Abstract
Depression is a highly prevalent and recurrent neuropsychiatric disorder associated with alterations in emotional and cognitive domains. Neuroplastic phenomena are increasingly considered central to the etiopathogenesis of and recovery from depression. Nevertheless, a high number of remitted patients experience recurrent episodes of depression, remaining unclear how previous episodes impact on behavior and neuroplasticity and/or whether modulation of neuroplasticity is important to prevent recurrent depression. Through re-exposure to an unpredictable chronic mild stress protocol in rats, we observed the re-appearance of emotional and cognitive deficits. Furthermore, treatment with the antidepressants fluoxetine and imipramine was effective to promote sustained reversion of a depressive-like phenotype; however, their differential impact on adult hippocampal neuroplasticity triggered a distinct response to stress re-exposure: while imipramine re-established hippocampal neurogenesis and neuronal dendritic arborization contributing to resilience to recurrent depressive-like behavior, stress re-exposure in fluoxetine-treated animals resulted in an overproduction of adult-born neurons along with neuronal atrophy of granule neurons, accounting for an increased susceptibility to recurrent behavioral changes typical of depression. Strikingly, cell proliferation arrest compromised the behavior resilience induced by imipramine and buffered the susceptibility to recurrent behavioral changes promoted by fluoxetine. This study shows that previous exposure to a depressive-like episode impacts on the behavioral and neuroanatomical changes triggered by subsequent re-exposure to similar experimental conditions and reveals that the proper control of adult hippocampal neuroplasticity triggered by antidepressants is essential to counteract recurrent depressive-like episodes.
Highlights
Major depression is a prevalent neuropsychiatric disorder affecting around 16% of the population worldwide, which experiences one or several episodes of depression during their lifetime.[1]
Treatment with the antidepressants fluoxetine and imipramine was effective to promote sustained reversion of a depressive-like phenotype; their differential impact on adult hippocampal neuroplasticity triggered a distinct response to stress re-exposure: while imipramine re-established hippocampal neurogenesis and neuronal dendritic arborization contributing to resilience to recurrent depressive-like behavior, stress re-exposure in fluoxetine-treated animals resulted in an overproduction of adult-born neurons along with neuronal atrophy of granule neurons, accounting for an increased susceptibility to recurrent behavioral changes typical of depression
As previously shown,[9,25] exposure to unpredictable chronic mild stress (uCMS) elicited an anhedonic state manifested by decreased sucrose preference in the sucrose preference test that was reverted by both fluoxetine and imipramine treatment
Summary
Major depression is a prevalent neuropsychiatric disorder affecting around 16% of the population worldwide, which experiences one or several episodes of depression during their lifetime.[1]. The deleterious effects evoked by re-exposure to stress were associated to altered expression of cytoskeletal proteins.[6] other studies revealed that animals subjected to stress during adolescence were resilient to depressive- and anxiety-like behavior on chronic stress re-exposure in adulthood[7] and abrogation of hippocampal neurogenesis in adolescence blocked susceptibility to chronic social defeat in adulthood.[8]. UCMS and drug treatments Rats were subjected to a validated uCMS protocol for 6 weeks, as previously described[9,20,23] and detailed in the Supplementary Information.
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