Earticle

For humans, maternal old age means the age of 35 or older at the time of childbirth. Maternal metabolism not only affects the cognitive func-tion of the offspring, but also affects their physical and neurological de-velopment. This study aims to elucidate the effects of exercise training on spatial learning memory, neurogenesis, and apoptosis in the off-spring of old mice. Using mice, the offspring of old mothers showed im-paired spatial learning memory, decreased brain-derived neurotrophic factor and postsynaptic density protein 95 levels, suppressed neuro-genesis, and increased hippocampal apoptotic cell death. In contrast, the offspring of the old mothers had improved spatial learning memory, increased brain-derived neurotrophic factor and postsynaptic density protein 95 levels, increased neurogenesis, and decreased hippocampal apoptotic cell death when they received exercise training. The present results indicate that there is apparent spatial learning memory impair-ment among the offspring of old mothers, but by contrast, exercise can ameliorate spatial learning memory impairment. Exercise can be an ef-fective countermeasure against memory decline in the offspring of old mothers.

Memory state of rat pups born to old and obese mother rats and the ef-fect 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 spa-tial learning memory, and the level of tumor necrosis factor-α, interleu-kin (IL)-1β, and IL-6 in the hippocampus was measured by enzyme- linked immunoassay. Western blotting was performed for the expres-sion of nuclear factor kappa-light-chain-enhancer (NF-κB), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, al-pha (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 fol-lowing 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 proinflam-matory cytokines production, NF-κB expression, and IκB-α phosphory-lation 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. There-fore, it can be seen that exercise during pregnancy of older and obese mothers is an important factor in fetal health management.

Autism is a complex neurodevelopmental disability with impairments of social interaction and communication, and repetitive behavior. Reelin is an extracellular glycoprotein that is essential for neuronal migration and brain development. Neuroprotective effects of exercise on various brain insults are well documented, however, the effects of exercise on autism in relation with reelin expression are not clarified. In the present study, we investigated the effects of treadmill exercise on the functional recovery and on the expressions of reelin and its downstream molecules, phosphatidylinositol-3-kinase (PI3K), phosphorylated Akt (p-Akt), phosphorylated extracellular signal-regulated protein kinase 1 and 2 (p-ERK1/2), using autistic rats. For the induction of autism-like animal model, 400 mg/kg valproic acid was subcutaneously injected into the rats on the postnatal day 14. The rat in the treadmill exercise groups were forced to run on a treadmill for 30 min once a day, five times a week for 4 weeks, starting postnatal day 28. To investigate autism-like behaviors and memory deficit, open field, social interaction, and radial 8-arm maze were performed. Immunohistochemistry and western blotting were conducted. In the present results, treadmill exercise alleviated aggressive tendency and improved correct decision in the spatial learning memory in the autistic rats. Treadmill exercise increased neurogenesis and the expressions of reelin and its down-stream molecules, PI3K, p-Akt, and p-ERK1/2, in the hippocampus of the autistic rats. The present study showed that treadmill exercise ameliorated aggressive behavior and improved spatial learning memory through activation of reeling signaling pathway in the valproic acid-induced autistic rats.

Post-traumatic stress disorder (PTSD) is a condition which occurs after a person has experienced unusual stress. The neurons in the hippo-campus are especially vulnerable to the PTSD. In the present study, the effect of treadmill exercise on spatial learning memory and cell prolifer-ation in the hippocampus of rats with PTSD. Radial 8-arm maze test and immunohistochemistr for 5-bromo-2´-deoxyridine (BrdU) and double-cortin (DCX) were conducted for this experiment. For the inducing PTSD, the rats were exposure to 0.2 mA electric foot shock for 7 consecutive days. Electric foot shock continued 6 seconds, repeated 10 times with a 30 sec interval per one trial, and repeated 3 trials per day. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 4 weeks, stating one day after finishing last electric food shock. Presently, the PTSD rats showed longer time of successful per-formance, higher error number, and lower correct number in the radi-al-8-arm maze test. Cell proliferation and DCX expression in the hippo-campal dentate gyrus were suppressed in the PTSD rats. In contrast, treadmill exercise alleviated PTSD-induced impairment of spatial learn-ing memory. The rats performed treadmill exercise showed longer time of successful performance, higher error number, and lower correct num -ber in the radial-8-arm maze test. Treadmill exercise also enhanced cell proliferation and DCX expression in the hippocampal dentate gyrus of PTSD rats. The present study demonstrated that treadmill exercise ameliorated PTSD-induced memory impairment through enhancing cell prolif- eration in the hippocampus.

