Effects of Different Teaching Approaches on Proxy Measures of Physical Fitness of Italian Kindergarten Children.

Developing physical fitness (PF) behaviors early in life enhances physical development and facilitates sustained participation in physical activity and sports across childhood. This study addressed the effect of different teaching approaches on precursors of PF in kindergarten children. A total of 178 children (5.45 ± 0.40 years, female = 92) from 11 classes were organized into three groups. Group 1 (structured activity + free play) and Group 2 (only free play) attended the same playground (PrimoSport0246) for one hour/week for 10 weeks. Group 3 (structured activity + free play in kindergarten) followed their standard physical education curriculum at school. PF tests (standing long jump, medicine ball throw, and 20 m running speed) were administered pre- and post-intervention. Factorial ANOVA was implemented using a percentage change in PF performance (PFC) as the dependent variable, and teaching approaches, gender, and age as factors. Group 1 demonstrated significant improvements in fitness performance compared with Groups 2 and 3. Moderate to large effect sizes (Cohen's d range: 0.68-1.40) were noted in both males and females. Six-year-old demonstrated the greatest improvement in composite PFC compared to Groups 2 and 3. A structured teaching plan, even with a limited dose of once per week, supported the development of PF attributes in kindergarteners.

Children's Physical Activity During the COVID-19 Lockdown: A Cross Cultural Comparison Between Portugal, Brazil and Italy.

The COVID-19 pandemic forced governments to implement measures that disrupted the daily routines of many families worldwide. We studied how the COVID-19 lockdown affected children's routines in Portugal (PT), Brazil (BR), and Italy (IT) to determine if children's age and country impacted their physical activity (PA) and sedentary time. We launched an anonymous online survey to assess how 3-12 years old children adjusted their daily routines to this situation. Parents reported the times each child was engaged in different activities throughout the day, and we used these data to calculate separately overall sedentary and physical activity time. We conducted separate analyses of variance for age and country on the percentage of time spent in the different activities. Results, based on the data from 3045 children in these three countries (PT n = 2044; BR n = 836; IT n = 165), showed that, during lockdown, most children spent most of their awake daily hours in sedentary activities. There was a clear age effect on the way their routines were organized. Percentages of time spent in intellectual activity, playful screen activity, and overall sedentary time were greater in the older age groups, whereas percentages of time spent in play (with and without PA) and in overall PA were greater in the younger groups. We found a main effect of country for all variables except play without PA. The country effect was mainly due to the difference between the routines in BR when compared to PT and IT. Values of playful screen time and overall sedentary activity were higher in BR than in the two European countries. Conversely, values for play with PA, PA, and overall PA (except in the older group) were lower in BR. Patterns of time spent in these activities were similar in IT and PT, but PA and overall PA times were higher in the two younger age groups in IT. In summary, percentage of PA time of confined children was low and decreased with age across all three countries and was particularly low for children in BR relative to those in PT and IT.

Effects of Free Play and Partly Structured Playground Activity on Motor Competence in Preschool Children: A Pragmatic Comparison Trial.

Both the indoor and the outdoor environments and their organization exert pronounced influence upon physical activity behavior and motor development of preschool children. The aim of this study was to explore whether partly structured activity or free play in a specific playground had different impacts on motor competence development in 4-6-year-old preschoolers. The study had a pretest-post-test design, with two intervention groups and one control. Sixty-two children were included in a partly structured activity group and forty-three children in a free-play group. Both groups participated in playground activities consisting of 10 sessions (once a week), each lasting 1 h, in a specific playground setting. For the partly structured activity group, activities in each session consisted of a combination of both structured and free activity while the free-play group were engaged in unstructured play only. The control group did not attend the playground activities (N = 36). To assess levels of motor skills, each child completed pre- and post-tests using the Movement Assessment Battery for children (MABC-2), the Test of Motor Competence (TMC) and two playground-specific tests. A 3 (study group) and X 2 (gender) ANCOVAs were conducted on post-test scores on each of the test items from TMC, MABC-II and playground tests, with pre-test scores as covariates. Post hoc pairwise multiple comparisons were conducted with the alpha Bonferroni corrected, and the partial eta-squared (η2p) was applied as a measure of effect size. The results indicate no significant differences in motor competence measured by the TMC or the MABC-2 between groups. On the contrary, a significant improvement in performance in the playground-specific tests was observed in the partly structured activity group compared to the free-play and control groups.

