1.Experimental Neurobiology: The Past, Present, and Future
Young Jun OH ; Pyung Lim HAN ; C Justin LEE
Experimental Neurobiology 2019;28(4):447-450
No abstract available.
Neurobiology
2.Functional Connectivity of Basolateral Amygdala Neurons Carrying Orexin Receptors and Melanin-concentrating Hormone Receptors in Regulating Sociability and Mood-related Behaviors.
Experimental Neurobiology 2016;25(6):307-317
Chronic stress induces changes in neuronal functions in specific brain regions regulating sociability and mood-related behaviors. Recently we reported that stress-induced persistent upregulation of the neuropeptides orexin and melanin-concentrating hormone (MCH) in the basolateral amygdala (BLA) and the resulting activation of orexin receptors or MCH receptors within the BLA produced deficits in sociability and mood-related behaviors. In the present study, we investigated the neural targets that were innervated by BLA neurons containing orexin receptors or MCH receptors. The viral vector system AAV2-CaMKII-ChR2-eYFP was injected into the BLA to trace the axonal tracts of BLA neurons. This axon labeling analysis led us to identify the prelimbic and infralimbic cortices, nucleus accumbens (NAc), dorsal striatum, paraventricular nucleus (PVN), interstitial nucleus of the posterior limb of the anterior commissure, habenula, CA3 pyramidal neurons, central amygdala, and ventral hippocampus as the neuroanatomical sites receiving synaptic inputs of BLA neurons. Focusing on these regions, we then carried out stimulus-dependent c-Fos induction analysis after activating orexin receptors or MCH receptors of BLA neurons. Stereotaxic injection of an orexin receptor agonist or an MCH receptor agonist in the BLA induced c-Fos expression in the NAc, PVN, central amygdala, ventral hippocampus, lateral habenula and lateral hypothalamus, which are all potentially important for depression-related behaviors. Among these neural correlates, the NAc, PVN and central amygdala were strongly activated by stimulation of orexin receptors or MCH receptors in the BLA, whereas other BLA targets were differentially and weakly activated. These results identify a functional connectivity of BLA neurons regulated by orexin and MCH receptor systems in sociability and mood-related behaviors.
Axons
;
Basolateral Nuclear Complex*
;
Brain
;
Central Amygdaloid Nucleus
;
Depression
;
Extremities
;
Habenula
;
Hippocampus
;
Hypothalamic Area, Lateral
;
Neurons*
;
Neuropeptides
;
Nucleus Accumbens
;
Orexin Receptors*
;
Paraventricular Hypothalamic Nucleus
;
Pyramidal Cells
;
Up-Regulation
3.Physiological Parameters in the Blood of a Murine Stress-Induced Depression Model before and after Repeated Passive Exercise.
Tae Kyung KIM ; Jin Young PARK ; Pyung Lim HAN
Endocrinology and Metabolism 2015;30(3):371-380
BACKGROUND: Animal models are necessary to study the mechanism underlying the effects of exercise on depression but an effective procedure for exercise treatment and exercise effects on physiological parameters in a specific depression model need to be characterized. METHODS: Physiological parameters including lactate, partial pressue of O2 (pO2) and CO2 (pCO2) saturated O2 (sO2), pH, HCO3, total CO2 (TCO2), and base excess extracellular fluid (BEecf) levels in the blood were measured after treatment with passive exercise in normal mice and a stress-induced depression model. RESULTS: Normal mice or mice that were subjected to daily 2-hour restraint for 14 days (2 hoursx14 days of restraint) were placed on a running wheel that was rotating at a speed of 9 m/min for 1 hour per day for 1 to 21 days. After repeated exercise in mice that were previously subjected to 2 hoursx14 days restraint, plasma lactate levels decreased, the levels of pO2, sO2, and pH tended to increase, and the levels of pCO2 decreased in the absence of significant changes in HCO3, TCO2, and BEecf. However, none of these changes were additive to the stress effects or were much more severe than those induced after repeated passive exercise in normal mice. CONCLUSION: These results suggest that passive exercise for 1 hour daily for 14 to 21 consecutive days on a running wheel rotating at a speed of 9 m/min may be used as an exercise protocol without inducing severe additive effects on physiological burdens.
Animals
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Depression*
;
Extracellular Fluid
;
Hydrogen-Ion Concentration
;
Lactic Acid
;
Mice
;
Models, Animal
;
Plasma
;
Running
4.An Update of Animal Models of Alzheimer Disease with a Reevaluation of Plaque Depositions.
