The ameliorating effect of exercise on long-term memory impairment and dendritic retraction via the mild activation of AMP-activated protein kinase in chronically stressed hippocampal CA1 neurons

( Yea-hyun Leem ),( Hyukki Chang ) 한국운동영양학회 2018 Physical Activity and Nutrition (Phys Act Nutr) Vol.22 No.3

[Purpose] Chronic stress affects the neuronal architecture of hippocampal subfields including the Cornu Ammonis 1 (CA1) region, which governs long-term memory. Exercise exerts a beneficial effect on memory improvement via hippocampal AMP-activated protein kinase (AMPK) activation. However, the relationship between the two phenomena is poorly understood. This study used animal and cell culture experimental systems to investigate whether chronic stress-induced impairment of memory consolidation and maladaptation of the neuronal architecture in the hippocampal CA1 area is prevented by regular exercise through AMPK activation. [Methods] Mice underwent four weeks of treadmill running with or without a 6h/21d-restraint stress regimen, along with treatment with Compound C. Memory consolidation was assessed using the Morris Water Maze (MWM). Dendritic rearrangement of hippocampal CA1 neurons was evaluated using the Golgi-Cox stain and Sholl analysis. Additionally, the primary hippocampal culture system was adopted for in vitro experiments. [Results] Chronic stress-induced failure of memory retention and reduction in AMPK activation were ameliorated by the exercise regimen. Chronic stress- or repeated corticosterone (CORT)- provoked malformation of the neuronal architecture was also suppressed by both exercise and treatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). [Conclusion] Chronic stress causes dendritic retraction among dorsal hippocampal CA1 neurons via the downregulation of AMPK activation, thereby leading to failure of memory retention. In contrast, regular exercise protects against chronic stress-evoked defects in memory consolidation and changes in neuronal morphology in the dorsal hippocampal CA1 area via mild activation of AMPK.

Papaverine Exerts Neuroprotective Effect by Inhibiting NLRP3 Inflammasome Activation in an MPTP-Induced Microglial Priming Mouse Model Challenged with LPS

( Yea-hyun Leem ),( Jin-sun Park ),( Jung-eun Park ),( Do-yeon Kim ),( Hee-sun Kim ) 한국응용약물학회 2021 Biomolecules & Therapeutics(구 응용약물학회지) Vol.29 No.3

Microglial priming is the process of microglial proliferation and activation in response to neurodegeneration and abnormal protein accumulation. Priming makes microglia susceptible to secondary inflammatory stimuli and causes exaggerated inflammatory responses. In the present study, we established a microglial priming model in mice by administering a single injection of 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg). MPTP induced microglial activation without dopaminergic degeneration; however, subsequent treatment with a sub-toxic dose of lipopolysaccharides (LPS) induced an amplified inflammatory response and caused nigrostriatal dopaminergic degeneration. These pathological and inflammatory changes, including microglial activation and dopaminergic cell loss in the substantia nigra (SN) area were reversed by papaverine (PAP) administration. In addition, MPTP/LPS enhanced interleukin-1β (IL-1β) expression and processing via nod-like receptor protein 3 (NLRP3) inflammasome activation in the SN region of mice. However, PAP treatment suppressed inflammasome activation and subsequent IL-1β maturation. Moreover, PAP inhibited nuclear factor-κB (NF-κB) and enhanced cAMP-response element binding protein (CREB) activity in the SN of MPTP/LPS mice. These results suggest that PAP inhibits the activation of NLRP3 inflammasome by modulating NF-κB and CREB signaling pathways, which results in reduced microglial activation and neuronal cell death. Thus, PAP may be a potential candidate for the treatment of Parkinsons’s disease, which is aggravated by systemic inflammation.

Imipramine Ameliorates Depressive Symptoms by Blocking Differential Alteration of Dendritic Spine Structure in Amygdala and Prefrontal Cortex of Chronic Stress-Induced Mice

( Yea-hyun Leem ),( Sang-sun Yoon ),( Sangmee Ahn Jo ) 한국응용약물학회 2020 Biomolecules & Therapeutics(구 응용약물학회지) Vol.28 No.3

