Alves N D, Correia J S, Patrício P, Mateus-Pinheiro A, Machado-Santos A R, Loureiro-Campos E, Morais M, Bessa J M, Sousa N, Pinto L
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Transl Psychiatry. 2017 Mar 14;7(3):e1058. doi: 10.1038/tp.2017.29.
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.
抑郁症是一种高度普遍且反复发作的神经精神疾病，与情绪和认知领域的改变有关。神经可塑性现象越来越被认为是抑郁症发病机制和恢复过程的核心。然而，大量缓解的患者会经历抑郁症的复发，目前尚不清楚先前的发作如何影响行为和神经可塑性，以及神经可塑性的调节对于预防复发性抑郁症是否重要。通过让大鼠再次暴露于不可预测的慢性轻度应激方案中，我们观察到情绪和认知缺陷再次出现。此外，使用抗抑郁药氟西汀和丙咪嗪进行治疗有效地促进了抑郁样表型的持续逆转；然而，它们对成年海马神经可塑性的不同影响引发了对应激再次暴露的不同反应：虽然丙咪嗪重新建立了海马神经发生和神经元树突分支，有助于抵御复发性抑郁样行为，但氟西汀治疗的动物再次暴露于应激后，导致成年新生神经元过度产生以及颗粒神经元萎缩，这解释了它们对抑郁症典型的复发性行为变化的易感性增加。令人惊讶的是，细胞增殖停滞损害了丙咪嗪诱导的行为恢复力，并缓冲了氟西汀促进的复发性行为变化的易感性。这项研究表明，先前暴露于抑郁样发作会影响随后再次暴露于类似实验条件所引发的行为和神经解剖学变化，并揭示抗抑郁药引发的成年海马神经可塑性的适当控制对于对抗复发性抑郁样发作至关重要。