Experimental Neurobiology 2013;22(2):84-95
Animal models of Alzheimer disease (AD) are used to study the mechanisms underlying AD pathogenesis, genetic interactions with genes of interest, and environmental risk factors that cause sporadic AD as well as to test the therapeutic effects of AD drug-candidates on neuropathology and cognitive function. To attain a comparative view on the AD models developed, representative AD lines were selected and summarized with respect to transgenic constructs and AD-related pathology. In addition, age-dependent plaque deposition data available in the literature for six representative AD models such as Tg2576, PDAPP, TgAPP23, Tg-APPswe/PS1dE9, 3xTg-AD, and 5XFAD mice were reevaluated using a photographic plaque reference scale method that was introduced recently. Tg2576, PDAPP, and TgAPP23 mice, which carry the amyloid precursor protein (APP) transgene, produced initially slow, but progressively accelerated plaque deposition as they aged, resulting in logistic plaque deposition. In contrast, Tg-APPswe/PS1dE9 and 3xTg-AD mice, which carry both APP and PS1 transgenes, developed abruptly accelerated plaque formation from the beginning, resulting in logarithmic plaque deposition. 5XFAD mice, which also carry both the APP and PS1 transgenes, developed a logarithmic deposition beginning at 2 months. This comparative analysis suggests that AD models may be classified into two distinct plaque deposition groups, and that early plaque models such as APPswe/PS1dE9, 3xTg-AD and 5XFAD might be useful to study the biochemical aspects of APP metabolism, whereas late plaque models such as Tg2576, PDAPP, and TgAPP23 might be useful to study more physiological and environmental aspects of AD pathogenesis, which occur on a longer time scale.
Aged
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Alzheimer Disease
;
Amyloid
;
Animals
;
Humans
;
Mice
;
Models, Animal
;
Risk Factors
;
Transgenes
5.Physical Exercise Counteracts Stress-induced Upregulation of Melanin-concentrating Hormone in the Brain and Stress-induced Persisting Anxiety-like Behaviors.
Experimental Neurobiology 2016;25(4):163-173
Chronic stress induces anxiety disorders, whereas physical exercise is believed to help people with clinical anxiety. In the present study, we investigated the mechanisms underlying stress-induced anxiety and its counteraction by exercise using an established animal model of anxiety. Mice treated with restraint for 2 h daily for 14 days exhibited anxiety-like behaviors, including social and nonsocial behavioral symptoms, and these behavioral impairments lasted for more than 12 weeks after the stress treatment was removed. Despite these lasting behavioral changes, wheel-running exercise treatment for 1 h daily from post-stress days 1 - 21 counteracted anxiety-like behaviors, and these anxiolytic effects of exercise persisted for more than 2 months, suggesting that anxiolytic effects of exercise stably induced. Repeated restraint treatment up-regulated the expression of the neuropeptide, melanin-concentrating hormone (MCH), in the lateral hypothalamus, hippocampus, and basolateral amygdala, the brain regions important for emotional behaviors. In an in vitro study, treatment of HT22 hippocampal cells with glucocorticoid increased MCH expression, suggesting that MCH upregulation can be initially triggered by the stress hormone, corticosterone. In contrast, post-stress treatment with wheel-running exercise reduced the stress-induced increase in MCH expression to control levels in the lateral hypothalamus, hippocampus and basolateral amygdala. Administration of an MCH receptor antagonist (SNAP94847) to stress-treated mice was therapeutic against stress-induced anxiety-like behaviors. These results suggest that repeated stress produces long-lasting anxiety-like behaviors and upregulates MCH in the brain, while exercise counteracts stress-induced MCH expression and persisting anxiety-like behaviors.
Animals
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Anti-Anxiety Agents
;
Anxiety
;
Anxiety Disorders
;
Basolateral Nuclear Complex
;
Behavioral Symptoms
;
Brain*
;
Corticosterone
;
Exercise*
;
Hippocampus
;
Hypothalamic Area, Lateral
;
In Vitro Techniques
;
Mice
;
Models, Animal
;
Neuropeptides
;
Up-Regulation*
6.Two Cases of Wolff-Parkinson-White Syndrome in a Family.