Learning to Cycle: A Cross-Cultural and Cross-Generational Comparison.

Background: Learning to cycle is an important milestone for children, but the popularity of cycling and the environmental factors that promote the development and practice of this foundational movement skill vary among cultures and across time. This present study aimed to investigate if country of residence and the generation in which a person was born influence the age at which people learn to cycle. Methods: Data were collected through an online survey between November 2019 and December 2020. For this study, a total of 9,589 responses were obtained for adults (self-report) and children (parental report) living in 10 countries (Portugal, Italy, Brazil, Finland, Spain, Belgium, United Kingdom, Mexico, Croatia, and the Netherlands). Participants were grouped according to their year of birth with 20-year periods approximately corresponding to 3 generations: 1960-79 (generation X; n = 2,214); 1980-99 (generation Y; n = 3,994); 2000-2019 (generation Z; n = 3,381). Results: A two-way ANOVA showed a significant effect of country, F(9,8628) = 90.17, p < 0.001, ηp2 = 0.086, and generation, F(2,8628) = 47.21, p < 0.001, ηp2 = 0.122, on the age at which individuals learn to cycle. Countries with the lowest learning age were the Netherlands, Finland and Belgium and countries with the highest learning age were Brazil and Mexico. Furthermore, the age at which one learns to cycle has decreased across generations. There was also a significant country x generation interaction effect on learning age, F(18,8628) = 2.90, p < 0.001; however, this effect was negligible ( ηp2 = 0.006). Conclusions: These findings support the socio-ecological perspective that learning to cycle is a process affected by both proximal and distal influences, including individual, environment and time.

Therapeutic induction of energy metabolism reduces neural tissue damage and increases microglia activation in severe spinal cord injury.

Neural tissue has high metabolic requirements. Following spinal cord injury (SCI), the damaged tissue suffers from a severe metabolic impairment, which aggravates axonal degeneration and neuronal loss. Impaired cellular energetic, tricarboxylic acid (TCA) cycle and oxidative phosphorylation metabolism in neuronal cells has been demonstrated to be a major cause of neural tissue death and regeneration failure following SCI. Therefore, rewiring the spinal cord cell metabolism may be an innovative therapeutic strategy for the treatment of SCI. In this study, we evaluated the therapeutic effect of the recovery of oxidative metabolism in a mouse model of severe contusive SCI. Oral administration of TCA cycle intermediates, co-factors, essential amino acids, and branched-chain amino acids was started 3 days post-injury and continued until the end of the experimental procedures. Metabolomic, immunohistological, and biochemical analyses were performed on the injured spinal cord sections. Administration of metabolic precursors enhanced spinal cord oxidative metabolism. In line with this metabolic shift, we observed the activation of the mTORC1 anabolic pathway, the increase in mitochondrial mass, and ROS defense which effectively prevented the injury-induced neural cell apoptosis in treated animals. Consistently, we found more choline acetyltransferase (ChAT)-expressing motor neurons and increased neurofilament-positive corticospinal axons in the spinal cord parenchyma of the treated mice. Interestingly, oral administration of the metabolic precursors increased the number of activated microglia expressing the CD206 marker suggestive of a pro-resolutive, M2-like phenotype. These molecular and histological modifications observed in treated animals ultimately led to a significant, although partial, improvement of the motor functions. Our data demonstrate that rewiring the cellular metabolism can represent an effective strategy to treat SCI.

Murine cerebral organoids develop network of functional neurons and hippocampal brain region identity.

Brain organoids are in vitro three-dimensional (3D) self-organized neural structures, which can enable disease modeling and drug screening. However, their use for standardized large-scale drug screening studies is limited by their high batch-to-batch variability, long differentiation time (10-20 weeks), and high production costs. This is particularly relevant when brain organoids are obtained from human induced pluripotent stem cells (iPSCs). Here, we developed, for the first time, a highly standardized, reproducible, and fast (5 weeks) murine brain organoid model starting from embryonic neural stem cells. We obtained brain organoids, which progressively differentiated and self-organized into 3D networks of functional neurons with dorsal forebrain phenotype. Furthermore, by adding the morphogen WNT3a, we generated brain organoids with specific hippocampal region identity. Overall, our results showed the establishment of a fast, robust and reproducible murine 3D in vitro brain model that may represent a useful tool for high-throughput drug screening and disease modeling.

