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Catalysing brain plasticity through adult neural stem cell modulation : the role of cannabinoids and neurotrophic factors
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The adult mammalian brain is endowed with a considerable amount of regenerative potential through the generation of new cells, particularly neurons, throughout adulthood from adult neural stem cells (NSCs). This adult neurogenesis phenomenon mainly operates in two regions – the neurogenic niches – in the subventricular zone (SVZ) of the lateral ventricles and in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG). In the latter, in a process of adult hippocampal neurogenesis (AHN), adultborn neurons participate in hippocampal-dependent functions such as cognitive processing and emotional flexibility by promoting circuitry remodelling and endogenous brain plasticity. This process is tightly regulated by several factors present in the surrounding extracellular milieu that shape the dynamics of NSCs and progenitors. Among these, neurotrophic factors are key molecules that support neural growth and survival and contribute to NSC regulation. On the other hand, cannabinoids are known modulators of homeostasis, neuroplasticity and proliferation, differentiation and maturation of NSCs and progenitor cells. Nevertheless, there is still a lack of knowledge about the mechanisms by which these molecules control adult neurogenesis and NSC activity.
This work aimed to evaluate and dissect the individual and combined actions of both neurotrophic factors and cannabinoids in the regulation of adult NSC dynamics in physiological and pathological contexts.
In the first study of this thesis (chapter 4), we show that cannabinoid type 1 (CB1R) and type 2 (CB2R) receptors and brain-derived neurotrophic factor (BDNF) are key players responsible for fine-tuning early SVZ and DG postnatal neurogenesis. Furthermore, we demonstrate that BDNF is essential for cannabinoid-mediated neurogenesis. Importantly, in DG neurogenesis, we show that BDNF-mediated actions in cell proliferation are dependent on CB2Rs while CB2R-mediated effects in neuronal differentiation require endogenous BDNF, depicting an interdependence between these two systems.
These findings led us to investigate the actions of other exercise-associated neurotrophic factors, namely vascular endothelial growth factor (VEGF) and insulin-like growth factor 1 (IGF-1) as well as the role of CB2Rs in the regulation of DG postnatal neurogenesis. In the second study of this thesis (chapter 5), we found that a cocktail of these neurotrophic factors, composed of BDNF+VEGF+IGF-1, significantly enhanced DG cell proliferation, an effect that was partially abrogated by CB2R blockage. Moreover, the actions of this exercise-mimicking cocktail in early neuronal commitment, but not late neuronal differentiation, were abrogated by CB2R blockage, suggesting that CB2Rs have a determinant role in the regulation of early stages of DG neurogenesis.
Taking this into consideration, and aiming at a translational rationale with a putative stress-countering strategy, in a third study (chapter 7) we evaluated the combined actions of CB2Rs together with physical exercise (PE), which is a known inductor of neurotrophic factor upregulation, in the context of depression. For this, we have submitted adult mice to an unpredictable chronic mild stress (uCMS) protocol to induce core symptoms of depressive-like behaviour. At the end of uCMS, animals were submitted to a PE regimen and treatment with CB2R modulators, independently or in combination with PE, for 2 weeks. We found that CB2R blockage, but not CB2R activation, together with PE treatment significantly ameliorated chronic stress-evoked emotional changes (anxious- and anhedonic-like behaviours) as well as cognitive deficits (long-term memory). Importantly, we show that this combined strategy critically influences stress-induced changes in AHN dynamics, leading to a significant increase in the rates of proliferation and differentiation of newborn neurons. Moreover, CB2R blockage together with PE reduced the overall neuroinflammatory tone, counteracting the deleterious effects exerted by chronic stress. This reveals a synergistic effect of CB2R blockage and PE treatment that is critical to counter the detrimental effects of chronic stress and sheds light on the potential of multitargeted approaches for stressrelated pathologies.
Altogether, the data herein revealed a novel layer of interaction between different adult NSC modulators, namely neurotrophic factors and cannabinoids, showing for the first time how CB2Rs fine-tune adult neurogenesis in collaboration with exercise-associated neurotrophic factors. These results also contribute to a better understanding of NSC dynamics and the importance of these neurogenic modulators in physiological and pathological contexts. Finally, this work provides new insights on the potential of CB2Rs and PE as promising targets for the development of brain repair and regeneration strategies for stress-related disorders such as depression.
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neurogénese adulta moduladores neurogénicos fatores neurotróficos canabinóides depressão adult neurogenesis neurogenic modulators neurotrophic factors cannabinoids depression