본 연구에서는 트레드밀 운동이 외상성 뇌손상 쥐의 공간학습장애와 뇌의 흑질(substantia nigra), 선조체(striatum), 그 리고 해마(hippocampus) 부위에서 tyrosine hydroxylase(TH) 발현에 미치는 효과를 규명고자 하였다. 본 연구의 실험동물 은 Sprague-Dawley 계열 7주령 수컷(210 ± 10g) 60마리를 사용하였으며, 실험실 환경에 적응시킨 후 sham-operation 그룹, sham-operation and exercise 그룹, TBI-induced 그룹, 그리고 TBI-induced and exercise 그룹으로 각 15마리씩 무작위 배정하였다. TBI 그룹은 streotaxic frame을 사용하여 외상성 뇌손상을 유발하였고, sham 그룹은 동일한 수술 스트 레스를 주었으나 외상성 뇌손상은 유발하지 않았다. Exercise 그룹은 treadmill 운동을 실시하였는데, 1일 30분, 연속 10일 동 안 2m/min 5분, 3m/min 5분, 그리고 4m/min 20분 저강도 운동을 실시하였다. 또한 실험 전ㆍ후로 공간학습능력을 측정하기 위하여 radial 8-arm maze 검사를 실시하였고, 뇌 부위별 TH 발현을 검사하기 위하여 TH 면역조직화학법을 실시하였다. 실 험결과, sham-operation 그룹과 비교하여 TBI 그룹에서 공간학습장애가 나타났고, 모든 뇌 부위에서 TH 발현이 유의하게 감 소하였다. 그러나 트레드밀 운동은 TBI로 유발된 공간학습장애를 완화시켰고, TH 발현도 모든 뇌 부위에서 증가시켰다. 이 러한 연구결과는 규칙적인 운동은 다양한 뇌부위에서 외상성 뇌손상으로 인한 TH 발현 감소를 억제시킴으로써 외상성 뇌손 상으로 인한 인지기능의 감소를 완화시킬 수 있는 가능성이 있음을 보여준다.

본 연구는 노화 흰쥐를 대상으로 해마 신경영양인자와 공간학습 및 기억력에 미치는 영향을 알아봄으로써, 노인 운동처방학적 영역에서 운동의 필요성을 제시하고자 하였다. 이러한 목적을 위해 노화 쥐를 대상으로 트레드밀 운동을 8주간 실시한 후 공간학습기억력과 해마 신경가소성 인자인 BDNF 발현에 어떠한 영향을 미치는 지를 알아보았다. 본 연구에 사용된 실험동물은 Sprague-Dawley 계 흰쥐 72주령 수컷이 사용되었다. 이들은 무작위 표본추출에 의해 노 화 운동군(aging and exercise-trained group, AEG; n=10)과 노화 대조군(aging control group, ACG; n=10)으 로 분류되었다. 운동군은 본 실험하기 일주일 전부터 운동에 대한 적응을 거친 후, 트레드밀 운동을 1일 30분, 주 5회, 8주 동안 실시하였다. 공간학습 및 기억력 평가는 모리스수중미로 검사가 이용되었고, 해마 부위 신경가소성인자인 BDNF 단백질 분석은 Western blotting 분석법으로 분석하여 정량화하였다. 그 결과 트레드밀 운동을 수행한 그룹의 공간학습기억력과 해마 조직 신경가소성 인자인 BDNF발현이 높은 것으로 나타났다. 이와 같은 결과는 트레드밀 운동 이 노화 과정에서 저하되는 공간학습 및 기억력 감소를 지연시킬 수 있는 효과적인 운동이라 생각되며, 그 기저에는 해 마 조직 신경가소성 인자의 증가와 밀접한 관련이 있는 것으로 판단된다.

The purpose of this study was to investigate the effects of treadmill exercise on spatial learning memory ability and the neurotrophic factor in hippocampus in aged-rats. The experimental animals were divided into each the aging and exercise-trained group(AEG, n=10)and the aging control group(ACG, n=10). Animals in the exercise group were submitted to 5days a week exercise on the treadmill exercise during 8weeks. The spatial learning memory capability was evaluated by Morris water maze in a separate set of rats. Western blotting analysis for the BDNF expression was performed. In this study, treadmill exercises have shown increased spatial cognitive abilities, and also increased neurotrophic factors expression in the hippocampus of aging rats. The results of the present study indicate that treadmill exercise may facilitate recovery from the CNS complications associated with aging by inducing enhanced the neurotrophic factor expression in the hippocampus.