Environmental Enrichment Induces Meningeal Niche Remodeling through TrkB-Mediated Signaling.

Neural precursors (NPs) present in the hippocampus can be modulated by several neurogenic stimuli, including environmental enrichment (EE) acting through BDNF-TrkB signaling. We have recently identified NPs in meninges; however, the meningeal niche response to pro-neurogenic stimuli has never been investigated. To this aim, we analyzed the effects of EE exposure on NP distribution in mouse brain meninges. Following neurogenic stimuli, although we did not detect modification of the meningeal cell number and proliferation, we observed an increased number of neural precursors in the meninges. A lineage tracing experiment suggested that EE-induced ß3-Tubulin+ immature neuronal cells present in the meninges originated, at least in part, from GLAST+ radial glia cells. To investigate the molecular mechanism responsible for meningeal reaction to EE exposure, we studied the BDNF-TrkB interaction. Treatment with ANA-12, a TrkB non-competitive inhibitor, abolished the EE-induced meningeal niche changes. Overall, these data showed, for the first time, that EE exposure induced meningeal niche remodeling through TrkB-mediated signaling. Fluoxetine treatment further confirmed the meningeal niche response, suggesting it may also respond to other pharmacological neurogenic stimuli. A better understanding of the neurogenic stimuli modulation for meninges may be useful to improve the effectiveness of neurodegenerative and neuropsychiatric treatments.

Meninges: A Widespread Niche of Neural Progenitors for the Brain.

Emerging evidence highlights the several roles that meninges play in relevant brain functions as they are a protective membrane for the brain, produce and release several trophic factors important for neural cell migration and survival, control cerebrospinal fluid dynamics, and embrace numerous immune interactions affecting neural parenchymal functions. Furthermore, different groups have identified subsets of neural progenitors residing in the meninges during development and in the adulthood in different mammalian species, including humans. Interestingly, these immature neural cells are able to migrate from the meninges to the neural parenchyma and differentiate into functional cortical neurons or oligodendrocytes. Immature neural cells residing in the meninges promptly react to brain disease. Injury-induced expansion and migration of meningeal neural progenitors have been observed following experimental demyelination, traumatic spinal cord and brain injury, amygdala lesion, stroke, and progressive ataxia. In this review, we summarize data on the function of meninges as stem cell niche and on the presence of immature neural cells in the meninges, and discuss their roles in brain health and disease. Furthermore, we consider the potential exploitation of meningeal neural progenitors for the regenerative medicine to treat neurological disorders.

Complete neural stem cell (NSC) neuronal differentiation requires a branched chain amino acids-induced persistent metabolic shift towards energy metabolism.

Neural stem cell (NSC) neuronal differentiation requires a metabolic shift towards oxidative phosphorylation. We now show that a branched-chain amino acids-driven, persistent metabolic shift toward energy metabolism is required for full neuronal maturation. We increased energy metabolism of differentiating neurons derived both from murine NSCs and human induced pluripotent stem cells (iPSCs) by supplementing the cell culture medium with a mixture composed of branched-chain amino acids, essential amino acids, TCA cycle precursors and co-factors. We found that treated differentiating neuronal cells with enhanced energy metabolism increased: i) total dendritic length; ii) the mean number of branches and iii) the number and maturation of the dendritic spines. Furthermore, neuronal spines in treated neurons appeared more stable with stubby and mushroom phenotype and with increased expression of molecules involved in synapse formation. Treated neurons modified their mitochondrial dynamics increasing the mitochondrial fusion and, consistently with the increase of cellular ATP content, they activated cellular mTORC1 dependent p70S6 K1 anabolism. Global transcriptomic analysis further revealed that treated neurons induce Nrf2 mediated gene expression. This was correlated with a functional increase in the Reactive Oxygen Species (ROS) scavenging mechanisms. In conclusion, persistent branched-chain amino acids-driven metabolic shift toward energy metabolism enhanced neuronal differentiation and antioxidant defences. These findings offer new opportunities to pharmacologically modulate NSC neuronal differentiation and to develop effective strategies for treating neurodegenerative diseases.

