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The effect of combined approach of exercise training and bone marrow stromal cell (BMSC) engraftment on activation of brain-derived neurotrophic factor (BDNF)-extracellular signal-regulated kinase 1 and 2 (ERK1/2)-cyclic adenosine monophosphate response element-binding protein (CREB) signaling pathway after sciatic nerve injury (SNI) was investigated. Sixty male Sprague-Dawley rats divided into the normal control, nonexercise (NEX), exercise training (EX), BMSC transplantation (TP), and exercise training+BMSC transplantation (EX+TP) groups 4 weeks after SCI. Exercise training was carried out on the treadmill device at 5–10 m/min for 20 min for 4 weeks. Single dose of 5× 106 harvested BMSC was injected into the injury area of the injured sciatic nerve. In order to evaluate induction levels of BDNF-ERK1/2-CREB signaling molecules in the whole cell and nuclear cell lysates of the injured sciatic nerve, we applied Western blot analysis. BDNF was significantly increased only in EX+TP compared to NEX, EX, and TP groups. Phosphoinositide-dependent kinase-1 was more increased in EX, TP, and EX+TP groups than NEX group, but EX+TP group showed the most upregulation of phosphorylated protein kinase B compared to other groups. In addition, in the whole cell lysate, phosphorylated ERK1/2, but not activating transcription factor-3 (ATF-3) and phosphorylated CREB, was significantly increased in TP and EX+TP groups. In the nuclear cell lysate, ATF-3 and phosphorylated CREB were strongly activated in EX+TP group compared to EX group. Regular exercise training combined with BMSC engraftment would seem to be more effective in controlling activation of regeneration-related signaling pathway after SNI.

The purpose of this study was to investigate whether combination of low-intensity exercise with bone marrow stromal cell (BMSC) transplantation could regulate protein kinas B (Akt)- mammalian target of rapamycin (mTOR) and Wnt3a-β-catenin signaling pathways for prevention of soleus muscle atrophy after sciatic nerve injury (SNI). The experimental rats divided into 5 groups (n= 10): normal control group, SNI+sedentary group (SED), SNI+low-intensity treadmill exercise group (TEX), SNI+BMSC transplantation group (BMSC), SNI+TEX+BMSC transplantation group (TEX+BMSC). Sciatic nerve crush injury was applied into the middle of thigh twice for 1 min and 30 sec at interval. Low-intensity treadmill exercise was comprised of walking at a speed of 4 to 8 m/min for 30 min once a day. cultured BMSC at a density of 5× 106 in 50-μL phosphate-buffered saline was injected into the distal portion of the injured sciatic nerves. TEX+BMSC group dramatically upregulated expression levels of growth-associated protein-43 in the injured sciatic nerve at 2 weeks postinjury. Also, although Akt and mTOR signaling pathway significantly increased in TEX and BMSC groups than SED group, TEX+BMSC group showed more potent increment on this signaling in soleus muscle after SNI. Lastly, Wnt3a and the nuclear translocation of β-catenin and nuclear factor-kappa B in soleus were increased by SNI, but TEX+BMSC group significantly downregulated activity of this signaling pathway in the nuclear cell lysate of soleus muscle. Present findings provide new information that combination of low-intensity treadmill exercise might be effective therapeutic approach on restriction of soleus muscle atrophy after peripheral nerve injury.

Memory state of rat pups born to old and obese mother rats and the effect of a treadmill running of mother rats on the memory of rat pups were studied. The radial 8-arm maze test was performed to detect spatial learning memory, and the level of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in the hippocampus was measured by enzymelinked immunoassay. Western blotting was performed for the expression of nuclear factor kappa-light-chain-enhancer (NF-κB), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), matrix metalloproteinase (MMP)-9, and immunohistochemistry for caspase-3 was conducted. The newborn rats were classified into following groups: pups born to old mother rats, pups born to old mother rats with exercise, pups born to old and obese mother rats, and pups born to old and obese mother rats with exercise. Exercise of mother ameliorated spatial learning memory impairment, inhibited proinflammatory cytokines production, NF-κB expression, and IκB-α phosphorylation of the pups born to old and obese mother rats. Maternal exercise suppressed Bax expression, the number of caspase-3, the level of MMP-9, and enhanced Bcl-2 expression of the pups born to old and obese mother rats. When the maternal exercise was performed, the impairment of spatial learning memory in pups was ameliorated. Therefore, it can be seen that exercise during pregnancy of older and obese mothers is an important factor in fetal health management.

Prenatal stress causes learning deficits by inhibiting neurogenesis in the hippocampus. We studied the effects of maternal treadmill running or offspring treadmill running on the spatial learning ability of adolescent offspring rats or adult offspring rats born to maternal rats that received stress during pregnancy. For this study, spatial learning ability was measured by radial 8-arm maze task. Immunohistochemistry for 5-bromo-2'-deoxyuridine and Western blot for brain-derived neurotrophic factor (BDNF), tyrosine kinase B (TrkB), Bcl-2-associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2) were also conducted. Stress was induced by exposing pregnant rats to hound in an enclosed room. Maternal treadmill running or treadmill running of offspring improved spatial learning ability of adolescent and adult offspring rats born to maternal rats receiving stress during pregnancy. Maternal treadmill running or treadmill running of offspring increased hippocampal cell proliferation of adolescent and adult offspring rats born to maternal rats receiving stress during pregnancy. Maternal treadmill running or treadmill running of offspring increased BDNF and TrkB expression in the hippocampus of adolescent and adult offspring rats born to maternal rats receiving stress during pregnancy. Maternal treadmill running or treadmill running of offspring inhibited Bax expression and increased Bcl-2 expression in the hippocampus of adolescent and adult offspring rats born to maternal rats receiving stress during pregnancy. Mother's exercise during pregnancy or child's exercise after childbirth can improve the spatial learning ability deteriorated due to stress during pregnancy.

Maternal nutrition is necessary for the growth of the fetus, and excessive intake of nutrients interferes with brain development in offspring. In the current study, the effect of treadmill running during pregnancy in obese maternal rats on spatial learning memory and spatial working memory in rat pups was investigated. Phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), and extracellular signal-regulated kinase 1 and 2 (ERK1/2) was also identified in rat pups. Female rats were divided into the normal diet group and the high-fat diet group for 7 weeks, including pregnancy and lactation. Maternal treadmill running was performed for 4 weeks. The born rat pups were classified into a control group, a treadmill exercise group, a high-fat diet group, a high-fat diet and treadmill exercise group according to the status of maternal rats. Radial 8-arm maze task for spatial learning memory and Morris water maze task for spatial working memory were done. Western blot analysis was conducted to determine the expressions of PI3K, Akt, ERK1/2. In the current results, maternal treadmill running during pregnancy improved spatial learning memory and spatial working memory in rat pups born to obese maternal rats. This improving effect of memory was due to the enhanced phosphorylation of PI3K, Akt, and ERK1/2 by treadmill running.

