Cyclical administration of corticosterone results in aggravation of depression-like behaviors and accompanying downregulations in reelin in an animal model of chronic stress relevant to human recurrent depression.

Depression is recognized as a highly chronic and recurrent disorder. Each successive episode increases susceptibility to future relapses. The current study aimed to develop an animal model of chronic stress relevant to human recurrent depression in order to examine possible neurobiological mechanisms behind this increased vulnerability. We hypothesized that rats with a prior depression-like episode would be sensitized to subsequent stress, developing depression-like behaviors in response to shorter glucocorticoid exposures. Rats were given corticosterone (CORT) or vehicle injections for one, two, or three 21-day cycles, followed by recovery periods. A series of behavioural assessments were conducted at specific time points after CORT treatment or the recovery period. After behavioral testing, the rats were sacrificed for immunohistochemical analyses of the extracellular matrix protein reelin, which is involved in regulating neural plasticity and is decreased in the hippocampus of depression patients. We found that repeated and cyclic exposure to high levels of CORT escalated depression-like behavior (i.e., forced swim test, sucrose preference test) without altering general locomotor activity (i.e., open field test). Changes in depression-like behaviors were accompanied by cumulative and persistent decreases in reelin-positive cells in the dentate gyrus subgranular zone. These data support the idea of an exacerbation of behavioral and neurochemical alterations with recurrent episodes, which highlights the importance of early therapeutic interventions.

Changes in Membrane Protein Clustering in Peripheral Lymphocytes in an Animal Model of Depression Parallel Those Observed in Naïve Depression Patients: Implications for the Development of Novel Biomarkers of Depression.

Naïve depression patients show alterations in serotonin transporter (SERT) and serotonin 2A (5HT2A) receptor clustering in peripheral lymphocytes, and these alterations have been proposed as a biomarker of therapeutic efficacy in major depression. Repeated corticosterone (CORT) induces a consistent depression-like phenotype and has been widely used as an animal model to study neurobiological alterations underlying the depressive symptoms. In this experiment, we used the CORT paradigm to evaluate whether depression-like behavior is associated with similar changes in the pattern of SERT and 5HT2A membrane protein clustering as those observed in depression patients. We also analyzed the clustering of other proteins expressed in lipid rafts in lymphocytes. Rats received daily CORT or vehicle injections for 21 consecutive days. Afterward they underwent the forced swim test to evaluate depression-like behavior, and isolated lymphocytes were analyzed by immunocytochemistry coupled to image-analysis to study clustering parameters of the SERT, 5HT2A receptor, dopamine transporter (DAT), Beta2 adrenergic receptor (ß2AR), NMDA 2B receptor (NR2B), Pannexin 1 (Pnx1), and prion cellular protein (PrPc). Our results showed that CORT increases the size of protein clusters for all proteins with the exception of ß 2AR, which is decreased. CORT also increased the number of clusters for Pnx1 and PrPc only. Overall, these results indicate that alterations in SERT and 5HT2A protein clustering in naïve depression patients are paralleled by changes seen in an animal model of depression. The CORT paradigm may be a useful screen for examining additional proteins in lymphocytes as a preliminary step prior to their analysis as biomarkers of depression in human blood samples.