Pupil dynamics during very light exercise predict benefits to prefrontal cognition.

Physical exercise, even stress-free very-light-intensity exercise such as yoga and very slow running, can have beneficial effects on executive function, possibly by potentiating prefrontal cortical activity. However, the exact mechanisms underlying this potentiation have not been identified. Evidence from studies using pupillometry demonstrates that pupil changes track the real-time dynamics of activity linked to arousal and attention, including neural circuits from the locus coeruleus to the cortex. This makes it possible to examine whether pupil-linked brain dynamics induced during very-light-intensity exercise mediate benefits to prefrontal executive function in healthy young adults. In this experiment, pupil diameter was measured during 10 min of very-light-intensity exercise (30% V˙o2peak). A Stroop task was used to assess executive function before and after exercise. Prefrontal cortical activation during the task was assessed using multichannel functional near-infrared spectroscopy (fNIRS). We observed that very-light-intensity exercise significantly elicited pupil dilation, reduction of Stroop interference, and task-related left dorsolateral prefrontal cortex activation compared with the resting-control condition. The magnitude of change in pupil dilation predicted the magnitude of improvement in Stroop performance. In addition, causal mediation analysis showed that pupil dilation during very-light-intensity exercise robustly determined subsequent enhancement of Stroop performance. This finding supports our hypothesis that the pupil-linked mechanisms, which may be tied to locus coeruleus activation, are a potential mechanism by which very light exercise enhances prefrontal cortex activation and executive function. It also suggests that pupillometry may be a useful tool to interpret the beneficial impact of exercise on boosting cognition.

Long-term light and moderate exercise intervention similarly prevent both hippocampal and glycemic dysfunction in presymptomatic type 2 diabetic rats.

A prediabetic population has an increased risk of cognitive decline and type 2 diabetes mellitus (T2DM). This study investigated whether the progression of memory dysfunction and dysregulated brain glycogen metabolism is prevented with 4 mo of exercise intervention from the presymptomatic stage in a T2DM rat model. Memory function and biochemical and molecular profiles were assessed in the presymptomatic stage of Otsuka-Long-Evans-Tokushima fatty (OLETF) rats, a T2DM model, with Long-Evans Tokushima (LETO) rats as genetic control. These rats were subjected to light- or moderate-intensity treadmill running for 4 mo with repetition of the same experiments. Significant hippocampal-dependent memory dysfunction was observed in the presymptomatic stage of OLETF rats, accompanied by downregulated levels of hippocampal monocarboxylate transporter 2 (MCT2), a neuronal lactate-transporter, without alteration in hippocampal glycogen levels. Four months of light or moderate exercise from the presymptomatic stage of T2DM normalized glycemic parameters and hippocampal molecular normalization through MCT2, glycogen, and brain-derived neurotrophic factor (BDNF) levels with the improvement of memory dysfunction in OLETF rats. A 4-mo exercise regimen from the presymptomatic stage of T2DM at a light and moderate intensities contributed to the prevention of the development of T2DM and the progression of cognitive decline with hippocampal lactate-transport and BDNF improvement.NEW & NOTEWORTHY Type 2 diabetes mellitus is an independent risk factor for hippocampal memory dysfunction, which would progress since the prediabetic stage. We found that 4 mo of exercise both at the light and moderate intensity prevented the progression of memory dysfunction with an improvement of hippocampal MCT2 expression in presymptomatic diabetes, implying that light intensity exercise could be a therapeutic approach, and the alteration of hippocampal MCT2 would be a therapeutic target of memory dysfunction from presymptomatic diabetes.

Taurine supplementation enhances endurance capacity by delaying blood glucose decline during prolonged exercise in rats.