Previous studies have shown disrupted synaptic plasticity and neural activity in depression. Such alteration is strongly associated with disrupted synaptic structures. Chronic stress has been known to induce changes in dendritic structure in the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC), but antidepressant effect on structure of these brain areas has been unclear. Here, the effects of imipramine on dendritic spine density and morphology in BLA and mPFC subregions of stressed mice were examined. Chronic restraint stress caused depressive-like behaviors such as enhanced social avoidance and despair level coincident with differential changes in dendritic spine structure. Chronic stress enhanced dendritic spine density in the lateral nucleus of BLA with no significant change in the basal nucleus of BLA, and altered the proportion of stubby or mushroom spines in both subregions. Conversely, in the apical and basal mPFC, chronic stress caused a significant reduction in spine density. The proportion of stubby or mushroom spines in these subregions overall reduced while the proportion of thin spines increased after repeated stress. Interestingly, most of these structural alterations by chronic stress were reversed by imipramine. In addition, structural changes caused by stress and blocking the changes by imipramine were corelated well with altered activation and expression of synaptic plasticity-promoting molecules such as phospho-CREB, phospho-CAMKII, and PSD-95. Collectively, our data suggest that imipramine modulates stress-induced changes in synaptic structure and synaptic plasticity-promoting molecules in a coordinated manner although structural and molecular alterations induced by stress are distinct in the BLA and mPFC.

Arc/Arg3.1 protein expression in dorsal hippocampal CA1, a candidate event as a biomarker for the effects of exercise on chronic stress-evoked behavioral abnormalities

( Yea-hyun Leem ),( Hyukki Chang ) 한국운동영양학회 2017 Physical Activity and Nutrition (Phys Act Nutr) Vol.21 No.4

[Purpose] Chronic stress is a risk factor for behavioral deficits, including impaired memory processing and depression. Exercise is well known to have beneficial impacts on brain health. [Methods] Mice were forced to treadmill running (4-week) during chronic restraint stress (6h/21d), and then behavioral tests were conducted by Novel object recognition, forced swimming test: FST, sociality test: SI. Dissected brain was stained with anti-calbindin-d28k and anti-Arc antibodies. Also, mice were treated with CX546 intraperitoneally during chronic restraint stress, and behavioral tests were assessed using Morris water maze, FST, and SI. Dissected brain was stained with anti-Arc antibody. [Results] The current study demonstrated that chronic stress-induced impairment of memory consolidation and depression-like behaviors, along with the changes in calbindin-d28k and Arc protein levels in the hippocampal CA1 area, were attenuated by regular treadmill running. Further, prolonged ampakine treatment prevented chronic stress-evoked behavioral abnormalities and nuclear Arc levels in hippocampal CA1 neurons. Nuclear localization of Arc protein in hippocampal CA1 neurons, but not total levels, was correlated with behavioral outcome in chronically stressed mice in response to a regular exercise regimen. [Conclusion] These results suggest that nuclear levels of Arc are strongly associated with behavioral changes, and highlight the role of exercise acting through an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR)-mediated mechanisms in a chronic stress-induced maladaptive condition.

The potential role of exercise in chronic stress-related changes in AMPA receptor phenotype underlying synaptic plasticity

( Yea-hyun Leem ) 한국운동영양학회 2017 Physical Activity and Nutrition (Phys Act Nutr) Vol.21 No.4

[Purpose] Chronic stress can cause disturbances in synaptic plasticity, such as longterm potentiation, along with behavioral defects including memory deficits. One major mechanism sustaining synaptic plasticity involves the dynamics and contents of α-amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in the central nervous system. In particular, chronic stress-induced disruption of AMPARs includes it abnormal expression, trafficking, and calcium conductance at glutamatergic synapses, which contributes to synaptic plasticity at excitatory synapses. Exercise has the effect of promoting synaptic plasticity in neurons. However, the contribution of exercise to AMPAR behavior under chronic stressful maladaptation remains unclear. [Methods] The present article reviews the information about the chronic stress-related synaptic plasticity and the role of exercise from the previous-published articles. [Results] AMPAR-mediated synaptic transmission is an important for chronic stress-related changes of synaptic plasticity, and exercise may at least partly contribute to these episodes. [Conclusion] The present article discusses the relationship between AMPARs and synaptic plasticity in chronic stress, as well as the potential role of exercise.

Exercise exerts an anxiolytic effect against repeated restraint stress through 5-HT_2A-mediated suppression of the adenosine A_2A receptor in the basolateral amygdala

Leem, Yea-Hyun,Jang, Jee-Hun,Park, Jin-Sun,Kim, Hee-Sun Elsevier 2019 Psychoneuroendocrinology Vol.108 No.-