Maternal obesity is known to increase the likelihood of offspring becoming obese, high blood pressure, and other metabolic disorders. After inducing obesity, the effect of treadmill exercise in maternal rats during pregnancy on short-term memory was investigated in relation to neurogenesis in rat pups. Short-term memory was declined in rat pups born to obese maternal rats, and treadmill running during pregnancy alleviated short-term memory impairment in rat pups born to obese maternal rats. The number of doublecortin (DCX)-positive and 5-bro-mo-2'-deoxyuridine (BrdU)-positive cells in the hippocampal dentate gyrus was decreased in rat pups born to obese maternal rats. Treadmill running during pregnancy increased the number of DCX-positive and BrdU-positive cells in rat pups born to obese maternal rats. Expression of brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) in the hippocampus was decreased in the rat pups born to obese maternal rats. Treadmill running during pregnancy increased the expressions of BDNF and TrkB in rat pups born to obese maternal rats. Enhancing effect of short-term memory by treadmill exercise may be due to increased neurogenesis through activation of the BDNF-TrkB signaling pathway by treadmill exercise.

Maternal separation during early life causes psychiatric and neurologi-cal disorders such as anxiety and depression. Depression or anxiety is closely associated with memory impairment. The purpose of this study was to investigate the effect of treadmill exercise on activity, short-term memory, vascular dysfunction using maternal separation-induced de-pression model. Maternal separation started on 15-day-old rats. The rats in the maternal separation and fluoxetine injection group received intraperitoneal injection of 5 mg/kg of fluoxetine one time daily for 15 days from 21 to 35 days. The rats performed treadmill exercise once a day during 15 days from 21 to 35 days. There was low activity and short-term memory was decreased in the maternal separation rats. Treadmill exercise and fluoxetine injection increased activity and ameliorated memory impairment. The number of rat endothelial cells antigen-1 (RECA-1) of microvessels was decreased in the maternal separation rats. The number of RECA-1was increased by treadmill exercise and fluoxetine injection. Expression of matrix metalloproteinase-9 (MMP-9) was increased and expressions of zonula occludens-2 (ZO-2) and oc-cludin were decreased in the maternal separation rats. Treadmill exer-cise and fluoxetine injection suppressed MMP-9 expression and en-hanced ZO-2 and occludin expressions in the maternal separation rats. The present study shows treadmill exercise and antidepressant treat-ment ameliorates depressive symptom and short-term memory impair-ment by protecting from blood-brain barrier damage.

Neuronal cell death in the hippocampus by cerebral ischemia causes disability of memory function. Cerebral ischemia also alters the expressions of brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate-responsive element binding protein (CREB), extracellular signal-regulated protein kinase (ERK), and phosphatidylinositol 3-kinase/protein kinase B (Akt). In the present study, we investigated the effect of treadmill exercise on cerebral ischemia in relation with ERK-Akt-CREB-BDNF signaling pathway in the hippocampus using gerbils. Induction of cerebral ischemia deteriorated short-term memory with suppression of phosphorylation of ERK-Akt-CREB-BDNF pathway in the hippocampus of gerbils. Enhancement of apoptosis in the hippocampus was accompanied in the ischemia gerbils. Treadmill exercise improved short-term memory through enhancing phosphorylation of ERK-Akt-CREB-BDNF pathway with suppressing apoptosis in the hip-pocampus of the ischemia gerbils. The present results suggest that improvement of memory function after cerebral ischemia by treadmill exercise may be involved in the ERK-Akt-CREB-BDNF signaling pathway, resulting in inhibition of apoptosis in the hippocampus.

This study aimed to determine the effects of a single bout exercise on mitochondria-mediated apoptotic signaling in cardiac and skeletal muscles. Fischer 344 rats (4 months old) were randomly divided into the control or a single bout of exercise group (n=10 each). The rats performed a single bout of treadmill exercise for 60 min. Mitochondria-mediated apoptotic signaling (e.g., Bax, Bcl-2, mitochondrial permeability transition pore [mPTP] opening, cytochrome c, and cleaved caspase-3) was measured in cardiac (e.g., left ventricle) and skeletal (e.g., soleus and white gastrocnemius) muscles. A single bout of exercise significantly decreased mPTP opening sensitivity in all tissues. However, a single bout of exercise did not show any statistical differences in Bax, Bcl-2, cytochrome c, and cleaved caspase-3 in all tissues measured. A single bout of exercise did not show definite results on characteristics of mitochondria-mediated apoptotic signaling. Therefore, further research is necessary to provide a more mechanistic understanding of the apoptosis pathway.

Considering the potential action of exercise on neuroplasticity and the need to adapt protocols to enhance functional recovery after nerve injury, this study evaluated the effects of two intensities of treadmill exercise on nervous and muscular tissues and functional recovery after nerve crush injury. Wistar rats were distributed into sedentary group (SED), and 10 m/min (EG10) and 17 m/min (EG17) exercise groups. The exercise started one week after the injury. Ten daily sessions were performed with a 2-day interval after the fifth day. The flexor digitorum muscle and two segments of the median nerve were analysed histomorphometrically by light microscopy and computer analysis. Function was evaluated by grasping test, in 3 moments. Approval number: 016/2013. In the proximal segments of the median nerve, the diameter of myelinated fibres and axon, the myelin sheath thickness and the ratio of axon diameter to fibre diameter (g ratio) were significantly larger (P

The present study investigated whether treadmill exercise with bone marrow stromal cells (BMSCs) transplantation increase expression level of protein synthesis-related molecules in the soleus muscle after spinal cord injury (SCI). The spinal cord contusion injury was performed at the T9–10 level using the impactor (10 g×25 mm). BMSCs were cultured from femur and tibia of 4-week-old rats and then transplanted directly into the lesion 1-week post injury. The rats in exercise group were walking on treadmill device for 6 days per a week during 6 weeks. Prepared soleus muscles were used for examining mechanisms of protein synthesis after SCI. Myostatin induction level was increased by SCI, but BMSCs engrafting after SCI decreased compared to SCI group. Combination of treadmill exercise with BMSCs showed more potent decrement on myostatin expression. Protein kinase B (Akt) and mammalian target of rapamycin (mTOR) levels were significantly increased in SCI and BMSCs transplantation group compared to SCI group. Combination of treadmill exercise with BMSCs further facilitated expression levels of Akt and mTOR. Insulin-like growth factor-I (IGF-I) and phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) induction levels were more increased in SCI and BMSC transplantation group compared to SCI group. Combination of treadmill exercise with BMSCs further increased expression levels of IGF-I and p-CREB, although statistical significance was not appeared. Combining treadmill exercise with BMSCs transplantation might accelerate protein synthesis and hypertrophy in the soleus muscle after SCI through activation of IGF-I/mTOR signaling pathway.

