Highlights
  • Original Article | August 31, 2019

    The function of microglia/macrophages after ischemic stroke is poorly understood. This study examines the role of microglia/macrophages in the focal infarct area after transient middle cerebral artery occlusion (MCAO) in rhesus monkeys. We measured infarct volume and neurological function by magnetic resonance imaging (MRI) and non-human primate stroke scale (NHPSS), respectively, to assess temporal changes following MCAO. Activated phagocytic microglia/macrophages were examined by immunohistochemistry in post-mortem brains (n=6 MCAO, n=2 controls) at 3 and 24 hours (acute stage), 2 and 4 weeks (subacute stage), and 4, and 20 months (chronic stage) following MCAO. We found that the infarct volume progressively decreased between 1 and 4 weeks following MCAO, in parallel with the neurological recovery. Greater presence of cluster of differentiation 68 (CD68)-expressing microglia/macrophages was detected in the infarct lesion in the subacute and chronic stage, compared to the acute stage. Surprisingly, 98~99% of transforming growth factor beta (TGFβ) was found colocalized with CD68-expressing cells. CD68-expressing microglia/macrophages, rather than CD206+ cells, may exert anti-inflammatory effects by secreting TGFβ after the subacute stage of ischemic stroke. CD68+ microglia/macrophages can therefore be used as a potential therapeutic target.

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    The function of microglia/macrophages after ischemic stroke is poorly understood. This study examines the role of microglia/macrophages in the focal infarct area after transient middle cerebral artery occlusion (MCAO) in rhesus monkeys. We measured infarct volume and neurological function by magnetic resonance imaging (MRI) and non-human primate stroke scale (NHPSS), respectively, to assess temporal changes following MCAO. Activated phagocytic microglia/macrophages were examined by immunohistochemistry in post-mortem brains (n=6 MCAO, n=2 controls) at 3 and 24 hours (acute stage), 2 and 4 weeks (subacute stage), and 4, and 20 months (chronic stage) following MCAO. We found that the infarct volume progressively decreased between 1 and 4 weeks following MCAO, in parallel with the neurological recovery. Greater presence of cluster of differentiation 68 (CD68)-expressing microglia/macrophages was detected in the infarct lesion in the subacute and chronic stage, compared to the acute stage. Surprisingly, 98~99% of transforming growth factor beta (TGFβ) was found colocalized with CD68-expressing cells. CD68-expressing microglia/macrophages, rather than CD206+ cells, may exert anti-inflammatory effects by secreting TGFβ after the subacute stage of ischemic stroke. CD68+ microglia/macrophages can therefore be used as a potential therapeutic target.
    Hyeon-Gu Yeo, Jung Joo Hong, Youngjeon Lee et al.
  • Review Article | October 31, 2019

    Synucleinopathies are neurodegenerative disorders characterized by the progressive accumulation of α-synuclein (α-syn) in neurons and glia and include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). In this review, we consolidate our key findings and recent studies concerning the role of Toll-like receptor 2 (TLR2), a pattern recognition innate immune receptor, in the pathogenesis of synucleinopathies. First, we address the pathological interaction of α-syn with microglial TLR2 and its neurotoxic inflammatory effects. Then, we show that neuronal TLR2 activation not only induces abnormal α-syn accumulation by impairing autophagy, but also modulates α-syn transmission. Finally, we demonstrate that administration of a TLR2 functional inhibitor improves the neuropathology and behavioral deficits of a synucleinopathy mouse model. Altogether, we present TLR2 modulation as a promising immunotherapy for synucleinopathies.

    Show more full text
    Synucleinopathies are neurodegenerative disorders characterized by the progressive accumulation of α-synuclein (α-syn) in neurons and glia and include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). In this review, we consolidate our key findings and recent studies concerning the role of Toll-like receptor 2 (TLR2), a pattern recognition innate immune receptor, in the pathogenesis of synucleinopathies. First, we address the pathological interaction of α-syn with microglial TLR2 and its neurotoxic inflammatory effects. Then, we show that neuronal TLR2 activation not only induces abnormal α-syn accumulation by impairing autophagy, but also modulates α-syn transmission. Finally, we demonstrate that administration of a TLR2 functional inhibitor improves the neuropathology and behavioral deficits of a synucleinopathy mouse model. Altogether, we present TLR2 modulation as a promising immunotherapy for synucleinopathies.
    Somin Kwon, Michiyo Iba, Eliezer Masliah and Changyoun Kim
  • Review Article | October 31, 2019

