Publications by authors named "Hee Sup Shin"

172 Publications

Affective empathy and prosocial behavior in rodents.

Curr Opin Neurobiol 2021 06 3;68:181-189. Epub 2021 Jun 3.

Center for Cognition and Sociality, Institute for Basic Science (IBS), 55 Expo-ro, Yuseong-gu, Daejeon, 34126, Republic of Korea. Electronic address:

Empathy is an essential function for humans as social animals. Emotional contagion, the basic form of afffective empathy, comprises the cognitive process of perceiving and sharing the affective state of others. The observational fear assay, an animal model of emotional contagion, has enabled researchers to undertake molecular, cellular, and circuit mechanism of this behavior. Such studies have revealed that observational fear is mediated through neural circuits involved in processing the affective dimension of direct pain experiences. A mouse can also respond to milder social stimuli induced by either positive or negative emotional changes in another mouse, which seems not dependent on the affective pain circuits. Further studies should explore how different neural circuits contribute to integrating different dimensions of affective empathy.
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http://dx.doi.org/10.1016/j.conb.2021.05.002DOI Listing
June 2021

The Protective Effects of Statins Towards Vessel Wall Injury Caused by a Stent Retrieving Mechanical Thrombectomy Device : A Histological Analysis of the Rabbit Carotid Artery Model.

J Korean Neurosurg Soc 2021 May 14. Epub 2021 May 14.

Department of Neurosurgery, Veterans Health Service Medical Center, Seoul, Korea.

Objective: Endovascular mechanical thrombectomy (MT) has been regarded as one of the standard treatments for acute ischemic stroke caused by large vessel occlusion. Despite the wide use of stent retrievers for MT, arterial intimal damage caused when deployed stent is pulled has been a certain disadvantage. We hypothesized that statin could protect and stabilize vessel damage after endovascular MT using a stent retriever. In this animal study, we observed the protective effects of the statins towards MT-induced vessel wall injury.

Methods: Twenty-eight carotid arteries of fourteen rabbits were used in the experiments with MT using stent retriever. We divided the rabbits into four groups as follows : group 1, negative control; group 2, positive control; group 3, statin before MT; and group 4, statin after MT. After MT procedures, we harvested the carotid arteries and performed histomorphological and immunohistochemical analyses.

Results: In histomorphological analysis with hematoxylin and eosin and Masson's trichrome stain, significant intimal thickening (p<0.05) was observed in the positive control (group 2), compared to in the negative control (group 1). Intimal thickening was improved in the statin-administered groups (groups 3 and 4 vs. group 2, p<0.05). We also observed that statin administration after MT (group 4) resulted in a more effective decrease in intimal thickness than statin administration before MT (group 3) (p<0.05). We performed immunohistochemical analysis with the antibodies for tumor necrosis factor-alpha (TNF-α), cluster of differentiation (CD)11b, and CD163. In contrast to the negative control (group 1), the stained percentage areas of all immunological markers were markedly increased in the positive control (group 2) (p<0.05). Based on statin administration, the percentage area of TNF-α staining was significantly reduced (p<0.05) in group 3, compared to the positive control group (group 2). However, significant differences were not observed for CD11b and CD163 staining. In group 4, no significant differences were observed for TNF-α, CD11b, and CD163 staining (p≥0.05). The differences in the percentage areas of the different markers between the statin-administered groups (groups 3 and 4) were also not revealed.

Conclusion: We presented that statin administration before and after MT exerted protective effects towards vessel wall injury. The efficacy of statins was greater post-administration than pre-administration. Thus, statin administration in routine prescriptions in the peri-procedural period is strongly advised.
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http://dx.doi.org/10.3340/jkns.2020.0303DOI Listing
May 2021

Treatment for Hemifacial Spasm Associated with a Dissecting Vertebral Artery Aneurysm Requiring Microvascular Decompression in Addition to Endovascular Trapping: A Case Report with Literature Review.

J Neurol Surg A Cent Eur Neurosurg 2021 Mar 9. Epub 2021 Mar 9.

Department of Neurosurgery, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea.

Background:  The treatment protocol for hemifacial spasm (HFS) associated with dissecting vertebral artery aneurysm (DVAA) has not been established.

Case Description:  A-42-year-old man with left HFS underwent endovascular trapping for a DVAA that was identified on brain imaging. Although the dissecting segment was treated successfully, the HFS persisted for 3 months, and subsequently microvascular decompression (MVD) was needed. The posteroinferior cerebellar artery (PICA) was found to be interposed between the root exit zone of the facial nerve and DVAA during surgery. After pulling out the PICA, the HFS ceased immediately.