Nicotine withdrawal symptoms comprise insomnia, depression, anxiety, attention disorders, and increased craving. We evaluated the ameliorating effect of treadmill exercise on nicotine withdrawal symptoms. The rats in the nicotine withdrawal groups received subcutaneous injection with 6-mg/kg nicotine hydrogen tartrate salt for 17 days. And then, the injection of nicotine hydrogen tartrate salt was stopped next for 2 weeks. The rats in the exercise groups performed treadmill running once a day, 5 days per week, for 31 days. In the present results, activity was decreased and anxiety-like behavior was observed in the nicotine withdrawal rats. Treadmill running increased activity and ameliorated anxiety-like behavior in the nicotine-withdrawal rats. Expressions of tryptophan hydroxylase (TPH) and 5-hydroxytryptamine (5-HT) in the dorsal raphe were decreased in the nicotine withdrawal rats, in contrast, treadmill running increased TPH and 5-HT expressions. Impaired short-term memory and deteriorated spatial learning ability were observed in the nicotine withdrawal rats, in contrast, treadmill running ameliorated impairment of short-term memory and spatial learning ability. Expressions of brain-derived neurotrophic factor and tyrosine kinase B (TrkB) were decreased in the nicotine withdrawal rats, in contrast, treadmill running increased brain-derived neurotrophic factor and TrkB expressions. The numbers of the doublecortin (DCX)-positive cells and 5-bromo-2'-deoxyuridine (BrdU)-positive cells in the dentate gyrus were suppressed in the nicotine withdrawal rats, in contrast, treadmill running enhanced the numbers of DCX-positive cells and BrdU-positive cells. The present study demonstrate that treadmill exercise ameliorated nicotine withdrawal-induced anxiety, depression, and memory impairment.

Obesity causes atrophy of the brain, leading to deterioration in working memory, learning, and cognitive function. The status of short-term memory in rat pups born to older obese mother rats was verified, and the effect of treadmill exercise on short-term memory in rat pups was investigated. Step-down avoidance test for short-term memory, termi-nal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining for apoptosis, and immunohistochemistry for Ki67 for new cell generation were done. The old female rats were fed with nor-mal diet (5% of fat), and the old and obese female rats were fed with high-fat diet (60% of fat) for up to 50 weeks in age (for 44 weeks in ex-perimental period). The newborn rats were divided into four groups ac-cording to the conditions of the mother rats as follows: the rat pups group born to old rats, the rat pups group born to old rats with exercise, the rat pups group born to old and obese rats, the rat pups group born to old and obese rats with exercise. Maternal exercise improved short-term memory, decreased TUNEL-positive cell number, and increased Ki67-positive cell number of the pups born to old and obese rats. Mater-nal exercise has been found to contribute to eliminating the health risks of fetuses born to old obese mothers.

The purpose of this study was to determine whether treadmill walking exercise can improve mechanical allodynia through regulation of Wnt/β-catenin signaling in dorsal root ganglion (DRG) neurons at the early stage of regeneration after sciatic nerve injury (SNI). The experimental rats were divided into seven groups: the normal control, sedentary groups for 3-, 7-, and 14-day post crush (dpc), and exercise group for 3, 7, and 14 dpc. The rats in exercise groups performed treadmill walking exercise at a speed of 8 m/min for 20 min once a day according to ex-periment duration. For evaluating neuropathic pain-like behavior after SNI, the mechanical allodynia was examined by von Frey apparatus. And the expression levels of pain-related protein were identified in the cytoplasm or nucleus of DRG neurons using Western blot techniques. Mechanical allodynia was significantly ameliorated in the exercise group at 7 and 14 dpc. Treadmill exercise further decreased Wnt3a ex-pression at 3, 7, and 14 dpc compared to in the sedentary group. Also, phosphorylated-low-density lipoprotein receptor 6 was decreased in exercise groups at 3 and 14 dpc. Beta-catenin was significantly de-creased in exercise groups at 3 and 14 dpc compared to sedentary groups as well as treadmill exercise decreased translocation of β-cat-enin towards the nucleus of DRG neurons at 14 dpc. Our findings indi-cate that treadmill walking exercise may be an important regulator of neuropathic pain after peripheral nerve injury through delayed Wnt/β-catenin signaling pathway in DRG neurons.

The effect of treadmill exercise on the social isolation-induced memory impairment in relation with the silent information regulator-1 (SIRT-1) was investigated. The rats in the control groups lived four in the stan-dard cages for 8 weeks. The rats in the social isolation groups lived alone in the small cages for 8 weeks. The rats in the treadmill exercise groups were subjected to run on a treadmill for 30 min once a day for 8 weeks. We used step-through avoidance test for short-term memory and Morris water maze task for spatial working memory. Immunohisto-chemistry for SIRT-1 and western blot analysis for Bax, Bcl-2, cleaved caspase-3, brain-derived neurotrophic factor (BDNF), and tropomyosin receptor kinase B (TrkB) were performed. The rats in the social isolation group showed a decrease in short-term memory and spatial working memory. Treadmill exercise alleviated short-term memory and spatial working memory in the social isolation rats. SIRT-1 expression in the hippocampus was decreased in the rats of social isolation group. Treadmill exercise increased SIRT-1 expression in the social isolation rats. Bax expression was increased, Bcl-2 expression was decreased, and cleaved caspase-3 expression in the hippocampus was increased in the rats of social isolation group. Treadmill exercise decreased Bax expression, increased Bcl-2 expression, and decreased cleaved caspase-3 expression in the social isolation rats. Hippocampal BDNF and TrkB expression was decreased in the rats of social isolation group. Treadmill exercise increased BDNF and TrkB expression in the social isolation rats.

The purpose of this study was to investigate the effect of treadmill exer-cise on activating transcription factors such as activating transcription factor 3 (ATF3) and extracellular signal-regulated kinase (ERK1/2) sig-naling pathway to facilitate axonal regrowth after sciatic nerve injury (SNI). The experimental rats divided into the normal control (n=10), sedentary groups for 7 (n=10) and 14 days (n=10) post crush, exercise group for 7 (n=10) and 14 days (n=10) post crush (dpc). The rats in ex-ercise groups run on treadmill device at a speed of 8 m/min for 20 min once a day according to exercise duration. In order to evaluate specific regeneration markers and axonal elongation in injured sciatic nerve, we applied immunofluorescence staining and western blot techniques. Treadmill exercise further increased growth-associated protein (GAP-43) expression and axonal regrowth at 7 and 14 dpc than those in sed-entary group. Among mitogen-activated protein kinase downstream molecules, phospho-ERK1/2 (p-ERK1/2) was enhanced by treadmill ex-ercise at only 7 dpc and decreased to basal level 14 days later. But c-Jun N-terminal kinase, c-Jun, and phospho-cyclic adenosine mono-phosphate response element-binding protein showed a tendency to in-crease continuously until 14 dpc by exercise. ATF3 expression in exer-cise group was upregulated at both 7 and 14 dpc compared to the sed-entary group. These results indicate that treadmill exercise had benefi-cial effect on expression of regeneration-related proteins after SNI, suggesting that exercise might be one of various therapeutic strategies for sciatic nerve regeneration.