Fingolimod Plays Role in Attenuation of Myocardial Injury Related to Experimental Model of Cardiac Arrest and Extracorporeal Life Support Resuscitation.

BACKGROUND: Sudden cardiac arrest is a major global health concern, and survival of patients with ischemia-reperfusion injury is a leading cause of myocardial dysfunction. The mechanism of this phenomenon is not well understood because of the complex pathophysiological nature of the disease. Aim of the study was to investigate the cardioprotective role of fingolimod in an in vivo model of cardiac arrest and resuscitation. METHODS: In this study, an in vivo rat model of cardiac arrest using extracorporeal membrane oxygenation resuscitation monitored by invasive hemodynamic measurement was developed. At the beginning of extracorporeal life support (ECLS), animals were randomly treated with fingolimod (Group A, n = 30) or saline (Group B, n = 30). Half of the animals in each group (Group A1 and B1, n = 15 each) were sacrificed after 1 h, and the remaining animals (Group A2 and B2) after 24 h of reperfusion. Blood and myocardial tissues were collected for analysis of cardiac features, inflammatory biomarkers, and cell signaling pathways. RESULTS: Treatment with fingolimod resulted in activation of survival pathways resulting into reduced inflammation, myocardial oxidative stress and apoptosis of cardiomyocytes. This led to significant improvement in systolic and diastolic functions of the left ventricle and improved contractility index. CONCLUSIONS: Sphingosine1phosphate receptor activation with fingolimod improved cardiac function after cardiac arrest supported with ECLS. Present study findings strongly support a cardioprotective role of fingolimod through sphingosine-1-phosphate receptor activation during reperfusion after circulatory arrest.

Comparing Free Play and Partly Structured Play in 4-5-Years-Old Children in an Outdoor Playground.

The aim of this study was to compare how the organization of a movement session as partly structured play or free play influenced the physical activity engagement in 4-5 years old pre-schoolers. The partly structured playgroup consisted of 46 children and the free playgroup consisted of 33 children. The playground activities consisted of 10 sessions each lasting 1 h, executed once per week in the period Mars to May 2017 at a specific playground setting. The partly structured playgroup conducted a movement activity session that included a combination of both structured- and free play activities. The free playgroup engaged in unstructured play, only. To detect the intensity of the physical activity each child carried an accelerometer 1 h the first week and last week of the intervention. Results indicate a significant difference in physical activity level between the two groups for the 5-year-old in the favor of the partly structured playgroup. There was a significant difference between the four-and 5-year-old in relation to physical activity level. No significant difference between the activity in March and May for the whole group was found.

Psychedelics and reconsolidation of traumatic and appetitive maladaptive memories: focus on cannabinoids and ketamine.

RATIONALE: Clinical data with 3,4-methylenedioxymethamphetamine (MDMA) in post-traumatic stress disorder (PTSD) patients recently stimulated interest on the potential therapeutic use of psychedelics in disorders characterized by maladaptive memories, including substance use disorders (SUD). The rationale for the use of MDMA in PTSD and SUD is being extended to a broader beneficial "psychedelic effect," which is supporting further clinical investigations, in spite of the lack of mechanistic hypothesis. Considering that the retrieval of emotional memories reactivates specific brain mechanisms vulnerable to inhibition, interference, or strengthening (i.e., the reconsolidation process), it was proposed that the ability to retrieve and change these maladaptive memories might be a novel intervention for PTSD and SUD. The mechanisms underlying MDMA effects indicate memory reconsolidation modulation as a hypothetical process underlying its efficacy. OBJECTIVE: Mechanistic and clinical studies with other two classes of psychedelic substances, namely cannabinoids and ketamine, are providing data in support of a potential use in PTSD and SUD based on the modulation of traumatic and appetitive memory reconsolidation, respectively. Here, we review preclinical and clinical data on cannabinoids and ketamine effects on biobehavioral processes related to the reconsolidation of maladaptive memories. RESULTS: We report the findings supporting (or not) the working hypothesis linking the potential therapeutic effect of these substances to the underlying reconsolidation process. We also proposed possible approaches for testing the use of these two classes of drugs within the current paradigm of reconsolidation memory inhibition. CONCLUSIONS: Metaplasticity may be the process in common between cannabinoids and ketamine/ketamine-like substance effects on the mediation and potential manipulation of maladaptive memories.