    Parkinson’s disease (PD) is the second most progressive neurodegenerative disorder of the aging population after Alzheimer’s disease (AD). Defects in the lysosomal systems and mitochondria have been suspected to cause the pathogenesis of PD. Nevertheless, the pathogenesis of PD remains obscure. Abnormal cholesterol metabolism is linked to numerous disorders, including atherosclerosis. The brain contains the highest level of cholesterol in the body and abnormal cholesterol metabolism links also many neurodegenerative disorders such as AD, PD, Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). The blood brain barrier effectively prevents uptake of lipoprotein-bound cholesterol from blood circulation. Accordingly, cholesterol level in the brain is independent from that in peripheral tissues. Because cholesterol metabolism in both peripheral tissue and the brain are quite different, cholesterol metabolism associated with neurodegeneration should be examined separately from that in peripheral tissues. Here, we review and compare cholesterol metabolism in the brain and peripheral tissues. Furthermore, the relationship between alterations in cholesterol metabolism and PD pathogenesis is reviewed.

    Show more full text
    Parkinson’s disease (PD) is the second most progressive neurodegenerative disorder of the aging population after Alzheimer’s disease (AD). Defects in the lysosomal systems and mitochondria have been suspected to cause the pathogenesis of PD. Nevertheless, the pathogenesis of PD remains obscure. Abnormal cholesterol metabolism is linked to numerous disorders, including atherosclerosis. The brain contains the highest level of cholesterol in the body and abnormal cholesterol metabolism links also many neurodegenerative disorders such as AD, PD, Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). The blood brain barrier effectively prevents uptake of lipoprotein-bound cholesterol from blood circulation. Accordingly, cholesterol level in the brain is independent from that in peripheral tissues. Because cholesterol metabolism in both peripheral tissue and the brain are quite different, cholesterol metabolism associated with neurodegeneration should be examined separately from that in peripheral tissues. Here, we review and compare cholesterol metabolism in the brain and peripheral tissues. Furthermore, the relationship between alterations in cholesterol metabolism and PD pathogenesis is reviewed.
    Uram Jin, Soo Jin Park and Sang Myun Park
  • Original Article | October 31, 2019

    The thalamus is a brain structure known to modulate sensory information before relaying to the cortex. The unique ability of a thalamocortical (TC) neuron to switch between the high frequency burst firing and single spike tonic firing has been implicated to have a key role in sensory modulation including pain. Of the two firing modes, burst firing, especially maintaining certain burst firing properties, was suggested to be critical in controlling nociceptive behaviors. Therefore, understanding the factors that influence burst firing properties would offer important insight into understanding sensory modulation. Using computational modeling, we investigated how the balance of excitatory and inhibitory inputs into a TC neuron influence TC bursting properties. We found that intensity of inhibitory inputs and the timing of excitatory input delivery control the dynamics of bursting properties. Then, to reflect a more realistic model, excitatory inputs delivered at different dendritic locations—proximal, intermediate, or distal—of a TC neuron were also investigated. Interestingly, excitatory input delivered into a distal dendrite, despite the furthest distance, had the strongest influence in shaping burst firing properties, suggesting that not all inputs equally contribute to modulating TC bursting properties. Overall, the results provide computational insights in understanding the detailed mechanism of the factors influencing temporal pattern of thalamic bursts.