Brain inflammation is involved in many brain disorders, such as brain ischemic injury, Alzheimer diseases, and Parkinson disease. Physical exercise has been recommended for the prevention and treatment of many brain inflammatory diseases. In the present study, the effects of exercise on motor function in relation with apoptotic neuronal cell death following neuroinflammation were investigated. Moreover, we compared the effect of forced exercise with voluntary exercise on neuroinflammation-induced motor malfunction. For this study, rota-rod test, vertical pole test, foot fault test, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, immunohistochemistry for caspase-3, and western blot for Bcl-2 and Bax were performed. Lipopolysaccharide was intraventricular infused for induction of brain inflammation. Treadmill exercise and wheel exercise were conducted during 6 weeks. In the present results, Treadmill exercise and wheel exercise alleviated brain inflammation-induced motor impairments by suppressing apoptotic neuronal cell death in the motor cortex. These effects of treadmill exercise and wheel exercise were similarly appeared.

Stress is the physiological responses of organisms to harmful or threatening stimuli that allow appropriate behavioral responses to the stressor. In the present study, the effect of treadmill exercise on stress-induced anxiety was evaluated using rats. To induce stress, the rats were exposed to an inescapable electric foot shock. Exposure of rats to the electric foot shock was performed for 7 days. The rats in the exercise groups were made to run on a motorized treadmill for 30 min once a day for 4 weeks stating one day after last electric food shock. Anxiety-like behaviors were determined by open field test and elevated plus-maze test. The expressions of c-Fos and neuronal nitric oxide synthase (nNOS) in the hypothalamus and locus coeruleus were detected by immunohistochemistry. In the present results, locomotor activity in the center of the open field test and the number of entries and time in the open arms of the elevated plus-maze test were reduced in the rats with stress-induced anxiety. Treadmill running enhanced these locomotor activities, the number of entries and time in the stress-induced anxiety rats. c-Fos and nNOS expressions in the hypothalamus and locus coeruleus were increased in the stress-induced rats. Treadmill exercise reduced c-Fos and nNOS overexpressions in the stress-induced rats. In the present study, treadmill exercise ameliorated anxiety-like behaviors in the stress-induced rats. The improving effect of treadmill exercise on anxiety-like behaviors might be ascribed to the suppressing effect of exercise on c-Fos and nNOS expressions.

Epilepsy is characterized by recurrent seizures and loss of neurons with abnormal rhythmic firing in the brains. In the present study, we investigated the effect of treadmill exercise on memory function in relation with cell proliferation and apoptosis in the hippocampus using pilocarpine-induced seizure rats. Epilepsy was initiated by intraperitoneal injection of pilocarpine hydrochloride. The rats in the exercise group were forced to run on a motorized treadmill for 30 min once a day for 2 weeks. In the present results, treadmill exercise alleviated short-term and spatial learning memory impairments in the epileptic rats. Treadmill exercise suppressed neuronal degeneration and enhanced neuronal maturation in the epileptic rats. Treadmill exercise suppressed cell proliferation and apoptosis in the epileptic rats. Treadmill exercise alleviated pilocarpine-induced memory impairments and suppressed neuronal loss in the hippocampus through down-regulation of apoptosis. These findings offer a possibility that treadmill exercise may provide a preventive or therapeutic value to the epilepsy-induced learning and memory impairments.

Transplantation of bone marrow stromal cells (BMSCs) has been known as one of the effective therapeutic methods for functional recovery of spinal cord injury (SCI). Treadmill exercise also facilitates the functional recovery of SCI. Previously, we reported that combination of BMSCs transplantation with treadmill exercise potentiated the locomotor function in SCI rats. In the present study, we investigated whether recovery effect of BMSCs transplantation or treadmill exercise appears through the brain-derived neurotrophic factor (BDNF)-extracellular signal–regulated kinases 1/2 (ERK1/2) pathway. The spinal cord contusion injury was performed at the T9–T10 level using the impactor. Cultured BMSCs were transplanted directly into the lesion 1 week after SCI. Treadmill exercise was performed 6 days per a week for 6 weeks. Western blot for Bax, Bcl-2, BDNF, tyrosine kinase B (TrkB), and phosphorylated ERK1/2 (p-ERK1/2), phosphorylated JNK was performed. In the present results, combination of BMSCs transplantation with tread-mill exercise potently decreased Bax expression, potently increased Bcl-2 expression, and potently enhanced BDNF and TrkB expressions in the injured spinal cord. Combination of BMSCs transplantation with treadmill exercise further facilitated p-ERK1/2 and p-c-Jun expression levels. The present findings demonstrated the synergistic effect of treadmill exercise on neuroregenerative effect of BMSCs transplantation appeared through the activation of BDNF-ERK1/2 pathway in SCI.

Traumatic brain injury (TBI) causes deficit in spatial learning and memory function. Physical activity ameliorates neurological dysfunction after TBI. We investigated the effect of late starting treadmill exercise on spatial learning ability in relation with cAMP-response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathway using TBI rats. For this study, radial 8-arm maze test, TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) staining, caspase-3 immunohistochemistry, and western blot for Bax, Bcl-2, BDNF, tyrosine kinase B (TrkB), CREB, and phosphorylated CREP (p-CREB) were performed. TBI was induced by an electromagnetic-controlled cortical impact. The rats in the exercise groups were scheduled to run on a treadmill for 30 min once a day for 8 weeks starting 3 weeks after TBI. TBI impaired spatial learning ability and increased caspase-3 expression in the hippocampal dentate gyrus. TBI enhanced Bax expression and suppressed Bcl-2 expression in the hip-pocampus. TBI increased BDNF and TrkB expressions, resulted in the enhancement of p-CREB/CREB ratio in the hippocampus. However, treadmill exercise improved spatial learning ability, decreased caspase-3 expression, suppressed Bax expression, and increased Bcl-2 expression. Treadmill exercise alleviated TBI-induced over-expression of BDNF and TrkB, which suppressed phosphorylation of CREB in the hippocampus. In the present study, late starting treadmill exercise improved spatial learning ability through suppressing TBI-induced activation of CREB/BDNF/TrkB signaling pathway after TBI.

