Hyukki Chang

Threshold-like pattern of neuronal activation in the hypothalamus during treadmill running: establishment of a minimum running stress (MRS) rat model.

Despite the indication that the hypothalamo-pituitary-adrenal (HPA) axis is activated during treadmill running, there have not been any studies focusing on the relationship between exercise intensity and region-specific neural activities in hypothalamus. To address this, rats were subjected to 30 min of running, either at middle (supra-LT, 25 m min(-1)) or low speeds (sub-LT, 15 m min(-1)), and c-Fos-(+) cells were counted and compared with control rats. Significant increases in blood glucose and lactate levels, and plasma ACTH and osmolality levels were observed during supra-LT running. Only supra-LT running significantly increased c-Fos induction in various hypothalamic regions, namely, the medial preoptic area (MPO), periventricular nucleus (Pe), suprachiasmatic nucleus (SCN), supraoptic nucleus (SON), parvocellular division of the paraventricular nucleus (pPVN), anterior hypothalamic area (AH), arcuate nucleus (ARC) and posterior hypothalamic nucleus (PH). However, sub-LT caused no effect on c-Fos accumulation. This indicates that the hypothalamus responds uniquely to running in a threshold-like pattern distinct from the speed-dependent pattern previously reported for the medulla oblongata [Ohiwa et al., 2006a,b]. In addition, these results showed a physiologic basis for mild exercise useful for establishing our minimum running stress (MRS) rat model, or the running conditions that minimize the activation of the HPA axis.

Exercise ameliorates cognition impairment due to restraint stress-induced oxidative insult and reduced BDNF level.

We assessed whether chronic treadmill exercise attenuated restraint stress-induced cognition impairment. Although serum corticosterone was not significantly altered by exercise, the restraint-induced increases in hippocampal malondialdehyde (MDA) and 4-hydroxynonenal (HNE) were reduced by chronic exercise. The exercise paradigm also reversed stress-induced reductions in brain-derived neurotrophic factor (BDNF), which increased cAMP response element-binding protein (CREB) and AKT activation. We verified the relationship between oxidative stress and BDNF signaling by treating primary hippocampal cultures with hydrogen peroxide (H2O2), which reduced BDNF and phosphorylated CREB and AKT (p-CREB, p-AKT) in a dose-dependent manner. Notably, pretreatment with N-acetylcysteine (NAC) reversed these decreases in a dose-dependent manner. These findings suggest that chronic exercise can ameliorate repeated stress-induced cognitive impairment by detoxifying reactive oxygen species (ROS) in the hippocampus and activating BDNF signaling.

Long-term Mild Exercise Training Enhances Hippocampus-dependent Memory in Rats

Although exercise training improves hippocampus-related cognition, the optimum exercise intensity is still disputed. Based on the lactate threshold (LT, approximately 20 m/min on treadmill) of rats, we have shown that 2 weeks of training with stress-free mild exercise (ME, LT), comprising exercise stress, promotes adult hippocampal neurogenesis (Okamoto et al., PNAS, 2012), a potential substrate for memory improvement. These results led us to postulate that long-term ME, but not IE, training leads to improved hippocampal function as assessed with a Morris water maze (MWM) task. To test this hypothesis, we investigated the changes in physiological stress levels and MWM task performance in rats assigned to 6 weeks of sedentary control (CONT), ME-training or IE-training conditions. Results showed that, compared to the other conditions, only IE causes general adaptive syndrome (GAS), including adrenal hypertrophy, thymic atrophy and hypercorticosteronemia. In the MWM, ME led to enhanced memory, but not learning, compared with CONT, while IE produced no change in either capacity, probably due to GAS. These findings support the hypothesis that 6 weeks of continuous ME training leads to enhanced hippocampus-related memory, which may have implications for both healthy adults and subjects with low physical capacity.

Differential responsiveness of c-Fos expression in the rat medulla oblongata to different treadmill running speeds

Expression of the inducible transcription factor c-Fos was mapped in the rat medulla oblongata to identify the brain areas respond to different running speeds. Rats were subjected to 30 min of running, either at high speed, low speed or just sitting on a treadmill (control). Blood lactate levels were measured to confirm the physiological impact of different exercise intensities. The number of c-Fos-ir cells was counted and their spatial distributions were mapped through the rostral to the caudal level in the medulla. A statistically significant exercise intensity-dependent induction of c-Fos was observed in the nucleus of the solitary tract (NTS) and caudal ventrolateral medulla (CVL) in the medulla. Further, c-Fos induction was more predominant in the caudal part of each nucleus. The present data clearly show that different running speeds cause differential activation of each nucleus in the medulla, and in particular, the caudal parts of the NTS and the CVL are the most responsive to speed changes. The present study identifies brain areas newly found to be responsive to changes in running speed. These findings are likely to be particularly helpful in studies of specific neural circuits and their functions in response to different running speeds.