Conclusion:  HFS associated with DVAA should be considered carefully before formulating a treatment strategy. Moreover, the cause of pulsatile compression may not be visible on brain imaging, and MVD surgery may be indicated in such cases.
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http://dx.doi.org/10.1055/s-0040-1721681DOI Listing
March 2021

Facial Nerve Indentation in Hemifacial Spasm: An Analysis of Factors Contributing to the Formation of and Consequent Effects Associated with Indentation.

World Neurosurg 2021 02 24;146:e1083-e1091. Epub 2020 Nov 24.

Department of Neurosurgery, Stroke and Neurological Disorders Centre, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, Korea.

Background: An indentation, designating a furrowed hole on the facial nerve, has been used in many studies for locating pathophysiology and assessing relevant clinical outcomes after microvascular decompression for hemifacial spasm (HFS). In this study, we sought to elucidate the contributing factors forming indentation on the facial nerve and the consequent effect of having indentation on the clinical course.

Methods: We divided the patients into 2 groups: group A, the patients who had no indentation on the root exit zone of the facial nerve; and group B, the patients who had an indentation. Demographic data, intraoperative findings, and clinical outcomes were analyzed from retrospective review of the medical records.

Results: Of the 132 patients, 47.0% had an indentation on the facial nerve. Our statistical analyses showed that the preoperative symptom period, compression location, and compression pattern were associated with the occurrence of the indentation. Also, we showed that HFS reappearance developed more frequently in patients in group B, who needed more time for the resolution of HFS. The final clinical outcome was less influenced by the existence of the indentation, although it was slightly poorer for group B than for group A.

Conclusions: The indentation on the facial nerve was associated with longer duration of symptoms, the presence of compression in the proximal segment of the root exit zone, and loop-type pattern of compression. More patients with indentation experienced the HFS reappearance phenomenon, which lasted longer than in those who had no indentation.
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http://dx.doi.org/10.1016/j.wneu.2020.11.086DOI Listing
February 2021

Spatial and temporal diversity of glycome expression in mammalian brain.

Proc Natl Acad Sci U S A 2020 11 2;117(46):28743-28753. Epub 2020 Nov 2.

Graduate School of Analytical Science & Technology, Chungnam National University, 34134 Daejeon, South Korea;

Mammalian brain glycome remains a relatively poorly understood area compared to other large-scale "omics" studies, such as genomics and transcriptomics due to the inherent complexity and heterogeneity of glycan structure and properties. Here, we first performed spatial and temporal analysis of glycome expression patterns in the mammalian brain using a cutting-edge experimental tool based on liquid chromatography-mass spectrometry, with the ultimate aim to yield valuable implications on molecular events regarding brain functions and development. We observed an apparent diversity in the glycome expression patterns, which is spatially well-preserved among nine different brain regions in mouse. Next, we explored whether the glycome expression pattern changes temporally during postnatal brain development by examining the prefrontal cortex (PFC) at different time point across six postnatal stages in mouse. We found that glycan expression profiles were dynamically regulated during postnatal developments. A similar result was obtained in PFC samples from humans ranging in age from 39 d to 49 y. Novel glycans unique to the brain were also identified. Interestingly, changes primarily attributed to sialylated and fucosylated glycans were extensively observed during PFC development. Finally, based on the vast heterogeneity of glycans, we constructed a core glyco-synthesis map to delineate the glycosylation pathway responsible for the glycan diversity during the PFC development. Our findings reveal high levels of diversity in a glycosylation program underlying brain region specificity and age dependency, and may lead to new studies exploring the role of glycans in spatiotemporally diverse brain functions.
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http://dx.doi.org/10.1073/pnas.2014207117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682437PMC
November 2020

Predicting Arachnoid Membrane Descent in the Chiasmatic Cistern in the Treatment of Pituitary Macroadenoma.

J Korean Neurosurg Soc 2021 Jan 27;64(1):110-119. Epub 2020 Oct 27.

Stroke and Neurological Disorders Centre, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, Korea.

Objective: Preoperative prediction of the arachnoid membrane descent in pituitary surgery is useful for achieving gross total removal and avoiding cerebrospinal fluid leakage resulting from tearing of the arachnoid membrane in the chiasmatic cistern. In this study, we analyzed the patterns of arachnoid membrane descent during or after pituitary tumor surgery and identified the factors related to this descent.

