Sequential treadmill exercise and cognitive training synergistically increase adult hippocampal neurogenesis in mice

Ávila‐Gámiz, Fabiola; Pérez-Cano, A M; Pérez-Berlanga, J M; Mullor-Vigo, R M; Zambrana-Infantes, Emma; Santín, Luis J.; Guevara‐Miranda, David Ladrón de

doi:10.1016/j.physbeh.2023.114184

Cited by 4 publications

(3 citation statements)

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“…These data suggest that: (a) the increase in neurogenesis induced by the deletion of p21 in aNSCs induced a significant improvement in the working memory, a cognitive system dependent on adult hippocampal neurogenesis [ 71 – 74 ], (b) this improvement likely involves the functional contribution of 8-week-old newborn neurons. A similar correlation has been demonstrated recently by two studies which have shown how physical activity in synergy with cognitive training [ 72 ] or with the administration of lactate [ 70 ] is able to promote an increase in adult hippocampal neurogenesis and a consequent increase in working memory perfomance. The involvement of p21 in such mechanisms has not been taken into consideration, however we have demonstrated that the deletion of p21 is able to largely amplify the pro-neurogenic role of physical activity in the subventricular neurogenic niche [ 37 , 38 ].…”

Section: Discussionsupporting

confidence: 83%

Essential role of p21Waf1/Cip1 in the modulation of post-traumatic hippocampal Neural Stem Cells response

Chiani,

Mastrorilli,

Marchetti

et al. 2024

Stem Cell Res Ther

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Background Traumatic Brain Injury (TBI) represents one of the main causes of brain damage in young people and the elderly population with a very high rate of psycho-physical disability and death. TBI is characterized by extensive cell death, tissue damage and neuro-inflammation with a symptomatology that varies depending on the severity of the trauma from memory loss to a state of irreversible coma and death. Recently, preclinical studies on mouse models have demonstrated that the post-traumatic adult Neural Stem/Progenitor cells response could represent an excellent model to shed light on the neuro-reparative role of adult neurogenesis following damage. The cyclin-dependent kinase inhibitor p21Waf1/Cip1 plays a pivotal role in modulating the quiescence/activation balance of adult Neural Stem Cells (aNSCs) and in restraining the proliferation progression of progenitor cells. Based on these considerations, the aim of this work is to evaluate how the conditional ablation of p21Waf1/Cip1 in the aNSCS can alter the adult hippocampal neurogenesis in physiological and post-traumatic conditions. Methods We designed a novel conditional p21Waf1/Cip1 knock-out mouse model, in which the deletion of p21Waf1/Cip1 (referred as p21) is temporally controlled and occurs in Nestin-positive aNSCs, following administration of Tamoxifen. This mouse model (referred as p21 cKO mice) was subjected to Controlled Cortical Impact to analyze how the deletion of p21 could influence the post-traumatic neurogenic response within the hippocampal niche. Results The data demonstrates that the conditional deletion of p21 in the aNSCs induces a strong increase in activation of aNSCs as well as proliferation and differentiation of neural progenitors in the adult dentate gyrus of the hippocampus, resulting in an enhancement of neurogenesis and the hippocampal-dependent working memory. However, following traumatic brain injury, the increased neurogenic response of aNSCs in p21 cKO mice leads to a fast depletion of the aNSCs pool, followed by declined neurogenesis and impaired hippocampal functionality. Conclusions These data demonstrate for the first time a fundamental role of p21 in modulating the post-traumatic hippocampal neurogenic response, by the regulation of the proliferative and differentiative steps of aNSCs/progenitor populations after brain damage.

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Section: Discussionsupporting

confidence: 83%

Essential role of p21Waf1/Cip1 in the modulation of post-traumatic hippocampal Neural Stem Cells response

Chiani,

Mastrorilli,

Marchetti

et al. 2024

Stem Cell Res Ther

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“…Without ruling out a possible explanation of the benefit of executing PA in both DT and SeqT conditions at old age, one can also genuinely hypothesize a longlasting beneficial effect stemming from mice's activity as young adults. While previous studies have reported the benefits of a sequential combination of PA and CT in animals [25,26], this is the first paper suggesting such a long-lasting positive impact of DT training in aged mice. Moreover, the fact that all aged mice in both DT and SeqT groups took twice as many sessions as young adults to reach the criterion mirrors findings in humans, where young adults (20-29 years old) outperformed older ones (60 to 74 years old and > 75 years old), indicating an agerelated impact on dual-tasking [38].…”

Section: Discussionmentioning

confidence: 67%

“…Indeed, in the absence of verbal communication, cognitive tests in animals are based on the evaluation of a motor response (movement or absence of movement in an area of the testing device, interaction with another conspecific/an object, …), making it tricky to add a significant motor challenge during behavioral cognitive tasks, to build a DT condition. For this reason, most animal studies have focused on the benefits of combining PA and CT only sequentially [25,26]. Quite interestingly, some authors have recently used the animals' ambulatory speed during increasingly demanding cognitive tasks as a reflection of DT condition [27].…”

Section: Introductionmentioning

confidence: 99%

A Dual-Task Paradigm Combining Physical and Cognitive Training in Mice: Application to Aging

2024

Aging dis

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Physical Activity (PA) is often associated with better overall health status, especially in older adults. Numerous pieces of evidence indicate that PA would be more beneficial when applied in conjunction with Cognitive Training (CT) either simultaneously (i.e., in Dual-Task [DT]) or sequentially. Nonetheless, the underlying mechanisms of such benefits remain elusive. To help delve deeper into their understanding, we developed a cognitive-motor DT paradigm in young adult mice and subsequently tested its effect in old age. Three groups of young adults C57BL/6J mice (3.5 months of age; n=10/group) were required. They were given cognitive tasks, either alone (Control) or in combination with PA which was administered either sequentially (SeqT group) or simultaneously (DT group). Mice were trained in a touchscreen chamber: first on a Visual Discrimination (VD) learning task, then on its Reversal (RVD) which assesses cognitive flexibility alongside procedural learning. PA was given through a homemade treadmill, designed to fit in the touchscreen chambers and set at 9 m/min. Fourteen months later, we further evaluated the effects of PA administered in both DT and SeqT groups, on the performance of the now 19-month-old mice. When compared to SeqT and control groups, DT mice significantly displayed better procedural learning in both VD and RVD tasks as young adults. In the RVD task, this enhanced performance was associated with both poorer inhibition and motor performance. Finally, in 19-month-old mice, both DT and SeqT mice displayed better motor and cognitive performances than control mice. This new cognitive-motor DT paradigm in mice yields an interesting framework that should be useful for adapting DT training in aging, including providing knowledge on the neurobiological correlates, to get the most out of its benefits.

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Sequential physical and cognitive training disrupts cocaine-context associations via multi-level stimulation of adult hippocampal neurogenesis

Ávila-Gámiz,

Pérez-Cano,

Pérez-Berlanga

et al. 2025

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Sequential treadmill exercise and cognitive training synergistically increase adult hippocampal neurogenesis in mice

Cited by 4 publications

References 83 publications

Essential role of p21Waf1/Cip1 in the modulation of post-traumatic hippocampal Neural Stem Cells response

Essential role of p21Waf1/Cip1 in the modulation of post-traumatic hippocampal Neural Stem Cells response

A Dual-Task Paradigm Combining Physical and Cognitive Training in Mice: Application to Aging

Sequential physical and cognitive training disrupts cocaine-context associations via multi-level stimulation of adult hippocampal neurogenesis

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