Abstract
Maternal separation (MS), an early life stressful event, has been demonstrated to trigger neuropsychiatric disorders later in life, in particular depression. Experiments using rodents subjected to MS protocols have been very informative for the establishment of this association. However, the mechanism by which MS leads to neuropsychiatric disorders is far from being understood. This is probably associated with the multifactorial nature of depression but also with the fact that different research MS protocols have been used (that vary on temporal windows and time of exposure to MS). In the present study, MS was induced in rats in two developmental periods: for 6 h per day for 14 days between postnatal days 2–15 (MS2–15) and 7–20 (MS7–20). These two periods were defined to differ essentially on the almost complete (MS2–15) or partial (MS7–20) overlap with the stress hypo-responsive period. Behavioral, immunological, and endocrine parameters, frequently associated with depressive-like behavior, were analyzed in adulthood. Irrespectively from the temporal window, both MS exposure periods led to increased sera corticosterone levels. However, only MS2–15 animals displayed depressive and anxious-like behaviors. Moreover, MS2–15 was also the only group presenting alterations in the immune system, displaying decreased percentage of CD8+ T cells, increased spleen T cell CD4/CD8 ratio, and thymocytes with increased resistance to dexamethasone-induced cell death. A linear regression model performed to predict depressive-like behavior showed that both corticosterone levels and T cell CD4/CD8 ratio explained 37% of the variance observed in depressive-like behavior. Overall, these findings highlight the existence of “critical periods” for early life stressful events to exert programing effects on both central and peripheral systems, which are of relevance for distinct patterns of susceptibility to emotional disorders later in life.
Highlights
Depression is a devastating and prevalent mental disorder that causes great disability in modern societies and is predicted to rank in the second position for premature death in 2030 (Mathers and Loncar, 2006)
Particular relevant for Maternal separation (MS)-induced depressive-like behavior are studies using the forced swimming test (FST), revealing increased immobility time in animals submitted to MS (3–4 h per day during the first 15 postnatal days, which overlaps most of the stress hypo-responsive period in rodents) when compared with animals reared in typical housing conditions (Ruedi-Bettschen et al, 2005; Lee et al, 2007; Lambas-Senas et al, 2009; Martisova et al, 2012)
With respect to the anhedonic dimension of depression, measured by the sucrose preference test (SPT), MS animals display decreased sucrose consumption (Michaels and Holtzman, 2007). These results have not been confirmed by others, with respect to both immobility time in the FST (Marais et al, 2008) and sucrose consumption in the SPT (Shalev and Kafkafi, 2002)
Summary
Depression is a devastating and prevalent mental disorder that causes great disability in modern societies and is predicted to rank in the second position for premature death in 2030 (Mathers and Loncar, 2006). With respect to the anhedonic dimension of depression, measured by the sucrose preference test (SPT), MS animals display decreased sucrose consumption (Michaels and Holtzman, 2007). These results have not been confirmed by others, with respect to both immobility time in the FST (Marais et al, 2008) and sucrose consumption in the SPT (Shalev and Kafkafi, 2002). These discrepancies in the literature, possibly caused by small changes in the MS protocols used (Schmidt et al, 2011), deserve further investigation, on the mechanisms underlying depressive-like behavior
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