Update in the methodology of the chronic stress paradigm: internal control matters

To date, the reliability of induction of a depressive-like state using chronic stress models is
confronted by many methodological limitations. We believe that the modifications to the stress
paradigm in mice proposed herein allow some of these limitations to be overcome. Here, we
discuss a variant of the standard stress paradigm, which results in anhedonia. This anhedonic
state was defined by a decrease in sucrose preference that was not exhibited by all animals. As
such, we propose the use of non-anhedonic, stressed mice as an internal control in experimental
mouse models of depression. The application of an internal control for the effects of stress, along
with optimized behavioural testing, can enable the analysis of biological correlates of stressinduced anhedonia versus the consequences of stress alone in a chronic-stress depression model.
This is illustrated, for instance, by distinct physiological and molecular profiles in anhedonic and
non-anhedonic groups subjected to stress. These results argue for the use of a subgroup of
individuals who are negative for the induction of a depressive phenotype during experimental
paradigms of depression as an internal control, for more refined modeling of this disorder in
animals