Diabetes mellitus is associated with the impairment of sexual function including desire and orgasmic dysfunction. Sexual dysfunction in the diabetes mellitus is due to a selective defect of the nitric oxide synthase (NOS) within paraventricular nucleus (PVN). c-Fos is an immediate ear-ly gene and c-Fos expression represents neuronal activity in response to various stimuli. In the present study, we investigated the effects of treadmill exercise on sexual behaviors and the expressions of NOS and c-Fos in the PVN were evaluated using streptozotocin (STZ)-induced diabetic rats. Diabetes mellitus was induced by intraperitoneal injection of STZ. The rats in the treadmill exercise groups were made to run on a treadmill for 30 min once a day during 4 weeks. Male sexual behaviors were evaluated by recording the number of mounting, intromission, and ejaculation frequency. The present results revealed that treadmill exer-cise ameliorated sexual dysfunction in the STZ-induced diabetic rats. Treadmill exercise restored the contents of NOS and c-Fos in the PVN. The improving effect of treadmill exercise on sexual function can be considered as the neuronal activating effect of exercise through in-creasing expressions of NO and c-Fos.

Social isolation is known to induce emotional and behavioral changes in animals and humans. The effect of treadmill exercise on depression was investigated using social isolated rat pups. The rat pups in the social isolation groups were housed individually. The rat pups in the exercise groups were forced to run on treadmill for 30 min once a day from postnatal day 21 to postnatal day 34. In order to evaluate depression state of rat pups, forced swimming test was performed. Newly generated cells in the hippocampal dentate gyrus were determined by 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry. We examined the expression of 5-hydroxytryptamine (5-HT) and tryptophan hydroxylase (TPH) in the dorsal raphe using immunofluorescence. The expression of brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) was detected by Western blot analysis. The present results demonstrated that social isolation increased resting time and decreased mobility time. Expression of 5-HT and TPH in the dorsal raphe and expression of BDNF and TrkB in the hippocampus were decreased by social isolation. The number of BrdU-positive cells in the hippocampal dentate gyrus was suppressed by social isolation. Treadmill exercise decreased resting time and increased mobility in the social isolated rat pups. Expression of 5-HT, TPH, BDNF, and TrkB was increased by treadmill exercise. The present results suggested that treadmill exercise may ameliorates social isolation-induced depression through increasing neuronal generation.

The effect of exercise, which increases hippocampal neurogenesis and improves memory function, is well documented, however, differences in the effect of exercise on young children and adults are not yet known. In the present study, age-dependent differences of treadmill exercise on spatial learning ability between young- and adult-age rats were investigated. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 6 weeks. Radial 8-arm maze test was conducted for the determination of spatial learning ability. Cell proliferation in the hippocampal dentate gyrus was determined by 5-bromo-2′-deoxyuridine immunohistochemistry. Western blot for brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) was performed. In the present study, the number of errors in the young-age rats was effectively decreased by treadmill exercise. Hippocampal neurogenesis was more active in the young-age rats than in the adult-age rats. BDNF and TrkB expression in the hippocampus was greater in the adult-age rats than in the young-age rats. The results of this study showed that adults have excellent spatial learning abilities than children, but the improvement of exercise-induced spatial learning ability through neurogenesis is better in children.

Transplantation of bone marrow stromal cells (BMSCs) is regarded as a promising candidate for the spinal cord injury (SCI). In the present study, we investigated whether treadmill exercise potentiate the effect of BM-SCs transplantation on the functional recovery in the SCI rats. The spi-nal cord contusion injury applied at the T9–T10 level using the impactor. Cultured BMSCs were transplanted into the lesion at 1 week after SCI induction. Treadmill exercise was conducted for 6 weeks. Basso-Beat-tie-Bresnahan (BBB) scale for locomotor function was determined. Sprouting axons in the lesion cavity were detected by immunofluores-cence staining for neurofilament-200. Brain-derived neurotrophic factor (BDNF) and synapsin-I expressions were analyzed using western blot-ting. BMSCs transplantation improved BBB score and increased ex-pressions of neurofilament-200, BDNF, and synapsin-I in the SCI rats. Treadmill exercise potentiated the improving effect of BMSCs trans-plantation on BBB score in the SCI rats. This potentiating effect of treadmill exercise could be ascribed to the enhancement of BDNF ex-pression in the SCI rats.

Parkinson disease (PD) is characterized by selective loss of the dopaminergic neurons. The symptoms of depression following PD are closely associated with reduced activity of the serotonergic system in the dorsal raphe. We explored the antidepressive effect of exercise and its possible mechanism using the rotenone-induced PD rats. PD rats were induced by subcutaneously injection with rotenone for 14 days. The rats in the exercise groups were made to run on a treadmill for 30 min once a day during 14 consecutive days. Forced swimming test, immunohistochemistry for serotonin (5-hydroxytryptamine, 5-HT), tryptophan hydroxylase (TPH), and western blot for serotonin 1A (5-HT1A) receptor were conducted. Injection of rotenone induced PD rats. PD rats showed depressive state and treadmill exercise ameliorated this depressive state. 5-HT, TPH, and 5-HT1A receptor expressions in the dorsal raphe were suppressed by rotenone injection and treadmill exercise increased the expressions of 5-HT, TPH, and 5-HT1A receptor in the rotenone-injected rats. The present results show that treadmill exercise ameliorated depressive symptoms in the rotenone-induced PD rats. The antidepressive effect of treadmill exercise might be ascribed to the enhancement of serotonergic function through upregulation of 5-HT1A expression in the dorsal raphe.

Intracerebral hemorrhage (ICH) is a severe type of stroke causing neurological dysfunction with high mortality rate. Depression is one of the most common complications of ICH. In the present study, the effects of treadmill exercise on ICH-induced depressive symptoms in relation with apoptosis were investigated using rats. ICH rat model was induced by injection of collagenase into the hippocampus using stereotaxic instrument. Open field test for activity and forced swimming test for depressive symptoms were conducted. Apoptosis in the hippocampus was detected using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, immunohistochemistry for caspase-3, and western blot for Bcl-2 and Bax. Western blot analysis for 5-hydroxy-tryptamine (5-HT, serotonin) and tryptophan hydroxylase (TPH) in the dorsal raphe was also conducted for biomarkers of depression. In the present results, immobility time was increased and climbing time was decreased by induction of ICH and treadmill exercise inhibited immobility time and increased climbing time in ICH rats. DNA fragmentation and caspase-3 expression in the hippocampal dentate gyrus were enhanced by induction of ICH and treadmill exercise suppressed ICH-induced DNA fragmentation and caspase-3 expression. Bax expression in the hippocampus was increased by induction of ICH and treadmill exercise inhibited Bax expression in the ICH rats. Expressions of 5-HT and TPH in the dorsal raphe were decreased by induction of ICH and treadmill exercise increased expressions of 5-HT and TPH in the ICH rats. In the present study, treadmill exercise ameliorated depressive symptoms through inhibiting apoptosis.

