Prolonged stress-induced depression-like behaviors in aged rats are mediated by endoplasmic reticulum stress and apoptosis in the hippocampus.

Structural and functional recovery from stress-induced depression is impaired in the context of aging brain. Since investigating the molecular substrates that facilitate behavioral recovery may have important implications for understanding brain plasticity and resilience of individuals, we studied depressive-like behaviors in young and aged rats 6 weeks after chronic stress exposure as a recovery period and examined the levels of TNF-α and IL-6 inflammatory cytokines, NADH oxidase activity, NADPH oxidase, endoplasmic reticulum (ER) stress markers, and apoptosis in the hippocampus. Young (3 months old) and aged (22 months old) male Wistar rats were divided into four groups; young control (Young), depression model of young rats that received chronic stress procedure followed by a 6-week recovery period (Young+S), aged control (Aged), and depression model of aged rats that received chronic stress procedure followed by a 6-week recovery period (Aged+S). After the recovery period, aged but not young rats showed depression-like behaviors, evaluated by the sucrose preference test (SPT) and forced swimming test (FST), coincided with the altered levels of TNF-α, IL-6, NADH oxidase activity, NADPH oxidase, GRP78, CHOP, and cleaved caspase-12 in the hippocampus of these animals. These data suggested that oxidative and ER stress-induced apoptosis in the aging hippocampus may affect the recovery-related outcomes after the stress paradigm.

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