Taurine enhances physical performance; however, the underlying mechanism remains unclear. This study examined the effect of taurine on the overtime dynamics of blood glucose concentration (BGC) during endurance exercise in rats. Male F344 rats were subjected to transient treadmill exercise until exhaustion following 3 weeks of taurine supplementation or non-supplementation (TAU and CON groups). Every 10 min during exercise, BGC was measured in blood collected through cannulation of the jugular vein. Gluconeogenesis-, lipolysis-, and fatty acid oxidation-related factors in the plasma, liver, and skeletal muscles were also analyzed after 120-min run. Exercise time to exhaustion was significantly longer with taurine supplementation. BGC in the two groups significantly increased by 40 min and gradually and significantly decreased toward the respective exhaustion point. The decline in BGC from the peak at 40 min was significantly slower in the TAU group. The time when the once-increased BGC regressed to the 0-time level was significantly and positively correlated with exercise time until exhaustion. At the 120-min point, where the difference in BGC between the two groups was most significant, plasma free fatty acid concentration and acetyl-carnitine and N-acetyltaurine concentrations in skeletal muscle were significantly higher in the TAU group, whereas glycogen and glucogenic amino acid concentrations and G6Pase activity in the liver were not different between the two groups. Taurine supplementation enhances endurance capacity by delaying the decrease in BGC toward exhaustion through increases of lipolysis in adipose tissues and fatty acid oxidation in skeletal muscles during endurance exercise.

Exercise-Induced Adrenocorticotropic Hormone Response Is Cooperatively Regulated by Hypothalamic Arginine Vasopressin and Corticotrophin-Releasing Hormone.

INTRODUCTION: Exercise becomes a stress when performed at an intensity above the lactate threshold (LT) because at that point the plasma adrenocorticotropic hormone (ACTH), a marker of stress response, increases. It is possible that the exercise-induced ACTH response is regulated at least by arginine vasopressin (AVP) and possibly by corticotropin-releasing hormone (CRH), but this remains unclear. To clarify the involvement of these factors, it is useful to intervene pharmacologically in the regulatory mechanisms, with a physiologically acceptable exercise model. METHODS: We used a special stress model of treadmill running (aerobic exercise) for male Wistar rats, which mimic the human physiological response, where plasma ACTH levels increase at just above the LT for 30 min. Animals were administered the AVP V1b receptor antagonist SSR149415 (SSR) and/or the CRH type 1 receptor antagonist CP154526 (CP) intraperitoneally before the exercise, which allowed the monitoring of exercise-induced ACTH response. Immunohistochemical evaluation of activated AVP and CRH neurons with exercise was performed for the animals' hypothalami. RESULTS: A single injection of either antagonist, SSR or CP, resulted in inhibited ACTH levels after exercise stress. Moreover, the combined injection of SSR and CP strongly suppressed ACTH secretion during treadmill running to a greater extent than each alone. The running-exercise-induced activation of both AVP and CRH neurons in the hypothalamus was also confirmed. CONCLUSION: These results lead us to hypothesize that AVP and CRH are cooperatively involved in exercise-induced ACTH response just above the LT. This may also reflect the stress response with moderate-intensity exercise in humans.

High-intensity Intermittent Training Enhances Spatial Memory and Hippocampal Neurogenesis Associated with BDNF Signaling in Rats.

High-intensity intermittent (or interval) training (HIIT) has started to gain popularity as a time-effective approach to providing beneficial effects to the brain and to peripheral organs. However, it still remains uncertain whether HIIT enhances hippocampal functions in terms of neurogenesis and spatial memory due to unconsidered HIIT protocol for rodents. Here, we established the HIIT regimen for rats with reference to human study. Adult male Wistar rats were assigned randomly to Control, moderate-intensity continuous training (MICT; 20 m/min, 30 min/day, 5 times/week), and HIIT (60 m/min, 10 30-s bouts of exercise, interspaced with 2.5 min of recovery, 5 times/week) groups. The ratios of exercise time and volume between MICT and HIIT were set as 6:1 and 2:1-4:1, respectively. After 4 weeks of training, all-out time in the incremental exercise test was prolonged for exercise training. In skeletal muscle, the plantaris citrate synthase activity significantly increased only in the HIIT group. Simultaneously, both HIIT and MICT led to enhanced spatial memory and adult hippocampal neurogenesis (AHN) as well as enhanced protein levels of hippocampal brain-derived neurotrophic factor (BDNF) signaling. Collectively, we suggest that HIIT could be a time-efficient exercise protocol that enhances hippocampal memory and neurogenesis in rats and is associated with hippocampal BDNF signaling.