High Yield of Adult Oligodendrocyte Lineage Cells Obtained from Meningeal Biopsy.

Oligodendrocyte loss can lead to cognitive and motor deficits. Current remyelinating therapeutic strategies imply either modulation of endogenous oligodendrocyte precursors or transplantation of in vitro expanded oligodendrocytes. Cell therapy, however, still lacks identification of an adequate source of oligodendrocyte present in adulthood and able to efficiently produce transplantable cells. Recently, a neural stem cell-like population has been identified in meninges. We developed a protocol to obtain high yield of oligodendrocyte lineage cells from one single biopsy of adult rat meningeal tissue. From 1 cm2 of adult rat spinal cord meninges, we efficiently expanded a homogenous culture of 10 millions of meningeal-derived oligodendrocyte lineage cells in a short period of time (approximately 4 weeks). Meningeal-derived oligodendrocyte lineage cells show typical mature oligodendrocyte morphology and express specific oligodendrocyte markers, such as galactosylceramidase and myelin basic protein. Moreover, when transplanted in a chemically demyelinated spinal cord model, meningeal-derived oligodendrocyte lineage cells display in vivo-remyelinating potential. This oligodendrocyte lineage cell population derives from an accessible and adult source, being therefore a promising candidate for autologous cell therapy of demyelinating diseases. In addition, the described method to differentiate meningeal-derived neural stem cells into oligodendrocyte lineage cells may represent a valid in vitro model to dissect oligodendrocyte differentiation and to screen for drugs capable to promote oligodendrocyte regeneration.

Sphingosine 1-Phosphate Receptor Modulator Fingolimod (FTY720) Attenuates Myocardial Fibrosis in Post-heterotopic Heart Transplantation.

Background and Objective: Sphingosine 1-phosphate (S1P), and S1P receptor modulator fingolimod have been suggested to play important cardioprotective role in animal models of myocardial ischemia/reperfusion injuries. To understand the cardioprotective function of S1P and its mechanism in vivo, we analyzed apoptotic, inflammatory biomarkers, and myocardial fibrosis in an in vivo heterotopic rat heart transplantation model. Methods: Heterotopic heart transplantation is performed in 60 Sprague-Dawley (SD) rats (350-400 g). The heart transplant recipients (n = 60) are categorized into Group A (control) and Group B (fingolimod treated 1 mg/kg intravenous). At baseline with 24 h after heart transplantation, blood and myocardial tissue are collected for analysis of myocardial biomarkers, apoptosis, inflammatory markers, oxidative stress, and phosphorylation of Akt/Erk/STAT-3 signaling pathways. Myocardial fibrosis was investigated using Masson's trichrome staining and L-hydroxyline. Results: Fingolimod treatment activates both Reperfusion Injury Salvage Kinase (RISK) and Survivor Activating Factor Enhancement (SAFE) pathways as evident from activation of anti-apoptotic and anti-inflammatory pathways. Fingolimod treatment caused a reduction in myocardial oxidative stress and hence cardiomyocyte apoptosis resulting in a decrease in myocardial reperfusion injury. Moreover, a significant (p < 0.001) reduction in collagen staining and hydroxyproline content was observed in fingolimod treated animals 30 days after transplantation demonstrating a reduction in cardiac fibrosis. Conclusion: S1P receptor activation with fingolimod activates anti-apoptotic and anti-inflammatory pathways, leading to improved myocardial salvage causing a reduction in cardiac fibrosis.

Amino acid supplements and metabolic health: a potential interplay between intestinal microbiota and systems control.

Dietary supplementation of essential amino acids (EAAs) has been shown to promote healthspan. EAAs regulate, in fact, glucose and lipid metabolism and energy balance, increase mitochondrial biogenesis, and maintain immune homeostasis. Basic science and epidemiological results indicate that dietary macronutrient composition affects healthspan through multiple and integrated mechanisms, and their effects are closely related to the metabolic status to which they act. In particular, EAA supplementation can trigger different and even opposite effects depending on the catabolic and anabolic states of the organisms. Among others, gut-associated microbial communities (referred to as gut microbiota) emerged as a major regulator of the host metabolism. Diet and host health influence gut microbiota, and composition of gut microbiota, in turn, controls many aspects of host health, including nutrient metabolism, resistance to infection, and immune signals. Altered communication between the innate immune system and the gut microbiota might contribute to complex diseases. Furthermore, gut microbiota and its impact to host health change largely during different life phases such as lactation, weaning, and aging. Here we will review the accumulating body of knowledge on the impact of dietary EAA supplementation on the host metabolic health and healthspan from a holistic perspective. Moreover, we will focus on the current efforts to establish causal relationships among dietary EAAs, gut microbiota, and health during human development.