본 연구에서는 공간학습과 트레드밀 운동이 생쥐의 기억능력에 미치는 효과를 규명고자 하였다. 본 연구의 실험동물은 C57BL 계열 생쥐 6주령 수컷(32.5 ± 2.5 g) 60마리를 사용하였으며, 실험실 환경에 적응시킨 후 대조군, 학습군, 운동군, 그리고 학습- 운동군으로 각 15마리씩 무작위 배정하였다. 운동군과 학습-운동군은 트레드밀 운동을 실시하였는데, 1일 30분, 6주 동안 7 m/min 5분, 10 m/min 5분, 그리고 13 m/min 20분 중강도 운동을 각각 12회, 6회 실시하였다. 공간학습은 radial 8-arm maze 를 사용하여 절수한 실험동물이 5분 이내에 8개 통로의 물을 모두 찾을 때까지 연속적으로 학습군은 6주간 12회, 학습-운동군 은 6주간 6회 훈련시켰으며, 모든 그룹의 실험 전ㆍ후로 기억능력을 측정하기 위하여 radial 8-arm maze 검사와 step-down avoidance task를 실시하였다. 해마부위의 5-bromo-2'-deoxyuridine (BrdU) 양성세포수와 brain-derived neurotrophic factor (BDNF)의 발현량을 조사하기 위하여 각각 면역조직화학법과 역전사 중합효소 연쇄반응 (reverse transcription polymerase chain reaction, RT-PCR)법을 실시하였다. 실험결과, 기억능력 검사에서 예상했던 운동과 학습에 따른 가중효과가 관찰되지 않 았지만, 대조군과 비교하여 학습군과 학습-운동군의 기억능력이 유의하게 증가하였다(p < .05). 또한 해마 부위에서 BrdU 양성 세포수는 대조군과 비교하여 모든 실험군에서 유의하게 증가하였고(p < .05), 특히 운동군에서 가장 큰 증가를 보였다(p < .05). 동일한 부위의 BDNF mRNA도 대조군과 비교하여 모든 실험군에서 유의하게 증가하였으나(p < .05), BrdU 양성 세포수와 BDNF mRNA 발현이 일치하는 경향은 나타나지 않았다. 이러한 연구결과는 공간학습과 규칙적인 운동이 BDNF mRNA와 같 은 뇌의 신경영양성 인자를 증가시키고, 새로운 신경세포생성을 촉진시킴으로써 기억능력을 향상시킬 수 있는 가능성이 있음을 보여준다. 다만, 기억능력검사와 신경세포의 증식, 그리고 BDNF mRNA간 정량적 경향성이 일치하지 않는 것으로 보아 신경세 포 증식에 작용하는 다양한 신경영양성 인자의 발현을 함께 고려해야 할 것으로 생각된다.

Purpose: Exercise is known to reduce proinflammatory cytokines production and apoptosis. We investigated the effect of treadmill running on spatial learning memory in terms of activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathway in Alzheimer disease (AD) rats. We also evaluated the effect of treadmill running on proinflammatory cytokine production and apoptosis. Methods: Using the stereotaxic frame, amyloid-β (Aβ) was injected into the lateral ventricle of the brain. The rats belong to treadmill running groups were forced to run on a motorized treadmill for 30 minutes per a day during 4 weeks, starting 3 days after Aβ injection. Morris water maze task was done for the determination of spatial learning memory. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry for cleaved caspase-3, and western blot for NF-κB, inhibitory protein of NF-κB (IκB), MAPK signaling pathway, tumor necrosis factor (TNF)-α, interleukin (IL)-1β were done. Results: Induction of AD increased proinflammatory cytokine secretion by activating the NF-κB/MAPK signaling pathway. These changes induced apoptosis in the hippocampus and reduced spatial learning memory. In contrast, treadmill running inactivated the NF-κB/MAPK signaling pathway and suppressed proinflammatory cytokine production. These changes inhibited apoptosis and improved spatial learning memory. Conclusions: Current results showed that treadmill running promoted spatial learning memory through suppressing proinflammatory cytokine production and apoptosis via inactivation of NF-κB/MAPK signaling pathway. Treadmill exercise can be considered an effective intervention for symptom relieve of AD.