Socioeconomic and lifestyle factors associated with mental health problems among Mongolian elementary school children.

PURPOSE: Lifestyle factors of children and adolescents' mental health problems are an emerging health issue in low- and middle-income countries (LMICs). However, there is a lack of studies on lifestyle factors in LMICs. This study examined the socioeconomic and lifestyle factors associated with mental health problems among school-age children in Mongolia. METHODS: A population-based cross-sectional survey was conducted among 4th-year students at public elementary schools in one district in Ulaanbaatar. The Strengths and Difficulties Questionnaire (SDQ) and a self-administrated socioeconomic and lifestyle questionnaire were completed by participants' guardians. A multivariate logistic regression analysis was performed. RESULTS: Of the 2301 children surveyed, 1694 without missing responses were included in the analysis. The multivariate logistic regression analysis showed that male gender [adjusted odds ratio (AOR) 1.64 (1.29-2.10)], low maternal education [AOR 1.89 (1.16-3.05)], short sleep [AOR 1.41 (1.10-1.80)], no physical activity [AOR 1.31 (1.03-1.67)], and long screen time (AOR 1.53 (1.20-1.94)) were associated with high risk of mental health problems. Low maternal education, low household income, no physical activity habit, and long screen time were associated with internalising problems. Meanwhile, male gender, low maternal education, and long screen time were associated with externalising problems. CONCLUSION: The results are consistent with previous studies in high-income countries, indicating that there are globally common socioeconomic and lifestyle risk factors. The findings of this study may help develop a targeted preventive intervention for high-risk groups, such as socioeconomically disadvantaged groups, as well as a universal preventive intervention to foster a healthy lifestyle in Mongolia.

Leptin in hippocampus mediates benefits of mild exercise by an antioxidant on neurogenesis and memory.

Regular exercise and dietary supplements with antioxidants each have the potential to improve cognitive function and attenuate cognitive decline, and, in some cases, they enhance each other. Our current results reveal that low-intensity exercise (mild exercise, ME) and the natural antioxidant carotenoid astaxanthin (AX) each have equivalent beneficial effects on hippocampal neurogenesis and memory function. We found that the enhancement by ME combined with AX in potentiating hippocampus-based plasticity and cognition is mediated by leptin (LEP) made and acting in the hippocampus. In assessing the combined effects upon wild-type (WT) mice undergoing ME with or without an AX diet for four weeks, we found that, when administrated alone, ME and AX separately enhanced neurogenesis and spatial memory, and when combined they were at least additive in their effects. DNA microarray and bioinformatics analyses revealed not only the up-regulation of an antioxidant gene, ABHD3, but also that the up-regulation of LEP gene expression in the hippocampus of WT mice with ME alone is further enhanced by AX. Together, they also increased hippocampal LEP (h-LEP) protein levels and enhanced spatial memory mediated through AKT/STAT3 signaling. AX treatment also has direct action on human neuroblastoma cell lines to increase cell viability associated with increased LEP expression. In LEP-deficient mice (ob/ob), chronic infusion of LEP into the lateral ventricles restored the synergy. Collectively, our findings suggest that not only h-LEP but also exogenous LEP mediates effects of ME on neural functions underlying memory, which is further enhanced by the antioxidant AX.

Preventive role of regular low-intensity exercise during adolescence in schizophrenia model mice with abnormal behaviors.

