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

Depression is projected to become the second most common cause of disability worldwide by 2015. Depression as a major health issue is illustrated by its death-toll, which currently claims more lives per year than road-traffic accidents [1-4]. At the same time, there is an obvious need for an improvement in the treatment of depression, as up to 45% of depressed patients do not show improved mood after advanced therapy and 15% of patients do not respond to any antidepressant therapies [5]. The Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) defines depression by the presence of at least one of two core symptoms: anhedonia; a decreased ability to experience pleasures, and depressive mood; lasting minimally 2 weeks [6,7]. Since anhedonia, on the one hand, is a cardinal phenomenon of depressive disorders, and on the other, can be evoked in rodents, the hedonic deficit might be considered as a primary feature to be addressed in pre-clinical models of depression. Coping and cognitive deficits, low exploratory motivation, circadian and sleep disturbances, aggressive and anxiety traits, decreased sexual and increased submissive behaviour, social avoidance, deterioration of the coat state and other changes, which can be evoked in animals, with some considerations [8] are regarded as parallels of subsidiary depressive symptoms [9,10].The aim of this review is to analyze the major methodological drawbacks in mouse models of depression with a focus on its principal feature, anhedonia, in a chronic stress paradigm, and to share with the reader several procedural modifications resulting from our own experiences with a chronic stress model in C57BL/6N mice. We believe that the changes to methodology proposed here provide important advances in modelling the neurobiological basis of depression in rodents and that their implication can help develop more effective therapeutic strategies.The chronic stress paradigm is considered to have a greater aetiological relevance and fa