Abstract
Neural stem cells (NSCs), crucial for memory in the adult brain, are also pivotal to buffer depressive behavior. However, the mechanisms underlying the boost in NSC activity throughout life are still largely undiscovered. Here, we aimed to explore the role of deacetylase Sirtuin 3 (SIRT3), a central player in mitochondrial metabolism and oxidative protection, in the fate of NSC under aging and depression-like contexts. We showed that chronic treatment with tert-butyl hydroperoxide induces NSC aging, markedly reducing SIRT3 protein. SIRT3 overexpression, in turn, restored mitochondrial oxidative stress and the differentiation potential of aged NSCs. Notably, SIRT3 was also shown to physically interact with the long chain acyl-CoA dehydrogenase (LCAD) in NSCs and to require its activation to prevent age-impaired neurogenesis. Finally, the SIRT3 regulatory network was investigated in vivo using the unpredictable chronic mild stress (uCMS) paradigm to mimic depressive-like behavior in mice. Interestingly, uCMS mice presented lower levels of neurogenesis and LCAD expression in the same neurogenic niches, being significantly rescued by physical exercise, a well-known upregulator of SIRT3 and lipid metabolism. Our results suggest that targeting NSC metabolism, namely through SIRT3, might be a suitable promising strategy to delay NSC aging and confer stress resilience.
Highlights
Adult neurogenesis constitutively occurs in the adult mammalian brain where neural stem cells (NSCs) are able to differentiate into three neural lineages, including neurons, astrocytes, and oligodendrocytes [1]
Along with proliferation deficits, the differentiation potential of NSCs was markedly affected after tert-butyl hydroperoxide (tBHP) incubation, since immunoblot analysis showed a significant decrease in neural stem cell (Sox2) and neuronal (NeuN) markers (p < 0.05 and p < 0.001, respectively) (Figure 1C)
Sirtuin 3 (SIRT3), a central player in mitochondrial metabolism and oxidative protection, was markedly reduced in this cellular context (p < 0.01) (Figure 1D). These results demonstrate that tBHP induces a feasible NSC aging model, possibly through a reduction in the SIRT3-dependent mitochondrial antioxidant defense system
Summary
Adult neurogenesis constitutively occurs in the adult mammalian brain where neural stem cells (NSCs) are able to differentiate into three neural lineages, including neurons, astrocytes, and oligodendrocytes [1] These multipotent cells are able to self-renew through cell proliferation in order to maintain their pool [2]. This process occurs mainly in two restricted brain areas, the subventricular zone (SVZ) lining the lateral ventricles, and the subgranular zone (SGZ) within the dentate gyrus (DG) of the hippocampus [3,4]. The progressive decrease in NSCs’ ability to self-renew and differentiate into new neurons throughout aging ends up reflected in the progressive loss of brain physiological integrity and in the lower regenerative ability that follows the aging process [9,10,13]
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