2025/03/01 by Federico Picciau, Valdemar Brimnes Ingemann Johansen, Christoffer Merrild · 1 voice
Neuroscience · Biochemistry, Genetics and Molecular Biology · #Neurogenesis and neuroplasticity mechanisms #Mitochondrial Function and Pathology #Microtubule and mitosis dynamics
paper · pdf · doi:10.1113/jp288408
The global burden of neurodegenerative diseases and age-related cognitive decline is a growing concern, with limited effective interventions currently available. Neurogenesis, the generation of new neurons in the adult brain, is a key process for maintaining cognitive function and plasticity (Jurkowski et al., 2020). In adult mice, different populations of neuronal stem cells capable of neurogenesis have been identified; these include the subgranular zone (SGZ) of the dentate gyrus in the hippocampus and the ventricular–subventricular zone (V-SVZ) lining the lateral ventricles (Fig. 1A) (Jurkowski et al., 2020; Lambertus et al., 2024). Physical activity is a potent stimulus for neurogenesis and has been implicated in slowing the process of biological ageing (Jurkowski et al., 2020; Lambertus et al., 2024). Several substances produced during exercise promote neurogenesis. In mice, these include brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1) and lactate (Jurkowski et al., 2020; Lambertus et al., 2024). The last is an hydroxycarboxylic acid receptor 1 (HCA1) agonist (Lambertus et al., 2024; Lev-Vachnish et al., 2019). Despite these insights, the precise contributions of HCA1 activation and the influence of different physical activities on neurogenesis remain poorly understood (Fig. 1B). In a recent publication, Lambertus et al. shed light on the neurogenic role of HCA1 and different exercise regimens. In their study, wild-type (WT) and HCA1 knockout (KO) mice were randomly assigned to sedentary, high-intensity interval training (HIIT) or medium-intensity interval training (MIIT) protocols 5 days a week for 3 weeks, with exercise groups performing forced treadmill running (Fig. 1C). Following the intervention period, brain tissue was processed for immunofluorescence analysis of neuronal differentiation markers in the SGZ and V-SVZ areas (Fig. 1C). Specifically, the expression of nestin was assessed to identify neural stem cells (NSCs). Proliferation was examined using Ki-67 as a marker of actively dividing neuroprogenitor cells, while doublecortin (DCX) was used to identify migrating neuroblasts. The study by Lambertus et al. delineates the distinct impacts of HIIT, MIIT and no exercise on neurogenesis in the SGZ and V-SVZ of adult male and female mice brains (Fig. 1D). Importantly, the HIIT paradigm significantly enhances the density of DCX-positive cells (markers of immature neurons) in both the SGZ and V-SVZ. The increase in neurogenesis was particularly robust in the V-SVZ, where HIIT resulted in a 155% increase in DCX-positive cells compared to the sedentary control groups. This finding is particularly noteworthy, as it suggests that HIIT can potentiate neurogenesis in areas of the brain involved in olfactory and periventricular functions, which are less studied compared to hippocampal functions. MIIT also increased DCX-positive cell density but to a lesser extent and notably only within the V-SVZ. The effects in the SGZ did not reach statistical significance when comparing control animals with those undergoing the MIIT protocol, suggesting a differential sensitivity to exercise intensity between these two neurogenic zones. This outcome points to the possibility that MIIT exercise may be insufficient to trigger the neurogenic mechanisms in the hippocampus. A major mechanistic insight from this study involves the role of HCA1 in mediating the effects of exercise on neurogenesis. The study highlights that the enhanced neurogenesis observed in the V-SVZ following HIIT depends on HCA1 signalling, as demonstrated by the absence of HIIT-induced neurogenesis in HCA1 KO mice. Interestingly, this dependency was not observed in the SGZ, suggesting that distinct molecular pathways underlie neurogenesis in different brain regions in response to exercise. Furthermore, Lambertus et al. explored the specificity of exercise-induced neurogenesis on different stages of neuronal development. Their findings indicate that HIIT specifically increases the proliferation of neural progenitor cells and their subsequent development into immature neurons, as evidenced by increases in both Ki-67 (a marker of proliferation) and the colocalization of DCX and Ki-67 in the V-SVZ. This suggests that HIIT not only promotes the birth of new neurons but also supports their early development. The study by Lambertus et al. provides valuable insights into the differential effects of exercise intensity on neurogenesis in two key neurogenic niches of the adult brain: the SGZ and the V-SVZ. The authors selected these regions for their well-established roles in neurogenesis. It is important to note that exercise also activates other brain areas involved in cognitive and motor functions, such as the motor cortex, cerebellum and amygdala (Skovbjerg et al., 2024). Some of these regions activated in response to physical exercise could influence the outcomes observed in this study (Jurkowski et al., 2020). Thus, the neurogenic effects observed in Lambertus et al. may extend beyond the SGZ and V-SVZ, potentially engaging neurogenic processes in other brain regions. While the focus on the SGZ and V-SVZ is justified and contributes to our understanding, expanding the exploration to include these additional areas could provide a more comprehensive