Maternal exercise during pregnancy affects mitochondrial enzymatic activity and biogenesis in offspring brain

Abstract The present study addresses whether exercise during pregnancy in mouse alters mitochondrial function in the brains of the resultant offspring. We divided pregnant mice into four groups: a control group and groups of mice that exercised for 20 (E20m), 30 (E30m) and 40 min/d (E40m). The pregnant mice ran on a treadmill at 12 m/min, 5 d/week for a duration of 3 weeks. The protein expression of cytochrome c oxidase subunit Va (CVa) was downregulated in the offspring of the E20m group, unlike that in the control animals, whereas CVa expression was reserved in the E40m neonates. The F1-ATPase catalytic core (Core) protein expression levels were the highest in the E40m group neonates. Complex I, IV and ATPase activities were significantly lower in the E20m group than that in the control group neonates and were reserved in the E30m and E40m group neonates. The activities of citrate synthase and pyruvate dehydrogenase were consistent with those of complex I, IV and ATPase. Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha, mitochondrial transcription factor A, nuclear respiratory factor-1 and mitochondrial DNA showed high levels of expression in the E40m neonates compared with the other groups. Malondialdehyde (MDA) levels in E40m neonates were higher than that in the controls but were lower than that in the E20m neonates. Finally, 40 min/d of maternal exercise improved mitochondrial function in the resultant pups and was concomitant with brain-derived trophic factor induction in the hippocampus, thereby functionally improving short-term memory.

Activation of A1 and A2 noradrenergic neurons in response to running in the rat

Since running accompanied with blood lactate accumulation stimulates the release of adrenocorticotropic hormone (ACTH), running above the lactate threshold (LT) acts as stress (running stress). To examine whether A1/A2 noradrenergic neurons that project to the hypothalamus activate under running stress, c-Fos immunohistochemistry was used to compare the effects of running with or without stress response on A1/A2 noradrenergic neurons. Blood lactate and plasma ACTH concentrations significantly increased in the running stress group, but not in the running without stress response and control groups, confirming different physiological impacts between different intensity of running with or without stress. Running stress markedly increased c-Fos accumulation in the A1/A2 noradrenergic neurons. Running without stress response also induced a significant increase in c-Fos expression in the A1/A2 noradrenergic neurons, and the percentage of the increase was smaller than that of running stress. The extent of c-Fos expression in the A1/A2 noradrenergic neurons correlates with exercise intensity, signifying that this neuronal activation is running speed-dependent. We thus suggest that A1/A2 noradrenergic neurons are activated in response to not only running stress, but also to other physiological running, enhanced by non-stressful running. These findings will be helpful in studies of specific neurocircuits and in identifying their functions in response to running at different intensities.

Exercise training improves basal blood glucose metabolism with no changes of cytosolic inhibitor κB kinase or c-Jun N-terminal kinase activation in skeletal muscle of Otsuka Long–Evans Tokushima fatty rats

Redox‐sensitive stress kinases and heat shock protein 72 (Hsp72) have been considered to be associated with the development of type 2 diabetes in skeletal muscle. However, the effect of exercise training on skeletal muscle of type 2 diabetic models is largely unknown. The purpose of this study was to investigate the effect of 12 weeks of exercise training on gastrocnemius of type 2 diabetic rats, by examining the activation of c‐Jun N‐terminal kinase (JNK), the nuclear factor κB (NF‐κB) pathway and Hsp72. Total hydroperoxide and 4‐hydroxynoneal, as oxidative stress markers, were also examined. Otsuka Long–Evans Tokushima fatty (OLEFT) rats were randomly divided into an exercise training group (Ex‐OLETF, n= 8) and a sedentary group (Sed‐OLETF, n= 8), while Long–Evans Tokushima Otsuka (LETO) rats were used as a control group (Con‐LETO, n= 5). The Ex‐OLETF rats were trained on a treadmill five times a week for 12 weeks. The levels of hydroperoxide and 4‐hydroxynoneal in both Ex‐OLETF and Sed‐OLETF were significantly higher compared with Con‐LETO, but there was no difference between Ex‐OLETF and Sed‐OLETF. Levels of inhibitor κB kinase, JNK activation and p65 nuclear translocation followed a similar pattern to that observed in oxidative stress markers. The level of Hsp72 in Ex‐OLETF was increased by exercise training, but it did not reach the level observed in Con‐LETO. The NF‐κB DNA binding activity in Sed‐OLETF was significantly higher compared with Con‐LETO. Although it was not statistically significant, exercise training in Ex‐OLETF showed a trend to reduce the activation of NF‐κB DNA binding activity compared with Sed‐OLETF (P= 0.104). Our findings indicate that exercise training improves basal glucose metabolism without a change in stress kinases, and that nuclear regulation of NF‐κB activity in diabetic muscle could be regulated independently of the cytosolic pathway. Our study also suggests a possibility that exercise‐induced Hsp72 serves as a protective mechanism in skeletal muscle of OLETF rats.