Chan Uhng JOO ; So Hee LIM ; Pyung Han HWANG
Journal of the Korean Pediatric Society 2002;45(9):1150-1154
Wolff-Parkinson-White(WPW) syndrome is characterized by electrographic evidence of ventricular preexcitation, which predisposes to supraventicular arrhythmias. Familial occurrence of WPW syndrome is uncommon. We observed two affected siblings in a family. Five members of the family underwent 12-lead electrocardiography and echocardiography. Although known genetic abnormality of the 7q34-q36(PRKAG2) for the familial WPW syndrome was evaluated, the mutation was not detected in this family. Other unknown mutations responsible for this familial WPW syndrome were suggested.
Arrhythmias, Cardiac
;
Echocardiography
;
Electrocardiography
;
Humans
;
Siblings
;
Wolff-Parkinson-White Syndrome*
7.Hyperoxygenation Treatment Reduces Beta-amyloid Deposition via MeCP2-dependent Upregulation of MMP-2 and MMP-9 in the Hippocampus of Tg-APP/PS1 Mice
Juli CHOI ; Hyejin KWON ; Pyung-Lim HAN
Experimental Neurobiology 2021;30(4):294-307
Recently we reported that hyperoxygenation treatment reduces amyloid-beta accumulation and rescues cognitive impairment in the Tg-APP/PS1 mouse model of Alzheimer’s disease. In the present study, we continue to investigate the mechanism by which hyperoxygenation reduces amyloidbeta deposition in the brain. Hyperoxygenation treatment induces upregulation of matrix metalloproteinase-2 (MMP-2), MMP-9, and tissue plasminogen activator (tPA), the endopeptidases that can degrade amyloid-beta, in the hippocampus of Tg-APP/PS1 mice. The promoter regions of the three proteinase genes all contain potential binding sites for MeCP2 and Pea3, which are upregulated in the hippocampus after hyperoxygenation. Hyperoxygenation treatment in HT22 neuronal cells increases MeCP2 but not Pea3 expression. In HT22 cells, siRNA-mediated knockdown of Mecp2 decreases Mmp-9 expression and to a lesser extent, Mmp-2 and tPA expression. In mice, siRNA-mediated Mecp2 knockdown in the hippocampus reduces Mmp-9 expression, but not significantly Mmp-2 and tPA expression. The ChIP assay indicates that hyperoxygenation treatment in Tg-APP/PS1 mice increases MeCP2 binding to the promoter regions of MMP-2, MMP-9, and tPA genes in the hippocampus. Together, these results suggest that hyperoxygenation increases the expression of MMP-2, MMP-9, and tPA, of which MMP-9 is upregulated via MeCP2 in neuronal cells, and Mmp-2 and tPA are upregulated through MeCP2 and other nuclear factors.
8.Striatal Inhibition of MeCP2 or TSC1 Produces Sociability Deficits and Repetitive Behaviors.
Yunjin LEE ; Hannah KIM ; Pyung Lim HAN
Experimental Neurobiology 2018;27(6):539-549
Autism spectrum disorder (ASD) is a heterogeneous group of neurobehavioral disorders characterized by the two core domains of behavioral deficits, including sociability deficits and stereotyped repetitive behaviors. It is not clear whether the core symptoms of ASD are produced by dysfunction of the overall neural network of the brain or that of a limited brain region. Recent studies reported that excessive glutamatergic or dopaminergic inputs in the dorsal striatum induced sociability deficits and repetitive behaviors. These findings suggest that the dorsal striatum plays a crucial role in autistic-like behaviors. The present study addresses whether functional deficits of well-known ASD-related genes in the dorsal striatum also produce ASD core symptoms. This study also examines whether these behavioral changes can be modulated by rebalancing glutamate and/or dopamine receptor activity in the dorsal striatum. First, we found that the siRNA-mediated inhibition of Shank3, Nlgn3, Fmr1, Mecp2, or Tsc1 in the dorsal striatum produced mild to severe behavioral changes in sociability, cognition, and/or repetitive behaviors. The knockdown effects of Mecp2 and Tsc1 on behavioral changes were the most prominent. Next, we demonstrated that behavioral changes induced by striatal inhibition of MeCP2 and TSC1 were rescued by D-cycloserine (an NMDA agonist), fenobam (an mGluR5 antagonist), SCH23390 (a D1 antagonist), and/or ecopipam (a D1 partial antagonist), pharmacological drugs that are known to regulate ASD-like symptoms in animal models. Collectively, these results suggest that the dorsal striatum is a critical brain region that, when dysfunctional, produces the core symptoms of ASD.