Spinal cord injury (SCI) disrupts both axonal pathways and segmental spinal cord circuity, resulting in permanent neurological deficits. Physical exercise is known to increase the expression of neurotrophins for improving the injured spinal cord. In the present study, we investigated the effects of treadmill exercise on locomotor function in relation with brain-derived neurotrophic factor (BDNF) expression after SCI. The rats were divided into five groups: control group, sham operation group, sham operation and exercise group, SCI group, and SCI and exercise group. The laminectomy was performed at the T9–T10 level. The exposed dorsal surface of the spinal cord received contusion injury (10 g × 25 mm) using the impactor. Treadmill exercise was performed 6 days per a week for 6 weeks. In order to evaluate the locomotor function of animals, Basso-Beattie-Bresnahan (BBB) locomotor scale was conducted once a week for 6 weeks. We examined BDNF expression and axonal sprouting in the injury site of the spinal cord using Western blot analysis and immunofluorescence staining. SCI induced loss of locomotor function with decreased BDNF expression in the injury site. Treadmill exercise increased the score of BBB locomotor scale and reduced cavity formation in the injury site. BDNF expression and axonal sprouting within the trabecula were further facilitated by treadmill exercise in SCI-exposed rats. The present study provides the evidence that treadmill exercise may facilitate recovery of locomotor function through axonal regeneration via BDNF expression following SCI.

Autism is a complex developmental disorder with impairments in social interaction, communication, repetitive behavior and motor skills. Exercise enhances cognitive function, ameliorates motor dysfunction, and provides protective profits against neurodegeneration. In the present study, we evaluated the effect of treadmill exercise on the motor coordination and Purkinje cell loss in relation with reactive astrocytes and microglial activation in the cerebellum using valproic acid (VPA)-induced autism rat model. On the 12th day of pregnancy, the pregnant rats in the VPA-exposed group received intraperitoneal injections of 600-mg/kg VPA. After birth, the rat pups were divided into four groups: the control group, the exercise group, the VPA-treated group, the VPA-treated and exercise group. The rat pups in the exercise groups were forced to run on a treadmill for 30 min once a day, 5 times a week for 4 weeks. In the present results, motor balance and coordination was disturbed by induction of autism, in contrast, treadmill exercise alleviated motor dysfunction in the autistic rats. Purkinje cell loss, reactive astrocytes, and microglial activation were occurred by induction of autism, in contrast, treadmill exercise enhanced survival rate of Purkinje neurons through inhibition of reactive astrocytes and microglia in the autistic rats. The present study showed that exercise may provide a potential therapeutic strategy for the alleviation of motor dysfunction in autistic patients.

Physical exercise is one of the most effective methods for managing obesity, and exercise exerts positive effects on various brain functions. Excessive weight gain is known to be related to the impairment of cognitive function. High-fat diet-induced obesity impairs hippocampal neuroplasticity, which impedes cognitive function, such as learning ability and memory function. In this study, we investigated the effect of treadmill exercise on impairment of cognitive function in relation with hippocampal neuroplasticity using high-fat diet-induced obese mice. After obesity was induced by a 20-week high-fat (60%) diet, treadmill exercise was performed for 12 weeks. In the present results, cognitive function was impaired in the high-fat diet-induced obese mice. Brain-derived neurotrophic factor (BDNF) and tyrosin kinase B (TrkB) expression and cell proliferation were decreased in the high-fat diet-induced obese mice. Treadmill exercise improved cognitive function through enhancing neuroplasticity, including increased expression of BDNF and TrkB and enhanced cell proliferation. The present results suggest that treadmill exercise enhances hippocampal neuroplasticity, and then potentially plays a protective role against obesity-induced cognitive impairment.

Maternal infection is an important factor causing neonatal brain injury and later developmental disability. In the present study, we investigated the effects of treadmill exercise intensity on short-term memory, hippocampal neurogenesis, and expression of brain-derived neurotrophic factor (BDNF), and tyrosine kinase receptor B (TrkB) in the rats born of lipopolysaccharide (LPS)-exposed maternal rats. The rats were divided into six groups: control group, mild-intensity exercise group, moderate-intensity exercise group, maternal LPS-exposed group, maternal LPS-exposed and mild-intensity exercise group, maternal LPS-exposed and moderate-intensity exercise group. The rats in the exercise groups were forced to run on a treadmill for 30 min 5 times a week for 4 weeks. The exercise load consisted of running at the speed of 8 m/min for the mild-intensity exercise groups and 14 m/min for moderate-intensity exercise groups. The latency in the step-down avoidance task was deter-mined for the short-term memory. Immunohistochemistry for 5-bro-mo-2'-deoxyuridine was performed to determine hippocampal cell proliferation and neurogenesis. Western blot analysis was performed for the detection of BDNF and TrkB expression. In the present study, tread-mill exercise improved short-term memory deteriorated by maternal LPS exposure. Treadmill exercise increased cell proliferation and neurogenesis in the hippocampal dentate gyrus of the rats born of the LPS-exposed maternal rats. Treadmill exercise increased BDNF and TrkB expression in the hippocampus of the rats born of the LPS-exposed maternal rats. These effects of treadmill exercise were similarly appeared at both mild-intensity and moderate-intensity.

Brain-derived neurotrophic factor (BDNF) and its receptors tyrosine kinase B (trkB), and cyclic adenosine monophosphate response element binding protein (CREB) have been suggested as the neurobiological risk factors causing depressive disorder. Serotonin (5-hydroxytryptamine, 5-HT) plays an important role in the pathogenesis of depression. We in-vestigated the effect of treadmill exercise on social interaction in relation with BDNF and 5-HT expressions following stress in rats. Stress was induced by applying inescapable 0.2 mA electric foot shock to the rats for 7 days. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 4 weeks. Social interaction test and western blot for BDNF, TrkB, pCREB, and 5-HT1A in the hippocampus were performed. The results indicate that the spend time with unfamiliar partner was decreased by stress, in contrast, treadmill exercise increased the spending time in the stress-induced rats. Expressions of BDNF, TrkB, and pCREB were decreased by stress, in contrast, treadmill exercise enhanced expressions of BDNF, TrkB, and pCREB in the stress-induced rats. In addition, 5-HT1A receptor expression was de-creased by stress, in contrast, treadmill exercise enhanced 5-HT1A expression in the stress-induced rats. In the present study, treadmill exercise alleviated stress-induced social interaction impairment through enhancing hippocampal plasticity and serotonergic function in the hippocampus. These effects of treadmill exercise are achieved through 5-HT1A receptor activation.