Purpose: Exercise has been shown to protect against diverse brain diseases. Voluntary exercise improves cognition and has a neuroprotective effect. The aim of this investigation is to study the effect of voluntary wheel running on brain inflammation in rats with regard to inflammation and apoptosis. Methods: Brain inflammation was caused by intracranial injection of lipopolysaccharide using a stereotaxic instrument. Voluntary wheel running group were conducted during 21 consecutive days, staring 2 days after brain inflammation. Results: Brain inflammation increased proinflammatory cytokine production and apoptosis cell death in the hippocampus. There changes in the hippocampus deteriorated spatial learning memory. However, voluntary wheel running suppressed the secretion of inflammatory cytokines and apoptotic neuronal cell death via inactivation of nuclear factor kappa B (NF-κB)/NF- κB inhibitor-α pathway. Voluntary wheel running also promoted the recovery of the spatial learning memory impairment. Conclusions: Voluntary wheel running after brain inflammation enhanced spatial learning memory by suppressing proinflammatory cytokine secretion and apoptosis cell death. Voluntary wheel running is also expected to be effective in inflammatory diseases of the urogenital system.

Objective A radial arm maze (RAM) is an essential tool for assessing spatial learning and memory. Although this tool is widely used to study deficits in spatial memory in animal models, it has several restrictions that prevent its adaptation to human research and training. Therefore, we developed a head-mounted-display RAM (HMD-RAM) program for humans and verified its validity by comparing it to the results obtained by previous RAM studies. We also compared the HMD and a flat monitor as experimental devices. Methods Forty participants were recruited for the current study (Study 1: 20 participants with the HMD device; Study 2: 20 participants with the flat monitor). They navigated a virtual room as a first-person viewer and used environmental landmarks to remember their spatial position and orientation. The main dependent measures were working memory error, reference memory error, detection time, travel distance, and participant’s head movements. To validate the program, participants also conducted neuropsychological assessments and self-reported measures. Results The results for HMD-RAM tasks were consistent with the results of previous research conducted on animals, and the HMD elicited a higher sense of presence, immersion, and simulator sickness than the flat monitor. According to post-experiment questions on navigation strategy, creating landmarks was important when people were discovering locations in their environment, and an HMD was beneficial for better navigation strategy. Conclusion These results suggest that the HMD-RAM is valuable for estimating spatial learning and memory in humans and may be a useful tool for early diagnosis of deficits in spatial learning and memory, including amnestic mild cognitive impairment and Alzheimer’s disease.

Anesthetics are used extensively in surgeries and related procedures to prevent pain. However, there is some concern regarding neuronal degeneration and cognitive deficits arising from regular anesthetic exposure. Recent studies have indicated that brain-derived neurotrophic factor (BDNF) and cyclic AMP response element-binding protein (CREB) are involved in learning and memory processes. Genistein, a plant-derived isoflavone, has been shown to exhibit neuroprotective effects. The present study was performed to examine the protective effect of genistein against isoflurane-induced neurotoxicity in rats. Neonatal rats were exposed to isoflurane (0.75%, 6 hours) on postnatal day 7 (P7). Separate groups of rat pups were orally administered genistein at doses of 20, 40, or 80 mg/kg body weight from P3 to P15 and then exposed to isoflurane anesthesia on P7. Neuronal apoptosis was detected by TUNEL assay and FluoroJade B staining following isoflurane exposure. Genistein significantly reduced apoptosis in the hippocampus, reduced the expression of proapoptotic factors (Bad, Bax, and cleaved caspase-3), and increased the expression of Bcl-2 and Bcl-xL. RT-PCR analysis revealed enhanced BDNF and TrkB mRNA levels. Genistein effectively upregulated cAMP levels and phosphorylation of CREB and TrkB, leading to activation of cAMP/CREB-BDNF-TrkB signaling. PI3K/Akt signaling was also significantly activated. Genistein administration improved general behavior and enhanced learning and memory in the rats. These observations suggest that genistein exerts neuroprotective effects by suppressing isoflurane-induced neuronal apoptosis and by activating cAMP/CREB-BDNF-TrkB-PI3/Akt signaling.