Methods: Analysis was restricted to pituitary macroadenomas not extending into the third ventricle or over the internal carotid artery. To minimize confounding factors, patients who underwent revision surgery, those who had a torn arachnoid during operation or small medial diaphragma sellae (DS) opening, and subtotal resections were excluded. We enrolled 41 consecutive patients in this retrospective analysis. The degree of arachnoid descent was categorized using intraoperative videos. Preoperative magnetic resonance findings, including tumor height, suprasellar extension, and variables including DS area and medial opening size, tumor composition, and displacement of the pituitary stalk and gland were evaluated to determine their correlations with arachnoid membrane descent.

Results: Arachnoid membrane descent was significantly correlated with DS area and medial opening size. Based on T2-weighted images (T2WI) magnetic resonance (MR) images, tumor composition was significantly associated with arachnoid membrane descent. Other factors were not significantly correlated with arachnoid membrane descent.

Conclusion: T2WI of tumor composition and preoperative MR imaging of DS area and medial opening provided valuable information regarding arachnoid membrane descent. These parameters may serve as fundamental measures to facilitate complete resection of pituitary macroadenomas.
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http://dx.doi.org/10.3340/jkns.2020.0140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819790PMC
January 2021

Efficacy of Acupuncture Treatment to Prevent Cerebral Vasospasm After Subarachnoid Hemorrhage: A Double-Blind, Randomized Placebo-Controlled Trial.

J Altern Complement Med 2020 Dec 1;26(12):1182-1189. Epub 2020 Sep 1.

Department of Cardiology and Neurology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.

To investigate the efficacy of acupuncture in preventing cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) and explore its underlying mechanism. A randomized, double-blinded, and placebo-controlled trial. Subjects were recruited from Kyung Hee University Hospital at Gangdong, Seoul, Korea A total of 50 patients admitted with acute SAH. The study group received acupuncture treatments ( = 25), while the control group underwent mock transcutaneous electrical nerve stimulation and sham acupuncture ( = 25) six times/week for 2 weeks. The primary outcome was the incidence of delayed ischemic neurologic deficit (DIND), and secondary measurements included angiographic vasospasm, vasospasm-related infarction, modified Rankin Scale score, and plasma nitric oxide (NO) and endothelin-1 (ET-1) levels. The study group treated with acupuncture showed a lower incidence of DIND (9.1%) than the control group (20.8%); however, this difference in the incidence of DIND was not statistically significant. The study group demonstrated better clinical outcomes, especially in functional recovery. Significant alterations in plasma NO and ET-1 levels after the 2-week intervention were observed only in the study group. Their study shows that acupuncture treatment improved functional recovery after SAH and could potentially prevent cerebral vasospasm. These effects could be attributed to the recovery of endothelial dysfunction by acupuncture through modulating the plasma NO and ET-1 levels. The study protocol has been registered on www.clinicaltrials.gov (NCT02275949).
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http://dx.doi.org/10.1089/acm.2020.0156DOI Listing
December 2020

Acupuncture attenuates postoperative inflammation in patients after craniotomy: A prospective, open-label, controlled trial.

Medicine (Baltimore) 2020 Mar;99(11):e19071

Stroke and Neurological Disorders Center, Kyung Hee University Hospital at Gangdong.

Background: It is important to manage inflammation after craniotomy. It may be prudent to reduce the excessive usage of antibiotics and to add supplementary treatments like acupuncture, which would be effective and safe. However, there are only a few studies available to date on the effects of acupuncture on anti-inflammatory response after craniotomy. The aim of this study was to explore the anti-inflammatory effects of acupuncture in patients after a craniotomy.

Methods: This study was a single-center, prospective, open-label, controlled trial. Forty-four subjects who underwent craniotomy for an unruptured aneurysm, facial spasm, or brain tumor were allocated to either an acupuncture group or a control group. Both groups received postoperative routine care in the Department of Neurosurgery. The subjects in the acupuncture group also received a total of 6 acupuncture treatments sessions within 8 days after craniotomy. Acupuncture treatments included acupuncture, electroacupuncture, and intradermal acupuncture. The serum interleukin (IL)-1β and IL-6, tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and erythrocyte sedimentation rate levels were assessed four times within 7 days after surgery. The presence of fever, use of additional antibiotics, presence of infection including pneumonia or urinary tract infection, and safety were also reviewed.

Results: The IL-1β levels of subjects who underwent aneurysmal clipping were significantly lower in the acupuncture group (P = .02). TNF-α levels of subjects who underwent aneurysmal clipping at the seventh postoperative day were also significantly lower in the acupuncture group (P = .03). Six cases of fever of unknown origin were observed in the control group, while none were seen in the acupuncture group, revealing that the incidence of fever was significantly lower in the acupuncture group (P = .02). No adverse events occurred during the trial.