view of the neurogenic effects induced by exercise across the brain. Forced treadmill running (FTR), employed by Lambertus et al., provides control over exercise intensity, duration and progression, ensuring consistency across subjects and facilitating the structured implementation of exercise intervention protocols. This precision allows the neurogenic effects of exercise and HCA1 signalling to be isolated with minimal variability, aligning with the study's objectives. However, it is important to acknowledge that the use of a treadmill-based protocol could induce potential confounding factors due to its intrinsic stress induction (Skovbjerg et al., 2024). Skovbjerg et al. demonstrated that even placement on an inactive treadmill induces in mice significant stress responses, as evidenced by whole-brain c-Fos imaging showing activation of brain regions involved in stress, fear and pain, and elevation of plasma corticosterone levels (Skovbjerg et al., 2024). Stress responses can modulate neurogenesis both positively and negatively depending on the brain area, and on the context and intensity of the stressor (Jurkowski et al., 2020). Chronic stress reduces neurogenesis in the hippocampus, a region crucial for learning and memory, while simultaneously enhances neurogenesis in the amygdala, which is associated with fear and emotional responses (Jurkowski et al., 2020). Since Lambertus et al. did not administer frequent foot shocks, their FTR protocol may be less aversive compared to other FTR paradigms. Consequently, the potential confounding influence of stress from FTR may be less pronounced in the Lambertus et al. study than in other studies employing repeated aversive stimuli. Nonetheless, it cannot be entirely ruled out that some observed neurogenic effects may arise or be masked from stress responses rather than the direct effects of exercise. As the intrinsic stress of treadmill placement, with or without physical activity associated, can reduce hippocampal neurogenesis (Jurkowski et al., 2020; Skovbjerg et al., 2024), it is possible that the neurogenic effects observed in the hippocampus are attenuated. Adopting exercise methods aiming at minimizing stress, such as voluntary exercise on wheels, may lead to more pronounced hippocampal neurogenesis, further reinforcing the role of exercise as a potent stimulator of neurogenesis. However, these methods inherently lack the capability to standardize intensity and duration across subjects. To address this challenge, while still harnessing the benefits of controlled exercise conditions, a viable approach for future experiments could involve continuing the use of FTR but incorporating measurements of stress-related biomarkers. Alternatively, the addition of control groups subjected to treadmill placement with no physical activity intervention could contribute to disentangle stress effects from exercise-induced neurogenesis. Finally, while the findings of Lambertus et al. highlight the HCA1-dependent superior neurogenic effects of HIIT compared to MIIT for a short time intervention in young mice (Fig. 1D), important questions remain regarding the exact neurogenic role of lactate and the generalizability of these results across different age groups. Regarding the first question, Lambertus et al. acknowledge the gap between HIIT-induced neurogenesis and its functional relevance. A recent study demonstrating that lactate enhances hippocampal neurogenesis through monocarboxylate transporter 2, but not HCA1, adds an interesting layer to this discussion (Lev-Vachnish et al., 2019). Despite increased neurogenesis, no improvements in hippocampal-dependent cognitive function were observed, suggesting that lactate alone may be insufficient to drive functional gains (Lev-Vachnish et al., 2019). This highlights the complexity of the relationship between neurogenesis and cognitive outcomes, suggesting that additional factors may be necessary to translate neurogenic responses into behavioural benefits. In addressing the generalizability of the findings of Lambertus et al., integrating insights from van Praag et al. offers valuable context in this regard. van Praag's study illustrates that even voluntary wheel running enhances hippocampal neurogenesis and improves cognitive function in aged mice, effectively reversing age-related declines (van Praag et al., 2005). This suggests that the neurogenic benefits of exercise extend beyond young populations with non-voluntary physical activity and may provide protective effects against ageing-related cognitive deficits. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The authors have no competing interests or conflict of interests to disclose. All authors have read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed: F.P.: Conceptualization, Writing (original draft), Visualization, Writing (review & editing). V.B.I.J.: Conceptualization, Visualization, Writing (review & editing). C.M.: Conceptualization, Visualization, Writing (review & editing). Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) is an independent research center at the University of Copenhagen, Denmark, partially supported by an unconditional donation from the Novo Nordisk Foundation cbmr.ku.dk; grant number NNF23SA0084103. The authors acknowledge that not all information is cited due to reference limits but can be found in the reference list of the research article reviewed in the present journal club article. The authors would like to thank their mentor Associate Professor Dr Christoffer Clemmensen for the stimulating discussion related to this journal club paper.