Schizophrenia is probably ascribed to perinatal neurodevelopmental deficits, and its onset might be affected by environmental factors. Hypofrontality with glutamatergic and dopaminergic neuronal dysfunction are known factors, but a way to mitigate abnormalities remains unfound. An early enriched environment such as a wheel running in rodents may contribute to the prevention, but its clinical applicability is very limited. From our studies, low-intensity exercise training (LET) based on physiological indices, such as lactate threshold, easily translates to humans and positively affects the brains. Hence, LET during adolescence may ameliorate abnormalities in neurodevelopment and prevent the development of schizophrenia. In the current study, LET prevented sensitization to phencyclidine (PCP) treatment, impairment of cognition, and affective behavioral abnormalities in an animal model of schizophrenia induced by prenatal PCP treatment. Further, LET increased dopamine turnover and attenuated the impairment of phosphorylation of ERK1/2 after exposure to a novel object in the prenatal PCP-treated mice. These results suggest that LET during adolescence completely improves schizophrenia-like abnormal behaviors associated with improved glutamate uptake and the dopamine-induced ERK1/2 signaling pathway in the PFC.

Validation of the parent version of the Strengths and Difficulties Questionnaire (SDQ) to screen mental health problems among school-age children in Mongolia.

BACKGROUND: Child and adolescent mental health problems are urgent health issues in low- and middle-income countries. To promote child and adolescent mental health services, simple validated screening tools are helpful. In Mongolia, the Strengths and Difficulties Questionnaire (SDQ), an internationally used child and adolescent mental health screening tool for children aged 4-17, was translated but not yet validated. To use the questionnaire appropriately, validation is necessary. METHODS: Children at 4th year at elementary school (community sample) and children visited psychiatric outpatient service (clinical sample) were recruited and their parental version of the SDQ was compared. The discriminating ability of the parental version of the SDQ was examined using Receiver Operating Characteristics (ROC) analysis on the SDQ total difficulties score. The area under the ROC curve (AUC) was used as a measure. Cut-off score was determined by normative banding that categorizes children with the highest 10% score range as abnormal and the second highest 10% as borderline following the original method; this cut-off score was compared with the cut-off score candidates with good balance between sensitivity and specificity using ROC analysis. RESULTS: We included 2301 children in the community sample, and 429 children in the clinical sample. Mean age was 9.7 years (SD 0.4, range 8.3-12.0) among the community sample and 10.4 years (SD 3.8, range 4.0-17.8) among the clinical sample. The mean total difficulties score was 12.9 (SD 4.8) among the community sample and 20.4 (SD 6.2) among the clinical sample. A total of 88.8% of the community sample and 98.8% of the clinical sample answered the SDQ. Using ROC analysis, the AUC was 0.82 (95% confident interval 0.80-0.85), which meant moderate discriminating ability. Using normative banding, the borderline cut-off score was 16/17 and abnormal cut-off score was 19/20. For cut-off scores of 16/17 and 19/20, sensitivity was 71.9 and 53.8% and specificity was 78.5 and 90.5%, respectively. The cut-off score candidates by ROC analysis were 16/17 and 17/18. CONCLUSIONS: The parental version of the SDQ had moderate discriminating ability among Mongolian school-age children. For the screening of mental health problems among community children, cut-off score of 16/17 is recommended.

Rapid stimulation of human dentate gyrus function with acute mild exercise.

Physical exercise has beneficial effects on neurocognitive function, including hippocampus-dependent episodic memory. Exercise intensity level can be assessed according to whether it induces a stress response; the most effective exercise for improving hippocampal function remains unclear. Our prior work using a special treadmill running model in animals has shown that stress-free mild exercise increases hippocampal neuronal activity and promotes adult neurogenesis in the dentate gyrus (DG) of the hippocampus, improving spatial memory performance. However, the rapid modification, from mild exercise, on hippocampal memory function and the exact mechanisms for these changes, in particular the impact on pattern separation acting in the DG and CA3 regions, are yet to be elucidated. To this end, we adopted an acute-exercise design in humans, coupled with high-resolution functional MRI techniques, capable of resolving hippocampal subfields. A single 10-min bout of very light-intensity exercise (30%[Formula: see text]) results in rapid enhancement in pattern separation and an increase in functional connectivity between hippocampal DG/CA3 and cortical regions (i.e., parahippocampal, angular, and fusiform gyri). Importantly, the magnitude of the enhanced functional connectivity predicted the extent of memory improvement at an individual subject level. These results suggest that brief, very light exercise rapidly enhances hippocampal memory function, possibly by increasing DG/CA3-neocortical functional connectivity.

Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity.

Brain glycogen stored in astrocytes provides lactate as an energy source to neurons through monocarboxylate transporters (MCTs) to maintain neuronal functions such as hippocampus-regulated memory formation. Although prolonged exhaustive exercise decreases brain glycogen, the role of this decrease and lactate transport in the exercising brain remains less clear. Because muscle glycogen fuels exercising muscles, we hypothesized that astrocytic glycogen plays an energetic role in the prolonged-exercising brain to maintain endurance capacity through lactate transport. To test this hypothesis, we used a rat model of exhaustive exercise and capillary electrophoresis-mass spectrometry-based metabolomics to observe comprehensive energetics of the brain (cortex and hippocampus) and muscle (plantaris). At exhaustion, muscle glycogen was depleted but brain glycogen was only decreased. The levels of MCT2, which takes up lactate in neurons, increased in the brain, as did muscle MCTs. Metabolomics revealed that brain, but not muscle, ATP was maintained with lactate and other glycogenolytic/glycolytic sources. Intracerebroventricular injection of the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol did not affect peripheral glycemic conditions but suppressed brain lactate production and decreased hippocampal ATP levels at exhaustion. An MCT2 inhibitor, α-cyano-4-hydroxy-cinnamate, triggered a similar response that resulted in lower endurance capacity. These findings provide direct evidence for the energetic role of astrocytic glycogen-derived lactate in the exhaustive-exercising brain, implicating the significance of brain glycogen level in endurance capacity. Glycogen-maintained ATP in the brain is a possible defense mechanism for neurons in the exhausted brain.

The effectiveness of exercise intervention for academic achievement, cognitive function, and physical health among children in Mongolia: a cluster RCT study protocol.

BACKGROUND: Many studies have demonstrated positive effects of physical activity on children's health such as improved cardiorespiratory function and decreased obesity. Physical activity has also been found to have positive effects on academic achievement and cognitive function. However, there are few high quality RCT studies on this topic at present and the findings remain controversial. METHODS: This protocol describes cluster randomized controlled trials assessing the impact of school-based exercise intervention among children in Mongolia. The intervention consists of 3-min sessions of high intensity interval training combined with music implemented two times a week at school during study periods. The participants are children in the fourth grade in public elementary schools in the Sukhbaatar district in Ulaanbaatar, Mongolia. The participants are cluster randomized by school and allocated either to the intervention or control group. The primary outcome is academic achievement. Secondary outcomes are obesity/overweight, physical fitness function, lifestyle, mental health, and cognitive function. DISCUSSION: This cluster-RCT is designed and implemented to assess the effectiveness of exercise intervention on academic achievement, cognitive function, and physical and mental health among school-age children in Mongolia. This study will provide evidence to promote physical activities among children in low- and middle- income countries. TRIAL REGISTRATION: UMIN: UMIN000031062 . Registered on 1st February 2018.

A transferable high-intensity intermittent exercise improves executive performance in association with dorsolateral prefrontal activation in young adults.

Although growing attention has been drawn to attainable, high-intensity intermittent exercise (HIE)-based intervention, which can improve cardiovascular and metabolic health, for sedentary individuals, there is limited information on the impact and potential benefit of an easily attainable HIE intervention for cognitive health. We aimed to reveal how acute HIE affects executive function focusing on underlying neural substrates. To address this issue, we examined the effects of acute HIE on executive function using the color-word matching Stroop task (CWST), which produces a cognitive conflict in the decision-making process, and its neural substrate using functional near infrared spectroscopy (fNIRS). Twenty-five sedentary young adults (mean age: 21.0 ± 1.6 years; 9 females) participated in two counter-balanced sessions: HIE and resting control. The HIE session consisted of two minutes of warm-up exercise (50 W load at 60 rpm) and eight sets of 30 s of cycling exercise at 60% of maximal aerobic power (mean: 127 W ± 29.5 load at 100 rpm) followed by 30 s of rest on a recumbent-ergometer. Participants performed a CWST before and after the 10-minute exercise session, during both of which cortical hemodynamic changes in the prefrontal cortex were monitored using fNIRS. Acute HIE led to improved Stroop performance reflected by a shortening of the response time related to Stroop interference. It also evoked cortical activation related to Stroop interference on the left-dorsal-lateral prefrontal cortex (DLPFC), which corresponded significantly with improved executive performance. These results provide the first empirical evidence using a neuroimaging method, to our knowledge, that acute HIE improves executive function, probably mediated by increased activation of the task-related area of the prefrontal cortex including the left-DLPFC.