    Show more full text
    The thalamus is a brain structure known to modulate sensory information before relaying to the cortex. The unique ability of a thalamocortical (TC) neuron to switch between the high frequency burst firing and single spike tonic firing has been implicated to have a key role in sensory modulation including pain. Of the two firing modes, burst firing, especially maintaining certain burst firing properties, was suggested to be critical in controlling nociceptive behaviors. Therefore, understanding the factors that influence burst firing properties would offer important insight into understanding sensory modulation. Using computational modeling, we investigated how the balance of excitatory and inhibitory inputs into a TC neuron influence TC bursting properties. We found that intensity of inhibitory inputs and the timing of excitatory input delivery control the dynamics of bursting properties. Then, to reflect a more realistic model, excitatory inputs delivered at different dendritic locations—proximal, intermediate, or distal—of a TC neuron were also investigated. Interestingly, excitatory input delivered into a distal dendrite, despite the furthest distance, had the strongest influence in shaping burst firing properties, suggesting that not all inputs equally contribute to modulating TC bursting properties. Overall, the results provide computational insights in understanding the detailed mechanism of the factors influencing temporal pattern of thalamic bursts.
    Sanggeon Park, Jeong-Woo Sohn, Jeiwon Cho and Yeowool Huh
Vol.28 No.5 | October 31, 2019
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2017 Impact Factor 3.810. 2018 Impact Factor 2.360 en Experimental Neurobiology in SCIe As of August 2017 Covered from 2015

Current Issue

  • Review Article | October 31, 2019

    Synucleinopathies are neurodegenerative disorders characterized by the progressive accumulation of α-synuclein (α-syn) in neurons and glia and include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). In this review, we consolidate our key findings and recent studies concerning the role of Toll-like receptor 2 (TLR2), a pattern recognition innate immune receptor, in the pathogenesis of synucleinopathies. First, we address the pathological interaction of α-syn with microglial TLR2 and its neurotoxic inflammatory effects. Then, we show that neuronal TLR2 activation not only induces abnormal α-syn accumulation by impairing autophagy, but also modulates α-syn transmission. Finally, we demonstrate that administration of a TLR2 functional inhibitor improves the neuropathology and behavioral deficits of a synucleinopathy mouse model. Altogether, we present TLR2 modulation as a promising immunotherapy for synucleinopathies.

    Show more full text
    Synucleinopathies are neurodegenerative disorders characterized by the progressive accumulation of α-synuclein (α-syn) in neurons and glia and include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). In this review, we consolidate our key findings and recent studies concerning the role of Toll-like receptor 2 (TLR2), a pattern recognition innate immune receptor, in the pathogenesis of synucleinopathies. First, we address the pathological interaction of α-syn with microglial TLR2 and its neurotoxic inflammatory effects. Then, we show that neuronal TLR2 activation not only induces abnormal α-syn accumulation by impairing autophagy, but also modulates α-syn transmission. Finally, we demonstrate that administration of a TLR2 functional inhibitor improves the neuropathology and behavioral deficits of a synucleinopathy mouse model. Altogether, we present TLR2 modulation as a promising immunotherapy for synucleinopathies.
    Somin Kwon, Michiyo Iba, Eliezer Masliah and Changyoun Kim
  • Review Article | October 31, 2019

    Parkinson’s disease (PD) is the second most progressive neurodegenerative disorder of the aging population after Alzheimer’s disease (AD). Defects in the lysosomal systems and mitochondria have been suspected to cause the pathogenesis of PD. Nevertheless, the pathogenesis of PD remains obscure. Abnormal cholesterol metabolism is linked to numerous disorders, including atherosclerosis. The brain contains the highest level of cholesterol in the body and abnormal cholesterol metabolism links also many neurodegenerative disorders such as AD, PD, Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). The blood brain barrier effectively prevents uptake of lipoprotein-bound cholesterol from blood circulation. Accordingly, cholesterol level in the brain is independent from that in peripheral tissues. Because cholesterol metabolism in both peripheral tissue and the brain are quite different, cholesterol metabolism associated with neurodegeneration should be examined separately from that in peripheral tissues. Here, we review and compare cholesterol metabolism in the brain and peripheral tissues. Furthermore, the relationship between alterations in cholesterol metabolism and PD pathogenesis is reviewed.