Conclusion: Acupuncture showed a possibility of alleviating inflammation by attenuating the levels of proinflammatory cytokines and significantly reduced the incidence of fever of unknown origin in patients after craniotomy. Acupuncture would be suitable as an adjunctive therapy to alleviate inflammation after craniotomy.
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http://dx.doi.org/10.1097/MD.0000000000019071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440145PMC
March 2020

Non-invasive optical control of endogenous Ca channels in awake mice.

Nat Commun 2020 01 10;11(1):210. Epub 2020 Jan 10.

Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.

Optogenetic approaches for controlling Ca channels provide powerful means for modulating diverse Ca-specific biological events in space and time. However, blue light-responsive photoreceptors are, in principle, considered inadequate for deep tissue stimulation unless accompanied by optic fiber insertion. Here, we present an ultra-light-sensitive optogenetic Ca modulator, named monSTIM1 encompassing engineered cryptochrome2 for manipulating Ca signaling in the brain of awake mice through non-invasive light delivery. Activation of monSTIM1 in either excitatory neurons or astrocytes of mice brain is able to induce Ca-dependent gene expression without any mechanical damage in the brain. Furthermore, we demonstrate that non-invasive Ca modulation in neurons can be sufficiently and effectively translated into changes in behavioral phenotypes of awake mice.
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http://dx.doi.org/10.1038/s41467-019-14005-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954201PMC
January 2020

The rostroventral part of the thalamic reticular nucleus modulates fear extinction.

Nat Commun 2019 10 11;10(1):4637. Epub 2019 Oct 11.

Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, 305-338, Korea.

The thalamus has been implicated in fear extinction, yet the role of the thalamic reticular nucleus (TRN) in this process remains unclear. Here, in mice, we show that the rostroventral part of the TRN (TRNrv) is critically involved in the extinction of tone-dependent fear memory. Optogenetic excitation of TRNrv neurons during extinction learning dramatically facilitated, whereas the inhibition disrupted, the fear extinction. Single unit recordings demonstrated that TRNrv neurons selectively respond to conditioned stimuli but not to neutral stimuli. TRNrv neurons suppressed the spiking activity of the medial part of the dorsal midline thalamus (dMTm), and a blockade of this inhibitory pathway disrupted fear extinction. Finally, we found that the suppression of dMTm projections to the central amygdala promotes fear extinction, and TRNrv neurons have direct connections to this pathway. Our results uncover a previously unknown function of the TRN and delineate the neural circuit for thalamic control of fear memory.
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http://dx.doi.org/10.1038/s41467-019-12496-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789150PMC
October 2019

Neural Basis of Observational Fear Learning: A Potential Model of Affective Empathy.

Neuron 2019 10;104(1):78-86

Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Republic of Korea. Electronic address:

Observational fear learning in rodents is a type of context-dependent fear conditioning in which an unconditioned stimulus (US) is provided vicariously by observing conspecific others receiving foot shocks. This suggests the involvement of affective empathy, with several recent studies showing many similarities between this behavior and human empathy. Neurobiologically, it is important to understand the neural mechanisms by which the vicarious US activates the fear circuit via the affective pain system, obviating the sensory pain pathway and eventually leading to fear memory formation. This paper reviews current studies on the neural mechanisms underlying observational fear learning and provides a perspective on future research on this subject.
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http://dx.doi.org/10.1016/j.neuron.2019.09.013DOI Listing
October 2019

Neural circuits underlying a psychotherapeutic regimen for fear disorders.

Nature 2019 02 13;566(7744):339-343. Epub 2019 Feb 13.

Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, South Korea.

A psychotherapeutic regimen that uses alternating bilateral sensory stimulation (ABS) has been used to treat post-traumatic stress disorder. However, the neural basis that underlies the long-lasting effect of this treatment-described as eye movement desensitization and reprocessing-has not been identified. Here we describe a neuronal pathway driven by the superior colliculus (SC) that mediates persistent attenuation of fear. We successfully induced a lasting reduction in fear in mice by pairing visual ABS with conditioned stimuli during fear extinction. Among the types of visual stimulation tested, ABS provided the strongest fear-reducing effect and yielded sustained increases in the activities of the SC and mediodorsal thalamus (MD). Optogenetic manipulation revealed that the SC-MD circuit was necessary and sufficient to prevent the return of fear. ABS suppressed the activity of fear-encoding cells and stabilized inhibitory neurotransmission in the basolateral amygdala through a feedforward inhibitory circuit from the MD. Together, these results reveal the neural circuit that underlies an effective strategy for sustainably attenuating traumatic memories.
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http://dx.doi.org/10.1038/s41586-019-0931-yDOI Listing
February 2019

Genetic factors associated with empathy in humans and mice.