Autism Spectrum Disorder
;
Brain
;
Cognition
;
Glutamic Acid
;
Models, Animal
;
N-Methylaspartate
;
Receptors, Dopamine
9.Early-Life Stress in D2 Heterozygous Mice Promotes Autistic-like Behaviors through the Downregulation of the BDNF-TrkB Pathway in the Dorsal Striatum
Experimental Neurobiology 2019;28(3):337-351
A number of specific genetic variants including gene mutations and single nucleotide variations have been identified in genomewide association studies of autism spectrum disorder (ASD). ASD phenotypes in individuals carrying specific genetic variations are manifest mostly in a heterozygous state. Furthermore, individuals with most genetic variants show incomplete penetrance and phenotypic variability, suggesting that non-genetic factors are also involved in developing ASD. However, the mechanisms of how genetic and environmental factors interactively promote ASD are not clearly understood. In the present study, we investigated whether early-life stress (ELS) in D2 dopamine receptor heterozygous knockout (D2(+/−)) mice induces ASD-like symptoms. To address that, we exposed D2 heterozygous pups to maternal separation stress for 3 h daily for 13 days beginning on postnatal day 2. D2(+/−) adult mice that had experienced ELS exhibited impaired sociability in the three-chamber test and home-cage social interaction test and increased grooming behavior, whereas wildtype littermates exposed to ELS did not show those phenotypes. ELS-exposed D2(+/−) mice had decreased levels of BDNF, TrkB, phospho-ERK1/2 and phospho-CREB in the dorsal striatum. Administration of the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) to ELS-exposed D2(+/−) mice rescued the sociability deficits and repetitive behavior. In contrast, behavioral rescue by 7,8-DHF in ELS-exposed D2(+/−) mice was blocked when TrkB expression in the dorsal striatum was locally inhibited by the injection of TrkB-siRNA. Together, our results suggest that the interaction between ELS and defective D2 gene function promotes autistic-like behaviors by downregulating the BDNF-TrkB pathway in the dorsal striatum.
Adult
;
Animals
;
Autism Spectrum Disorder
;
Brain-Derived Neurotrophic Factor
;
Down-Regulation
;
Genetic Variation
;
Grooming
;
Humans
;
Interpersonal Relations
;
Mice
;
Penetrance
;
Phenotype
;
Receptor, trkB
;
Receptors, Dopamine
10.Hyperoxygenation Treatment Reduces Beta-amyloid Deposition via MeCP2-dependent Upregulation of MMP-2 and MMP-9 in the Hippocampus of Tg-APP/PS1 Mice
Juli CHOI ; Hyejin KWON ; Pyung-Lim HAN
Experimental Neurobiology 2021;30(4):294-307
Recently we reported that hyperoxygenation treatment reduces amyloid-beta accumulation and rescues cognitive impairment in the Tg-APP/PS1 mouse model of Alzheimer’s disease. In the present study, we continue to investigate the mechanism by which hyperoxygenation reduces amyloidbeta deposition in the brain. Hyperoxygenation treatment induces upregulation of matrix metalloproteinase-2 (MMP-2), MMP-9, and tissue plasminogen activator (tPA), the endopeptidases that can degrade amyloid-beta, in the hippocampus of Tg-APP/PS1 mice. The promoter regions of the three proteinase genes all contain potential binding sites for MeCP2 and Pea3, which are upregulated in the hippocampus after hyperoxygenation. Hyperoxygenation treatment in HT22 neuronal cells increases MeCP2 but not Pea3 expression. In HT22 cells, siRNA-mediated knockdown of Mecp2 decreases Mmp-9 expression and to a lesser extent, Mmp-2 and tPA expression. In mice, siRNA-mediated Mecp2 knockdown in the hippocampus reduces Mmp-9 expression, but not significantly Mmp-2 and tPA expression. The ChIP assay indicates that hyperoxygenation treatment in Tg-APP/PS1 mice increases MeCP2 binding to the promoter regions of MMP-2, MMP-9, and tPA genes in the hippocampus. Together, these results suggest that hyperoxygenation increases the expression of MMP-2, MMP-9, and tPA, of which MMP-9 is upregulated via MeCP2 in neuronal cells, and Mmp-2 and tPA are upregulated through MeCP2 and other nuclear factors.