Neural basis for reduced executive performance with hypoxic exercise.

While accumulating evidence suggests positive effects of exercise on executive function, such effects vary with environment. In particular, exercise in a hypoxic environment (hypobaric or normobaric hypoxia), leading to decreased oxygen supply, may dampen or cancel such effects. Thus, we further explore the relation between the effects of hypoxic exercise on executive function and their underlying neural mechanisms by monitoring changes of cortical activation patterns using functional near-infrared spectroscopy (fNIRS). Fifteen healthy participants performed color-word Stroop tasks (CWST) before and after a 10 min bout of moderate-intensity exercise (50%V̇O2peak) under normoxic and hypoxic conditions (fraction of inspired oxygen (FIO2) = 0.135). During the CWST, we monitored prefrontal activation using fNIRS. CWST performance under hypoxic conditions decreased compared with normoxic conditions. In addition, CWST-related activation in the left dorsolateral prefrontal cortex (DLPFC) was reduced after a bout of hypoxic exercise. There was statistically significant association between decreased CWST performance and activation in the left DLPFC. These results suggest that moderate exercise under normobaric hypoxic conditions has negative effects on executive function by reducing task-related activations in the DLPFC.

Moderate exercise ameliorates dysregulated hippocampal glycometabolism and memory function in a rat model of type 2 diabetes.

AIMS/HYPOTHESIS: Type 2 diabetes is likely to be an independent risk factor for hippocampal-based memory dysfunction, although this complication has yet to be investigated in detail. As dysregulated glycometabolism in peripheral tissues is a key symptom of type 2 diabetes, it is hypothesised that diabetes-mediated memory dysfunction is also caused by hippocampal glycometabolic dysfunction. If so, such dysfunction should also be ameliorated with moderate exercise by normalising hippocampal glycometabolism, since 4 weeks of moderate exercise enhances memory function and local hippocampal glycogen levels in normal animals. METHODS: The hippocampal glycometabolism in OLETF rats (model of human type 2 diabetes) was assessed and, subsequently, the effects of exercise on memory function and hippocampal glycometabolism were investigated. RESULTS: OLETF rats, which have memory dysfunction, exhibited higher levels of glycogen in the hippocampus than did control rats, and breakdown of hippocampal glycogen with a single bout of exercise remained unimpaired. However, OLETF rats expressed lower levels of hippocampal monocarboxylate transporter 2 (MCT2, a transporter for lactate to neurons). Four weeks of moderate exercise improved spatial memory accompanied by further increase in hippocampal glycogen levels and restoration of MCT2 expression independent of neurotrophic factor and clinical symptoms in OLETF rats. CONCLUSIONS/INTERPRETATION: Our findings are the first to describe detailed profiles of glycometabolism in the type 2 diabetic hippocampus and to show that 4 weeks of moderate exercise improves memory dysfunction in type 2 diabetes via amelioration of dysregulated hippocampal glycometabolism. Dysregulated hippocampal lactate-transport-related glycometabolism is a possible aetiology of type-2-diabetes-mediated memory dysfunction.

Acute moderate exercise improves mnemonic discrimination in young adults.