    Show more full text
    Parkinson’s disease (PD) is the second most progressive neurodegenerative disorder of the aging population after Alzheimer’s disease (AD). Defects in the lysosomal systems and mitochondria have been suspected to cause the pathogenesis of PD. Nevertheless, the pathogenesis of PD remains obscure. Abnormal cholesterol metabolism is linked to numerous disorders, including atherosclerosis. The brain contains the highest level of cholesterol in the body and abnormal cholesterol metabolism links also many neurodegenerative disorders such as AD, PD, Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). The blood brain barrier effectively prevents uptake of lipoprotein-bound cholesterol from blood circulation. Accordingly, cholesterol level in the brain is independent from that in peripheral tissues. Because cholesterol metabolism in both peripheral tissue and the brain are quite different, cholesterol metabolism associated with neurodegeneration should be examined separately from that in peripheral tissues. Here, we review and compare cholesterol metabolism in the brain and peripheral tissues. Furthermore, the relationship between alterations in cholesterol metabolism and PD pathogenesis is reviewed.
    Uram Jin, Soo Jin Park and Sang Myun Park
  • Original Article | October 31, 2019

    The thalamus is a brain structure known to modulate sensory information before relaying to the cortex. The unique ability of a thalamocortical (TC) neuron to switch between the high frequency burst firing and single spike tonic firing has been implicated to have a key role in sensory modulation including pain. Of the two firing modes, burst firing, especially maintaining certain burst firing properties, was suggested to be critical in controlling nociceptive behaviors. Therefore, understanding the factors that influence burst firing properties would offer important insight into understanding sensory modulation. Using computational modeling, we investigated how the balance of excitatory and inhibitory inputs into a TC neuron influence TC bursting properties. We found that intensity of inhibitory inputs and the timing of excitatory input delivery control the dynamics of bursting properties. Then, to reflect a more realistic model, excitatory inputs delivered at different dendritic locations—proximal, intermediate, or distal—of a TC neuron were also investigated. Interestingly, excitatory input delivered into a distal dendrite, despite the furthest distance, had the strongest influence in shaping burst firing properties, suggesting that not all inputs equally contribute to modulating TC bursting properties. Overall, the results provide computational insights in understanding the detailed mechanism of the factors influencing temporal pattern of thalamic bursts.

    Show more full text
    The thalamus is a brain structure known to modulate sensory information before relaying to the cortex. The unique ability of a thalamocortical (TC) neuron to switch between the high frequency burst firing and single spike tonic firing has been implicated to have a key role in sensory modulation including pain. Of the two firing modes, burst firing, especially maintaining certain burst firing properties, was suggested to be critical in controlling nociceptive behaviors. Therefore, understanding the factors that influence burst firing properties would offer important insight into understanding sensory modulation. Using computational modeling, we investigated how the balance of excitatory and inhibitory inputs into a TC neuron influence TC bursting properties. We found that intensity of inhibitory inputs and the timing of excitatory input delivery control the dynamics of bursting properties. Then, to reflect a more realistic model, excitatory inputs delivered at different dendritic locations—proximal, intermediate, or distal—of a TC neuron were also investigated. Interestingly, excitatory input delivered into a distal dendrite, despite the furthest distance, had the strongest influence in shaping burst firing properties, suggesting that not all inputs equally contribute to modulating TC bursting properties. Overall, the results provide computational insights in understanding the detailed mechanism of the factors influencing temporal pattern of thalamic bursts.
    Sanggeon Park, Jeong-Woo Sohn, Jeiwon Cho and Yeowool Huh

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Volume 28, Number 5, October 2019

Review Articles

547 Targeting Microglial and Neuronal Toll-like Receptor 2 in Synucleinopathies

Somin Kwon, Michiyo Iba, Eliezer Masliah and Changyoun Kim

Innate immune receptor Toll-like receptor 2 has been implicated in synucleinopathies such as Parkinson’s disease and dementia with Lewy bodies. Our recent work demonstrates the pathogenic interaction between α-syn and TLR2 on microglia and neurons to modulate neuroinflammation, α-synuclein deposition, and neurodegeneration. Modulation of TLR2 thus holds significant promise as a novel immunotherapeutic strategy against synucleinopathies.

554 Cholesterol Metabolism in the Brain and Its Association with Parkinson’s Disease

Uram Jin, Soo Jin Park and Sang Myun Park

The brain contains the highest level of cholesterol in the body and abnormal cholesterol metabolism links also many neurodegenerative disorders. Because cholesterol metabolism in both peripheral tissue and the brain are quite different, cholesterol metabolism associated with neurodegeneration should be examined separately from that in peripheral tissues. Here, we review cholesterol metabolism in the brain and peripheral tissues and summarize the relationship between alterations in cholesterol metabolism and PD pathogenesis is reviewed.