Bisphenol A (BPA) is a monomer used in a polymerization reaction in the production of polycarbonate plastics. It has been used in many consumer products, including plastics, polyvinyl chloride, food packaging, dental sealants, and thermal receipts. However, there is little information available on the inhalation toxicity of BPA. Therefore, the aim of this study was to determine its inhalation toxicity and effects on the estrous cycle, spatial learning, and memory. Sprague-Dawley rats were exposed to 0, 10, 30, and $90mg/m^3$ BPA, 6 hr/day, 5 days/week for 8 weeks via whole-body inhalation. Mortality, clinical signs, body weight, hematology, serum chemistry, estrous cycle parameters, performance in the Morris water maze test, and organ weights, as well as gross and histopathological findings, were compared between the control and BPA exposure groups. Statistically significant changes were observed in serum chemistry and organ weights upon exposure to BPA. However, there was no BPA-related toxic effect on the body weight, food consumption, hematology, serum chemistry, organ weights, estrous cycle, performance in the Morris water maze test, or gross or histopathological lesions in any male or female rats in the BPA exposure groups. In conclusion, the results of this study suggested that the no observable adverse effect level (NOAEL) for BPA in rats is above $90mg/m^3$/6 hr/day, 5 days/week upon 8-week exposure. Furthermore, BPA did not affect the estrous cycle, spatial learning, or memory in rats.

Sleep deprivation (SD) leads to cognitive impairment, especially hippocampus-dependent learning and memory (L&M). The hippocampal dentate gyrus (DG) is the key structure involved in spatial L&M while long-term potentiation (LTP) is an important cellular mechanism responsible for L&M. Physiological and behavioral evidences support the hypothesis that norepinephrine (NE) and β-adrenoceptors (β-AR) may play an important role in regulating L&M, including LTP. However, it is enigmatic how β-AR influences the LTP disruption or memory impairment under SD circumstances. In the present study, the rats were subjected to SD for 18 h per day for 21 consecutive days and cognitive capacity was assessed by the Morris water maze (MWM) test. We examined the extracellular concentration of NE in the DG using in vivo brain microdialysis and HPLC analysis. The amplitudes of field excitatory postsynaptic potential (fEPSP) were subsequently measured in the DG during MWM test in freely moving conscious rats. The extracellular concentrations of NE and fEPSP amplitudes in the DG were significantly increased during MWM test, while these responses were suppressed in SD rats. When fEPSP amplitudes in the DG were measured after local injection of isoproterenol (an agonist of β-AR), SD rats significantly alleviated the fEPSP impairment and rescued deficits of spatial L&M. In addition, the reduced expression of N-methyl-Daspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in SD rats significantly increased by activation of β-AR by isoproterenol in the DG. In conclusion, we propose that β-adrenergic signaling can improve memory impairment in sleep-deficient rats by regulating synaptic efficiency and glutamatergic receptor expression.

Alzheimer's disease is progressive neurodegenerative disorder by the loss of memory and learning abilities. Codonopsis lanceolata (C. lanceolata) is traditional medicinal plant used for the treatment of inflammatory diseases. The aim of study was to evaluate the effect of steamed C. lanceolata on scopolamine-induced memory impairment in the Morris water maze test and passive avoidance test. In addition, this study investigated the neuroprotective effects of steamed C. lanceolata on glutamate-induced cell death in HT22 cells using MTT assay. The results showed that steamed C. lanceolata (500 mg/kg body weight, p.o.) reversed spatial memory impairment by scopolamine in Morris water maze test and passive avoidance test. Steamed C. lanceolata attenuated memory impairment by scopolamine compared with common C. lanceolata. In addition, administration of steamed C. lanceolata significantly also reduced cell death. We suggest that steaming process more improve cognitive enhancing and neuroprotective effect of C. lanceolata than common C. lanceolata.

Alzheimer's disease (AD), most common form of dementia is characterized that memory deficit and loss of cognitive function. This study was evaluated cognitive enhancing effect of water and ethanol extracts of Codonopsis lanceolata and compared using Morris water maze and passive avoidance test. The water and 70% ethanol extracts (100, 300 and 500 mg/kg) were administered to mice. The neuroprotective effect on glutamate-induced cell death in HT22 cells was additionally investigated using MTT assay. Results showed 70% ethanol extract of Codonopsis lanceolata enhanced cognitive function than water extract, as shown by decrease in escape latency time in Morris water maze test. In passive avoidance test, 70% ethanol extract also increased the latency time compared to the water extract. Furthermore, 70% ethanol extract significantly protected neuronal cell against glutamate cytotoxicity and showed higher than neuroprotective effect of water extract. These results indicate that 70% ethanol extract more improve spatial cognitive ability and protected neuronal cells than water extract.