of sucrose consumption and preference, were the best parameters to monitor the progression of CUS, which also affected gene expression and neurotransmitter contents associated with that CUS-related phenotype. The behavioural characterisation after CUS placed locomotion and exploratory activity as the best stress predictors. By employing the exploratory factor analysis, we reduced each behavioural paradigm to few latent variables which clustered into two general domains that strongly predicted the CUS condition: (1) hyper-responsivity to novelty and mild threats, and (2) anxiety/depressive-like response. Altogether, the analyses of observable and latent variables indicate that early-life stress impairs the arousal-inhibition system leading to augmented and persistent responses towards novel, rewarding, and mildly-threatening stimuli, accompanied by lower body-weight gain.
Highlights
The chronic unpredictable stress (CUS) paradigm is extensively used in preclinical research
Our results suggest that SI alone or within the CUS protocol is capable of increasing sucrose consumption and preference in agreement with SI studies[25,26,28,36,39], but in disagreement with the CUS evidence[14,15,16,39,46,54,55,56,57,58]
We found lower corticotropin-releasing factor (CRF) expression after CUS, which may be inconsistent with a recent report showing higher CRF expression in cortical and subcortical regions associated with the extra-hypothalamic response to stress[90]
Summary
The chronic unpredictable stress (CUS) paradigm is extensively used in preclinical research. The effects of the CUS model are frequently monitored by measuring the reduction of sucrose preference or consumption in the sucrose preference test (SPT)[17], which is assumed as a measure of anhedonia This concept refers to a markedly diminished interest or pleasure in almost all activities, which is present most of the time and constitutes one of the two core symptoms of major depression, according to most psychiatric diagnostic manuals (e.g., DSM-V and ICD11)[18,19]. Post-weaning SI induces hyperlocomotion, increases immobility in the FST, and sucrose intake without affecting its preference[21,24] These findings, especially on sucrose consumption, were in agreement with earlier observations in SI rats from different strains[25,26]. We found that environmental enrichment –considered the opposite of SI– reduces sucrose consumption and preference[28]
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