Original Articles

568 A Computational Modeling Reveals that Strength of Inhibitory Input, E/I Balance, and Distance of Excitatory Input Modulate Thalamocortical Bursting Properties

Sanggeon Park, Jeong-Woo Sohn, Jeiwon Cho and Yeowool Huh

Conditions affecting bursting properties were analyzed with computational modeling, since maintaining specific thalamic bursting properties is suggested to be critical for gating sensory information. Characteristics of inhibitory input, the balance of excitatory and inhibitory inputs, and excitatory inputs delivered at different dendritic locations affected thalamic bursting properties, which determines modulation power.

578 Modulation of Dopaminergic Neuronal Excitability by Zinc through the Regulation of Calcium-related Channels

Jihyun Noh and Jun-mo Chung

Zinc-induced augmentation of firing activity was mediated through the inhibition of small-conductance calcium-activated potassium channels with contributions from voltage-gated L-type calcium channels (VGCCs) and ryanodine receptors, as well as by the activation of VGCCs via melastatin-like transient receptor potential channels.

593 3-Carene, a Phytoncide from Pine Tree has a Sleep-enhancing Effect by Targeting the GABAA-benzodiazepine Receptors

Junsung Woo, Hyejin Yang, Minseok Yoon, Changdev G. Gadhe, Ae Nim Pae, Suengmok Cho and C. Justin Lee

3-carene, a phytoncide and a bicyclic monoterpene of the pine tree oils, shows sleep-enhancing effects by acting as a positive modulator for GABAA-BZD receptor.

602 Combination of In Vivo [123I]FP-CIT SPECT and Microdialysis Reveals an Antipsychotic Drug Haloperidol-induced Synaptic Dopamine Availability in the Rat Midbrain and Striatum

So Hyeon Park, Yoo Sung Song, Byung Seok Moon, Byung Chul Lee, Hyun Soo Park and Sang Eun Kim

This study demonstrates that [123I]FP-CIT SPECT may be a useful preclinical technique for detecting increases in synaptic DA availability induced by haloperidol treatment in both the midbrain and the striatum, with results comparable to those obtained by in vivo microdialysis.

612 Transduced Tat-aldose Reductase Protects Hippocampal Neuronal Cells against Oxidative Stress-induced Damage

Su Bin Cho, Won Sik Eum, Min Jea Shin, Hyun Jung Kwon, Jung Hwan Park, Yeon Joo Choi, Jinseu Park, Kyu Hyung Han, Ju Hyeon Kang, Duk-Soo Kim, Sung-Woo Cho, Dae Won Kim and Soo Young Choi

Although aldose reductase (AR) have been considered as therapeutic agents for ischemia, the limitation is to deliver of this protein into target cells. Thus, protein transduction domain fused cell permeable Tat-AR fusion protein may overcome this challenge and help to realize the potential of AR for application as a therapeutic protein. In this study, we found that Tat-AR protein transduced into hippocampal CA1 region, passing through the BBB, and markedly inhibited hippocampal neuronal cell death induced by ischemic injury. Therefore, we suggest that Tat-AR protein could be used as potential therapeutic agent for ischemic injury.

628 LGR5 and Downstream Intracellular Signaling Proteins Play Critical Roles in the Cell Proliferation of Neuroblastoma, Meningioma and Pituitary Adenoma

Mina Hwang, Myung-Hoon Han, Hyun-Hee Park, Hojin Choi, Kyu-Yong Lee, Young Joo Lee, Jae Min Kim, Jin Hwan Cheong, Je Il Ryu, Kyueng-Whan Min, Young-Ha Oh, Yong Ko and Seong-Ho Koh

Our results may suggest a possible connection between LGR5 and its downstream signaling and neuroblastoma and brain tumors such as meningioma and pituitary adenoma. We hypothesized that activation of Wnt/β-catenin signaling by LGR5 activation may activate the hnRNP family and this process may result in hyperactivation of alternative pre-mRNA processing in human meningioma and pituitary adenoma.