<P><B>Abstract</B></P> <P>Repeated or chronic stressful stimuli induce emotion- and mood-related abnormalities, such as anxiety and depression. Conversely, regular exercise exerts protective effects. Here, we found that exercise recovered anxiety-like behaviors, as measured using the open field and elevated plus maze tests in an anxiety mouse model. In addition to behavioral improvement, exercise enhanced the synaptic density of the 5-hydroxytryptamine 2A receptor (5-HT<SUB>2A</SUB>R), but not the 5-HT<SUB>1A</SUB>R in the basolateral amygdala (BLA) region in this mouse model. Furthermore, global treatment with a selective 5-HT<SUB>2A</SUB>R antagonist (MDL11930) generated an anxiety phenotype. Thus, synaptic recruitment of 5-HT<SUB>2A</SUB>R in BLA neurons may mediate the anxiolytic effects of exercise. The exercise regimen also reduced adenosine A<SUB>2A</SUB> receptor (A<SUB>2A</SUB>R)-mediated protein kinase A (PKA) activation, and the anxiolytic effect of the exercise was blunted by local activation of A<SUB>2A</SUB>R within the BLA using CGS21680, a selective A<SUB>2A</SUB>R agonist. Particularly, A<SUB>2A</SUB>R-mediated PKA activity was shown to be dependent on 5-HT<SUB>2A</SUB>R signaling in the BLA. These results imply that repeated stress upregulates A<SUB>2A</SUB>R-mediated adenosine signaling to facilitate PKA activation, whereas regular exercise inhibits A<SUB>2A</SUB>R function by increasing 5-HT<SUB>2A</SUB>R in the BLA. Accordingly, this integrated modulation of 5-HT and adenosine signaling, via 5-HT<SUB>2A</SUB>R and A<SUB>2A</SUB>R respectively, may be a mechanism underlying the anxiolytic effect of regular exercise.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Exercise alleviated repeated-stress-induced anxiety-like behaviors. </LI> <LI> Exercise enhanced 5HT<SUB>2A</SUB>R levels and reduced A<SUB>2A</SUB>R levels in the BLA. </LI> <LI> Synaptic A<SUB>2A</SUB>R and PKA activity were modulated by 5HT<SUB>2A</SUB>Rs in the BLA. </LI> <LI> Synaptic 5HT<SUB>2A</SUB>R and A<SUB>2A</SUB>R are crucial for the anxiolytic effect of exercise. </LI> </UL> </P>

Regular exercise and creatine supplementation prevent chronic mild stress-induced decrease in hippocampal neurogenesis via Wnt/ GSK3β/β-catenin pathway

( Yea-hyun Leem ),( Morimasa Kato ),( Hyukki Chang ) 한국운동영양학회 2018 Physical Activity and Nutrition (Phys Act Nutr) Vol.22 No.2

[Purpose] Chronic stress can lead to mood-related psychomotor behaviors such as despair. Decreased hippocampal neurogenesis has been observed in patients with depression and in animal models of depression. Exercise enhances the population of the new born cells in the dentate gyrus (DG). A few studies have demonstrated that creatine has antidepressant effects in humans. However, the mechanism underpinning these effects is poorly understood. Therefore, we examined whether regular exercise and/or creatine was closely associated with the activity of the Wnt/GSK3β/β-catenin pathway in the hippocampal DG. [Methods] Mice were subjected to 4 weeks of chronic mild stress starting a week prior to the start of a 4-week protocol of treadmill running and creatine supplementation. Tail suspension (TST) and forced swimming tests (FST) were carried out 2 days after the final treadmill running session. Immunohistochemical and western blot analyses were conducted to evaluate hippocampal neurogenesis, GSK3β activity, and nuclear β-catenin protein levels in the DG. Furthermore, Wnt signaling antagonism in the DG using stereotaxic injection was performed. [Results] Chronic mild stress-induced increase in immobility in the TST and FST were restored by treadmill running and/or creatine supplementation. The number of Ki-67+ and doublecortin (DCX)+ cells were decreased by chronic stress, and this decline was reversed by the exercise and supplement regimen, along with the changes in GSK3β activity and nuclear β-catenin protein levels in the DG. Local antagonism of DG Wnt signaling caused an increase in immobility even 5 days after injection with C59. [Conclusion] Regular exercise combined with creatine supplementation had a greater effect on hippocampal neurogenesis via the Wnt/GSK3β/β-catenin pathway activation compared with each treatment in chronic mild stress-induced behavioral depression.

Repression of tau hyperphosphorylation by chronic endurance exercise in aged transgenic mouse model of tauopathies

Leem, Yea-Hyun,Lim, Hwa-Ja,Shim, Sun-Bo,Cho, Joon-Yong,Kim, Bum-Soo,Han, Pyung-Lim Wiley Subscription Services, Inc., A Wiley Company 2009 JOURNAL OF NEUROSCIENCE RESEARCH - Vol.87 No.11