New neurons in adult brain: distribution, molecular mechanisms and therapies.

"Are new neurons added in the adult mammalian brain?" "Do neural stem cells activate following CNS diseases?" "How can we modulate their activation to promote recovery?" Recent findings in the field provide novel insights for addressing these questions from a new perspective. In this review, we will summarize the current knowledge about adult neurogenesis and neural stem cell niches in healthy and pathological conditions. We will first overview the milestones that have led to the discovery of the classical ventricular and hippocampal neural stem cell niches. In adult brain, new neurons originate from proliferating neural precursors located in the subventricular zone of the lateral ventricles and in the subgranular zone of the hippocampus. However, recent findings suggest that new neuronal cells can be added to the adult brain by direct differentiation (e.g., without cell proliferation) from either quiescent neural precursors or non-neuronal cells undergoing conversion or reprogramming to neuronal fate. Accordingly, in this review we will also address critical aspects of the newly described mechanisms of quiescence and direct conversion as well as the more canonical activation of the neurogenic niches and neuroblast reservoirs in pathological conditions. Finally, we will outline the critical elements involved in neural progenitor proliferation, neuroblast migration and differentiation and discuss their potential as targets for the development of novel therapeutic drugs for neurodegenerative diseases.

Motor Skill Development in Italian Pre-School Children Induced by Structured Activities in a Specific Playground.

This study examined the effects and specificity of structured and unstructured activities played at the playground Primo Sport 0246 in Northern Italy on motor skill competence in five years old children. The playground was specifically designed to promote gross motor skills in preschool children; in this study 71 children from local kindergartens came to the park once a week for ten consecutive weeks and were exposed to 30 minutes of free play and 30 minutes of structured activities. Before and after the ten visits, each child completed nine tests to assess levels of motor skills, three for fine-motor skills and six for gross-motor skills. As control, motor skills were also assessed on 39 children from different kindergartens who did not come to the park. The results show that the experimental group who practiced gross-motor activities in the playground for 1 hour a week for 10 weeks improved significantly in 4 out of the 6 gross motor tasks and in none of the fine motor tasks. The data indicate that limited transfer occurred between tasks referring to different domains of motor competences while suggesting cross feeding for improvement of gross-motor skills between different exercises when domains related to physical fitness and strength of specific muscle groups are involved. These results are relevant to the issue of condition(s) appropriate for maintaining and developing motor skills in this age group as well as for the planning, organization and implementation of play and physical activities in kindergartens.

The modulation of BDNF expression and signalling dissects the antidepressant from the reinforcing properties of ketamine: Effects of single infusion vs. chronic self-administration in rats.

Ketamine is a drug of abuse with a unique profile, which besides its inherent mechanism of action as a non-competitive antagonist of the NMDA glutamate receptor, displays both antidepressant and reinforcing properties. The major aim of our study was to find a molecular signature of ketamine that may help in discriminating between its reinforcing and antidepressant effects. To this end, we focused our attention on BDNF, a neurotrophin that has been shown to play a role in both antidepressant and reinforcing properties of several drugs. Rats were exposed to self-administer intravenous (IV) ketamine (S/A) for 43 days or to receive a single IV ketamine 0.5mg/kg, or vehicle infusion. Although the dose we employed is lower than that reported by the literature, it however yields Cmax values that correspond to those achieved in humans after antidepressant treatment. Our results show that while the single infusion of ketamine increased the neurotrophin expression in the hippocampus while reducing it in the ventral striatum, a feature shared with other antidepressants, the repeated self-administration reduced mBDNF expression and its downstream signalling in both ventral striatum and hippocampus. Further, we here show that phosphorylation of Akt is oppositely regulated by ketamine, pointing to this pathway as central to the different actions of the drug. Taken together, we here point to BDNF and its downstream signalling pathway as a finely tuned mechanism whose modulation might subserve the different features of ketamine.