Increasing evidence suggests that regular moderate exercise increases neurogenesis in the dentate gyrus (DG) of the hippocampus and improves memory functions in both humans and animals. The DG is known to play a role in pattern separation, which is the ability to discriminate among similar experiences, a fundamental component of episodic memory. While long-term voluntary exercise improves pattern separation, there is little evidence of alterations in DG function after an acute exercise session. Our previous studies showing acute moderate exercise-enhanced DG activation in rats, and acute moderate exercise-enhanced prefrontal activation and executive function in humans, led us to postulate that acute moderate exercise may also activate the hippocampus, including more specifically the DG, thus improving pattern separation. We thus investigated the effects of a 10-min moderate exercise (50% V̇O2peak ) session, the recommended intensity for health promotion, on mnemonic discrimination (a behavioral index of pattern separation) in young adults. An acute bout of moderate exercise improved mnemonic discrimination performance in high similarity lures. These results support our hypothesis that acute moderate exercise improves DG-mediated pattern separation in humans, proposing a useful human acute-exercise model for analyzing the neuronal substrate underlying acute and regular exercise-enhanced episodic memory based on the hippocampus. © 2016 Wiley Periodicals, Inc.

Retroviral induction of GSK-3ß expression blocks the stimulatory action of physical exercise on the maturation of newborn neurons.

Adult hippocampal neurogenesis (AHN) is a key process for certain types of hippocampal-dependent learning. Alzheimer's disease (AD) is accompanied by memory deficits related to alterations in AHN. Given that the increased activity of GSK-3ß has been related to alterations in the population of hippocampal granule neurons in AD patients, we designed a novel methodology by which to induce selective GSK-3ß overexpression exclusively in newborn granule neurons. To this end, we injected an rtTA-IRES-EGFP-expressing retrovirus into the hippocampus of tTO-GSK-3ß mice. Using this novel retroviral strategy, we found that GSK-3ß caused a cell-autonomous impairment of the morphological and synaptic maturation of newborn neurons. In addition, we examined whether GSK-3ß overexpression in newborn neurons limits the effects of physical activity. While physical exercise increased the number of dendritic spines, the percentage of mushroom spines, and the head diameter of the same in tet-OFF cells, these effects were not triggered in tet-ON cells. This observation suggests that GSK-3ß blocks the stimulatory actions of exercise. Given that the activity of GSK-3ß is increased in the brains of individuals with AD, these data may be relevant for non-pharmacological therapies for AD.

The association between aerobic fitness and cognitive function in older men mediated by frontal lateralization.

Previous studies have shown that higher aerobic fitness is related to higher cognitive function and higher task-related prefrontal activation in older adults. However, a holistic picture of these factors has yet to be presented. As a typical age-related change of brain activation, less lateralized activity in the prefrontal cortex during cognitive tasks has been observed in various neuroimaging studies. Thus, this study aimed to reveal the relationship between aerobic fitness, cognitive function, and frontal lateralization. Sixty male older adults each performed a submaximal incremental exercise test to determine their oxygen intake (V·O2) at ventilatory threshold (VT) in order to index their aerobic fitness. They performed a color-word Stroop task while prefrontal activation was monitored using functional near infrared spectroscopy. As an index of cognitive function, Stroop interference time was analyzed. Partial correlation analyses revealed significant correlations among higher VT, shorter Stroop interference time and greater left-lateralized dorsolateral prefrontal cortex (DLPFC) activation when adjusting for education. Moreover, mediation analyses showed that left-lateralized DLPFC activation significantly mediated the association between VT and Stroop interference time. These results suggest that higher aerobic fitness is associated with cognitive function via lateralized frontal activation in older adults.

Effects of exercise on cognitive function: the possible strategy for anti-aging.

Aging is one of the major factors which decline cognitive function associated with hippo- campus and prefrontal cortex, so it is an urgent issue to develop the practical treatment for aging brain. Since many researchers show that physical exercise can increase hippocampal neurogenesis and gray matter volume of prefrontal cortex, physical exercise is a potential candidate for preventing cognitive decline. Recently, we have reported that mild intensity exercise training enhances neurogenesis in rodents. In addition, we found long term inter- vention of mild exercise has beneficial effects on prefrontal gray matter volume and cognitive function in older adults. Based on these facts, mild exercise could be optimal strategy for anti-aging of brain.