<P>The present study was undertaken to investigate whether chronic endurance exercise affects tau phosphorylation levels in the brain with Alzheimer's disease (AD)-like pathology. To address this, the transgenic (Tg) mouse model of tauopathies, Tg-NSE/htau23, which expresses human tau23 in the brain, was chosen. Animals were subjected to chronic exercise for 3 months from 16 months of age. The exercised Tg mouse groups were treadmill run at speeds of 12 m/min (intermediate exercise group) or 19 m/min (high exercise group) for 1 hr/day, 5 days/week, during the 3-month period. Chronic endurance exercise in Tg mice increased the expression of Cu/Zn-superoxide dismutase (SOD) and catalase, and also their enzymatic activities in the brain. In parallel, chronic exercise in Tg mice up-regulated the expression of phospho-PKCα, phospho-AKT, and phospho-PI3K, and down-regulated the expressions of phospho-PKA, phosphor-p38, phospho-JNK, and phospho-ERK. Moreover, chronic exercise up-regulated both cytosolic and nuclear levels of β-catenin, and the expression of T-cell factor-4 (Tcf-4) and cyclin D1 in the brain. As a consequence of such changes, the levels of phospho-tau in the brain of Tg mice were markedly decreased after exercise. Immunohistochemical analysis showed an exercised-induced decrease of the phospho-tau levels in the CA3 subregion of the hippocampus. These results suggest that chronic endurance exercise may provide a therapeutic potential to alleviate the tau pathology. © 2009 Wiley-Liss, Inc.</P>

BPA ‐toxicity via superoxide anion overload and a deficit in β‐catenin signaling in human bone mesenchymal stem cells

Leem, Yea‐,Hyun,Oh, Seikwan,Kang, Hong‐,Je,Kim, Jung‐,Hwa,Yoon, Juno,Chang, Jae‐,Suk John Wiley 2017 Environmental toxicology Vol. No.

<P><B>ABSTRACT</B></P><P>Bisphenol A (BPA), used in the manufacture of products based on polycarbonate plastics and epoxy resins, is well known as an endocrine‐disrupting monomer. In the current study, BPA increased cytotoxicity in hBMSCs in a dose‐ and time‐dependent manner, concomitantly with increased lipid peroxidation. Increased cell death in BPA‐treated cells was markedly blocked by pretreatment with the superoxide dismutase mimetic MnTBAP and MnTMPyP, but not by catalase, glutathione, the glutathione peroxidase mimetic ebselen, the NOS inhibitor NAME, or the xanthine oxidase inhibitor allopurinol. Furthermore, the decline in nuclear β‐catenin and cyclin D1 levels in hBMSCs exposed to BPA was reversed by MnTBAP treatment. Finally, treatment of hBMSCs with the GSK3β inhibitor LiCl<SUB>2</SUB> increased nuclear β‐catenin levels and significantly attenuated cytotoxicity compared with BPA treatment. Our current results in hBMSCs exposed to BPA suggest that BPA causes a disturbance in β‐catenin signaling via a superoxide anion overload. © 2016 The Authors Environmental Toxicology Published by Wiley Periodicals, Inc. Environ Toxicol 32: 344–352, 2017.</P>

Effects of creatine monohydrate supplementation and exercise on depression-like behaviors and raphe 5-HT neurons in mice

( Nari Ahn ),( Yea Hyun Leem ),( Morimasa Kato ),( Hyukki Chang ) 한국운동영양학회 2016 Physical Activity and Nutrition (Phys Act Nutr) Vol.20 No.3

[Purpose] The effects of creatine and exercise on chronic stress-induced depression are unclear. In the present study, we identified the effects of 4-week supplementation of creatine monohydrate and/or exercise on antidepressant behavior and raphe 5-HT expression in a chronic mild stress-induced depressed mouse model. [Methods] Seven-week-old male C57BL/6 mice (n=48) were divided randomly into 5 groups: (1) non-stress control (CON, n=10), (2) stress control (ST-CON, n=10), (3) stress and creatine intake (ST-Cr, n=10), (4) stress and exercise (ST-Ex, n=9), and (5) combined stress, exercise, and creatine intake (STCr+ Ex, n=9). After five weeks’ treatment, we investigated using both anti-behavior tests (the Tail Suspension Test (TST) and the Forced Swimming Test (FST)), and 5-HT expression in the raphe nuclei (the dorsal raphe (DR) and median raphe (MnR)). [Results] Stress for 4 weeks significantly increased depressive behaviors in the mice. Treatment with creatine supplementation combined with exercise significantly decreased depressive behaviors as compared with the CON-ST group in both the TST and FST tests. With stress, 5-HT expression in the raphe nuclei decreased significantly. With combined creatine and exercise, 5-HT positive cells increased significantly and had a synergic effect on both DR and MnR. [Conclusion] The present study found that even a single treatment of creatine or exercise has partial effects as an antidepressant inmice with chronic mild stress-induced depression. Furthermore, combined creatine and exercise has synergic effects and is a more effective prescription than a single treatment.