DNA microarray‐based analysis of voluntary resistance wheel running reveals novel transcriptome leading robust hippocampal plasticity

In two separate experiments, voluntary resistance wheel running with 30% of body weight (RWR), rather than wheel running (WR), led to greater enhancements, including adult hippocampal neurogenesis and cognitive functions, in conjunction with hippocampal brain‐derived neurotrophic factor (BDNF) signaling (Lee et al., J Appl Physiol, 2012; Neurosci Lett., 2013). Here we aimed to unravel novel molecular factors and gain insight into underlying molecular mechanisms for RWR‐enhanced hippocampal functions; a high‐throughput whole‐genome DNA microarray approach was applied to rats performing voluntary running for 4 weeks. RWR rats showed a significant decrease in average running distances although average work levels increased immensely, by about 11‐fold compared to WR, resulting in muscular adaptation for the fast‐twitch plantaris muscle. Global transcriptome profiling analysis identified 128 (sedentary × WR) and 169 (sedentary × RWR) up‐regulated (>1.5‐fold change), and 97 (sedentary × WR) and 468 (sedentary × RWR) down‐regulated (<0.75‐fold change) genes. Functional categorization using both pathway‐ or specific‐disease‐state‐focused gene classifications and Ingenuity Pathway Analysis (IPA) revealed expression pattern changes in the major categories of disease and disorders, molecular functions, and physiological system development and function. Genes specifically regulated with RWR include the newly identified factors of NFATc1, AVPR1A, and FGFR4, as well as previously known factors, BDNF and CREB mRNA. Interestingly, RWR down‐regulated multiple inflammatory cytokines (IL1B, IL2RA, and TNF) and chemokines (CXCL1, CXCL10, CCL2, and CCR4) with the SYCP3, PRL genes, which are potentially involved in regulating hippocampal neuroplastic changes. These results provide understanding of the voluntary‐RWR‐related hippocampal transcriptome, which will open a window to the underlying mechanisms of the positive effects of exercise, with therapeutic value for enhancing hippocampal functions.

The blood lactate increase in high intensity exercise is depressed by Acanthopanax sieboldianus.

This study investigates the anti-fatigue effects of Acanthopanax sieboldianus (A. sieboldianus) at various exercise intensities. Two experiments were conducted in 18 Sprague-Dawley rats. In Experiment 1, a three-stage increment test (15 m/min for 5 min, and 20 m/min for 5 min and 25 m/min for 10 min) was performed using a treadmill. In Experiment 2, a 10-min swimming test was conducted. Blood samples were extracted from each rat before, during and after the exercises and the blood concentrations of lactate and glucose measured. In both experiments, water (control) or A. sieboldianus solution (ASS) was administered orally using a zonde 30 min before the exercise. In the swimming test, ASS administration significantly decreased the blood lactate level measured at the end of the exercise and 5 min post-exercise relative to the water group, although the two groups did not differ significantly in the treadmill test. Our study demonstrates that a single oral administration of A. sieboldianus prior to high-intensity exercise significantly decreases the blood lactate concentration suggesting that A. sieboldianus has an intrinsic anti-fatigue effect.

Effects of Acute High-Intensity Resistance Exercise on Cognitive Function and Oxygenation in Prefrontal Cortex

[Purpose] Moderate-intensity exercise is known to be the best effective intensity to enhance cognitive function, including memory and learning. However, the effects of high-intensity exercise in comparison with moderate- intensity exercise on cognitive function remain controversial. The aim of this study was to investigate the effect of high-intensity resistance exercise on cognitive function. [Methods] Thirty-six healthy female college students volunteered to participate in this study. The participants were divided into four groups: (i) control group (CON); (ii) high-intensity resistance exercise group (HIR); (iii) high-intensity aerobic exercise group (HIA); and (iv) combined moderate-intensity exercise group (MIC). Immediately prior to and after exercise, the solved number (SN) and reaction times (RT) in the Stroop test (neutral task, NT and incongruent task, IT), as well as the tissue oxygen index (TOI) in the left and right prefrontal cortex (PFC) were measured in all groups. [Results] In the NT, both HIR and MIC groups showed significant improvements in SN and RT compared with the CON group. Meanwhile, performance in the HIA group was significantly attenuated compared with that in the MIC group. In the IT, only the MIC group showed a significant increase in SN and RT compared with the CON group. Furthermore, the TOI in the PFC (left PFC in the NT, and bilaterally in the IT) was significantly lower in the HIR group compared with that in the CON group. [Conclusion] The results of this study show worse cognitive performance and decreased PFC oxygenation in high-intensity exercise compared with moderate-intensity exercise and controls. These results suggest that high-intensity exercise may not improve cognition as effectively as moderate-intensity exercise.