Huntington's disease is a chronic neurodegenerative disorder inherited in an autosomal dominant fashion, and characterized as involuntary movement. Quinolinic acid has been used to produce an animal model of Huntington's disease. In the present study, the effect of treadmill exercise on spatial-learning ability and motor coordination focusing on the apoptosis in the hippocampus was investigated using quinolinic acid-induced Huntington's disease rats. Huntington's disease was induced by unilateral intrastriatal injection of quinolinic acid (2 μL of 100 nmol) using stereotaxic instrument. The rats in the treadmill exercise groups were subjected to run on a treadmill for 30 min once a day during 14 days. Spatial learning ability and motor coordination were determined by radial 8-arm maze test and rota-rod test. Immunohistochemistry for caspase-3 and western blot for Bax and Bcl-2 were also conducted for the detection of apoptosis. In the present results, spatial learning ability and motor coordination were deteriorated by intrastriatal injection of quinolinic acid. In contrast, treadmill exercise exerted ameliorating effect on quinolinic acid-induced deterioration of spatial learning ability and motor coordination. Bcl-2 expression in the hippocampus was de-creased and expressions of casepase-3 and Bax in the hippocampus were increased in the quinolinic acid-induced Huntington's disease rats. Treadmill exercise increased Bcl-2 expression and decreased expressions of casepase-3 and Bax in the Huntington's disease rats. The present results showed that treadmill exercise might ameliorate quinolinic acid-induced loss of spatial learning ability and motor coordination by suppressing apoptosis in the hippocampus.

Epilepsy is a common neurological disorder characterized by seizure and loss of neuronal cells by abnormal rhythmic firing of neurons in the brain. In the present study, we investigated the effect of treadmill exercise on gamma-aminobutyric acid (GABA)ergic neuronal loss in relation with neuronal activation using pilocarpine-induced epileptic rats. The rats were divided into four groups: control group, control and treadmill exercise group, pilocarpine-induced epilepsy group, and pilocarpine-induced epilepsy and treadmill exercise group. Epilepsy was induced by intraperitoneal injection of 320 mg/kg pilocarpine hydrochloride. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 2 weeks. In the present results, neuronal loss in the hippocampal CA1 region was increased after pilocarpine-induced seizure. Treadmill exercise inhibited hippocampal neuronal loss in the epileptic rats. Glutamic acid decarboxylase (GAD67) expression in the hippocampal CA1 region was reduced by pilocarpine-induced seizure. Treadmill exercise increased GAD67 expression in the epileptic rats. c-Fos expression in the hippocampal CA1 region was increased in response to epileptic seizure. Treadmill exercise inhibited c-Fos expression in the epileptic rats. Epileptic seizure increased brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB) expressions in the hippocampus. Treadmill exercise suppressed BDNF and TrkB expressions in the epileptic rats. In the present study, treadmill exercise prevented GABAergic neuronal loss and inhibited neuronal activation in the hippocampal CA1 region through the down-regulation of BDNF-TrkB signaling pathway.

Diabetes is a metabolic disorder, and it is considered as a major risk factor for Alzheimer’s disease (AD). In the present study, we evaluated whether treadmill exercise ameliorates progression of AD in relation with glycogen synthase kinase-3β (GSK-3β) activity using streptozotocin (STZ)-induced diabetic rats. For this study, step-down avoidance task, immunohistochemistry for glycogen synthase kinase-3β (GSK-3β) and tau, and western blot for phosphor-phosphoinositide 3 kinase (p-PI3K)/PI3K and phosphor-Akt (p-Akt)/Akt were performed. Diabetes mellitus was induced by intraperitoneal injection of STZ. The rats in the exercise groups were made to run on the treadmill for 30 min per one day, five times a week, during 12 weeks. The present results showed that short-term and long-term latencies in the step-down avoidance task were decreased by induction of diabetes, and treadmill exercise inhibited these latencies in the diabetic rats. Induction of diabetes suppressed the ratio of p-PI3K to PI3K and the ratio of p-Akt to Akt, and treadmill exercise increased these ratios in the diabetic rats. The numbers of GSK-3β-positive and tau-positive cells in the hippocampal dentate gyrus was higher in the diabetes-induction group than that in the control group, and treadmill exercise inhibited these numbers in the diabetic rats. In the present study, treadmill exercise suppressed hyperphosphorylation of tau in the hippocampus by decreased GSK-3β activity through PI3K/Akt pathway activation in the diabetic rats. Based on the present results, treadmill exercise may helpful to prevent diabetes-associated AD occurrence.

Huntington's disease (HD) is an inherited genetic disorder, characterized by cognitive dysfunction and abnormal body movements called chorea. Quinolinic acid (QA) is an endogenous metabolite of tryptophan in the kynurenine pathway. QA-induced alterations are similar to the symptoms of HD patients. Physical exercise has beneficial effects on the brain functions. Exercise increases production of neurotrophic factors in the brain and improves learning ability and memory function. In the present study, we investigated the effects of treadmill exercise short-term memory on QA-induced HD rats in relation with cell proliferation. For the induction of Huntington's animal model, 2 μL of 100 nmol QA was intrastriatal injected into the rats. The rats in the treadmill exercise groups were forced to run on a treadmill for 30 min once a day, five times a week for 2 weeks. Step-down avoidance test was conducted for the determination of short-term memory. Cell proliferation in the hippocampal dentate gyrus was determined by 5-bromo-2'-deoxyuridine (BrdU) and doublecortin (DCX) immunohistochemistry. Western blot for brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) were performed. In the present results, treadmill exercise alleviated QA-induced short-term memory impairment in HD rats. Treadmill exercise increased cell proliferation in the hippocampal dentate gyrus through enhancing BDNF expression in the HD rats. These results revealed that treadmill exercise is effective for the symptom improvement in the HD patients.

Maternal stress during pregnancy affects negative impact on health of offspring. In the present study, we compared the effects of maternal treadmill exercise and offspring treadmill exercise on prenatal stress-induced apoptosis and serotonin expression in offspring. Stress to the pregnant rats was induced by exposure of maternal rats to the hunting dog in an enclosed room. Exposure time was 10 min, three times per day, with a 1-h interval between exposures. This regimen was maintained from the seventh day of gestation until delivery. The pregnant rats in the exercise group were forced to run on a motorized tread-mill for 30 min once a day, started 7 days after pregnancy until delivery. The offspring in the exercise group were forced to run on a motorized treadmill for 30 min once a day, started 4 weeks after birth for 4 weeks. In the present results, offspring exposed to prenatal stress exhibited lower Bcl-2 level and higher Bax level in the hippocampus, lower 5-hydroxytryptamine (5-HT) and tryptophan hydroxylase (TPH) expression in the dorsal raphe, and higher c-Fos expression in the locus coeruleus compared to age-matched control rats. Treadmill exercise of offspring suppressed Bax expression and enhanced Bcl-2 expression in the hippocampus, increased 5-HT and TPH expression in the dorsal raphe, and enhanced c-Fos expression in the locus coeruleus of offspring. Tread-mill exercise of offspring suppressed prenatal stress-induced apoptosis and normalized prenatal stress-induced alterations in serotonin synthesis and neuronal activation. However maternal treadmill exercise during pregnancy exerted no significant effect on offspring.

Cerebral palsy (CP) is a chronic disorder characterized by physical disability and disruption of brain function. We evaluated the effects of treadmill exercise on motor and memory functions in relation with phosphatidylinositol 3-kinase (PI3K)-Akt pathway using CP rat model. Rota-rod test, step-down avoidance task, 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry, and western blot for synapsin I, postsynaptic density-95 (PSD-95), PI3K, Akt, and glycogen synthase kinase-3β (GSK-3β) were performed. CP was induced by maternal lipopolysaccharide (LPS)-injection with sensorimotor restriction. Five weeks after birth, the rats in the exercise groups were made to run on the treadmill for 30 min per one day, 5 times a week, during 4 weeks. Motor and memory functions were impaired in the LPS-induced CP rats and tread-mill exercise increased motor and memory functions in the CP rats. Cell proliferation in the hippocampus was suppressed in the LPS-induced CP rats and treadmill exercise increased hippocampal cell proliferation in the CP rats. Expressions of synapsin I, PSD-95, phosphorylated (p)-PI3K, and p-Akt were decreased in the LPS-induced CP rats and treadmill exercise enhanced the expressions of synapsin I, PSD-95, p-PI3K, and p-Akt in the CP rats. GSK-3β expression was increased in the LPS-induced CP rats and treadmill exercise suppressed GSK-3β expression in the CP rats. The present results suggest that treadmill exercise might improve motor and memory functions through activation of PI3K-Akt pathway.

Postpartum depression (PPD) is defined as the depressive symptoms that occur from the moment of delivery until 12 months after delivery. PPD symptoms are closely associated with reduced activity of the serotonergic system. Serotonin (5-hydroxytryptamine, 5-HT) plays an important role in the pathogenesis of depression. Tryptophan hydroxylase (TPH) catalyzes the rate-limiting step of 5-HT biosynthesis in the serotonergic neurons. Exercise exerts anti-depressive effect on depression patients as well as on animal models of depression. In the present study, the effect of treadmill exercise on PPD was investigated using rats. For this study, open field test for activity and forced swimming test for depressive symptoms, and immunohistochemistry for 5-HT and TPH were conducted. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 2 weeks. Activity in the open field test was decreased in the postpartum rats, however, performing treadmill running increased activity in the postpartum rats. The climbing time was decreased and the immobility time was increased in the postpartum rats. Treadmill exercise increased climbing time and suppressed immobility time in the postpartum rats. 5-HT and TPH expressions in the dorsal raphe were suppressed in the postpartum rats, and treadmill exercise enhanced 5-HT and TPH expressions in the postpartum rats. Treadmill exercise ameliorated the PPD very effectively by enhancing serotonin level.

The olfactory bulbectomy (OBX) is a well-known method inducing animal model of depression. Depression is associated with dysfunction of serotonin (5-hydroxytryptamine, 5-HT) system. In the present study, antidepressive effect of treadmill exercise was investigated using olfactory bulbectomized rats. After bilateral bulbectomy, the rats in the treadmill exercise groups were subjected to run on a treadmill for 30 min once a day during 28 days. Increased immobility time and decreased fast time in the forced swim test were observed in the olfactory bulbectomized rats. Sucrose preference in the sucrose preference test was decreased and activity in the open field test was also increased in the olfactory bulbectomized rats. Treadmill exercise decreased immobility time and activity and increased fast time and sucrose preference in the olfactory bulbectomized rats. Expressions of 5-HT and tryptophan hydroxylase (TPH) in the dorsal raphe of rats were suppressed by OBX and treadmill exercise increased the expressions of 5-HT and TPH in the olfactory bulbectomized rats. Serotonin receptor type 1A (5-HT1A) expression in the dorsal raphe was reduced by OBX and treadmill exercise increased 5-HT1A expression in the olfactory bulbectomized rats. In the present study, treadmill exercise ameliorated OBX-induced depressive symptoms. The antidepressive effect of treadmill exercise might be ascribed to the enhancement of serotonergic function through upregulation of 5-HT1A expression in the dorsal raphe.

Parkinson disease is one of the common brain diseases caused by dopaminergic neuronal loss in the substantia nigra and dopaminergic fiber loss in the striatum. In the present study, the effects of treadmill exercise on motor performance, dopaminergic loss of neurons and fibers, and α-synuclein expression in the nigrostriatum were evaluated using rotenone-induced Parkinson rats. For the induction of Parkinson rats, 3-mg/kg rotenone was injected, once a day for 14 consecutive days. Treadmill running was conducted for 30 min once a day during 14 consecutive days. Rota-rod test for motor balance and coordination and immunohistochemistry for tyrosine hydroxylase and α-synuclein in the nigrostriatum were performed. In the present study, motor balance and coordination was disturbed by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise alleviated motor dysfunction in the rotenone-induced Parkinson rats. Nigrostriatal dopaminergic loss of neurons and fibers was occurred by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise alleviated nigrostriatal dopaminergic loss of neurons and fibers in the rotenone-induced Parkinson rats. α-Synuclein expression in the nigrostriatum was enhanced by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise suppressed α-synuclein expression in the rotenone-induced Parkinson rats. Treadmill exercise improved motor function through preservation of nigrostriatal dopaminergic neurons and fibers and suppression of nigrostriatal formation of Lewy bodies in rotenone-induced Parkinson rats.

Alzheimer's disease (AD) is a most common age-related neurodegenerative disease. AD is characterized by a progressive loss of neurons causing cognitive dysfunction. The cerebellum is closely associated with integration of movement, including motor coordination, control, and equilibrium. In the present study, we evaluated the effect of tread-mill exercise on the survival of Purkinje neurons in relation with reactive astrocyte in the cerebellum using Aβ25-35-induced AD rats. AD was induced by a bilateral intracerebroventricular (ICV) injection of Aβ25-35. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 4 weeks, starting 2 days after Aβ25-35 injection. In the present results, ICV injection of Aβ25-35 deteriorated motor coordination and balance. The number of calbindin-positive cells in the cerebellar vermis was decreased and glial fibrillary acidic protein (GFAP) expression in the cerebellar vermis was increased in the Aβ25-35-induced AD rats. Treadmill exercise improved motor coordination and balance. Treadmill exercise increased the number of Purkinje neurons and suppressed GFAP expression in the cerebellar vermis. The present study demonstrated that treadmill exercises alleviated dysfunction of motor coordination and balance by reduction of Purkinje cell loss through suppressing reactive astrocytes in the cerebellum of AD rats. The present study provides the possibility that treadmill exercise might be an important therapeutic strategy for the symptom improvement of AD patients.