Neuropharmacology 2019 11 1;159:107514. Epub 2019 Feb 1.

Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, Republic of Korea. Electronic address:

The neurocognitive ability to recognize and share the mental states of others is crucial for our emotional experience and social interaction. Extensive human studies have informed our understanding of the psychobehavioral and neurochemical bases of empathy. Recent evidence shows that simple forms of empathy are conserved from rodents to humans, and rodent models have become particularly useful for understanding the neurobiological correlates of empathy. In this review, we first summarize aspects of empathy at the behavioral and neural circuit levels, and describe recent developments in rodent model behavioral paradigms. We then highlight different neurobiological pathways involved in empathic abilities, with special emphasis on genetic polymorphisms associated with individual differences in empathy. By directly assessing various neurochemical correlates at molecular and neural circuit levels using relevant animal models, we conclude with the suggestion that rodent research can significantly advance our understanding of the neural basis of empathy. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'.
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http://dx.doi.org/10.1016/j.neuropharm.2019.01.029DOI Listing
November 2019

Noninvasive optical activation of Flp recombinase for genetic manipulation in deep mouse brain regions.

Nat Commun 2019 01 18;10(1):314. Epub 2019 Jan 18.

Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.

Spatiotemporal control of gene expression or labeling is a valuable strategy for identifying functions of genes within complex neural circuits. Here, we develop a highly light-sensitive and efficient photoactivatable Flp recombinase (PA-Flp) that is suitable for genetic manipulation in vivo. The highly light-sensitive property of PA-Flp is ideal for activation in deep mouse brain regions by illumination with a noninvasive light-emitting diode. In addition, PA-Flp can be extended to the Cre-lox system through a viral vector as Flp-dependent Cre expression platform, thereby activating both Flp and Cre. Finally, we demonstrate that PA-Flp-dependent, Cre-mediated Ca3.1 silencing in the medial septum increases object-exploration behavior in mice. Thus, PA-Flp is a noninvasive, highly efficient, and easy-to-use optogenetic module that offers a side-effect-free and expandable genetic manipulation tool for neuroscience research.
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http://dx.doi.org/10.1038/s41467-018-08282-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338782PMC
January 2019

Noninvasive optical activation of Flp recombinase for genetic manipulation in deep mouse brain regions.

Nat Commun 2019 01 18;10(1):314. Epub 2019 Jan 18.

Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.

Spatiotemporal control of gene expression or labeling is a valuable strategy for identifying functions of genes within complex neural circuits. Here, we develop a highly light-sensitive and efficient photoactivatable Flp recombinase (PA-Flp) that is suitable for genetic manipulation in vivo. The highly light-sensitive property of PA-Flp is ideal for activation in deep mouse brain regions by illumination with a noninvasive light-emitting diode. In addition, PA-Flp can be extended to the Cre-lox system through a viral vector as Flp-dependent Cre expression platform, thereby activating both Flp and Cre. Finally, we demonstrate that PA-Flp-dependent, Cre-mediated Ca3.1 silencing in the medial septum increases object-exploration behavior in mice. Thus, PA-Flp is a noninvasive, highly efficient, and easy-to-use optogenetic module that offers a side-effect-free and expandable genetic manipulation tool for neuroscience research.
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http://dx.doi.org/10.1038/s41467-018-08282-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338782PMC
January 2019

Yin-and-yang bifurcation of opioidergic circuits for descending analgesia at the midbrain of the mouse.

Proc Natl Acad Sci U S A 2018 10 8;115(43):11078-11083. Epub 2018 Oct 8.

Center for Cognition and Sociality, Institute for Basic Science, 34141 Daejeon, Korea;

In the descending analgesia pathway, opioids are known to disinhibit the projections from the periaqueductal gray (PAG) to the rostral ventromedial medulla (RVM), leading to suppression of pain signals at the spinal cord level. The locus coeruleus (LC) has been proposed to engage in the descending pathway through noradrenergic inputs to the spinal cord. Nevertheless, how the LC is integrated in the descending analgesia circuit has remained unknown. Here, we show that the opioidergic analgesia pathway is bifurcated in structure and function at the PAG. A knockout as well as a PAG-specific knockdown of phospholipase C β4 (PLCβ4), a signaling molecule for G protein-coupled receptors, enhanced swim stress-induced and morphine-induced analgesia in mice. Immunostaining after simultaneous retrograde labeling from the RVM and the LC revealed two mutually exclusive neuronal populations at the PAG, each projecting either to the LC or the RVM, with PLCβ4 expression only in the PAG-LC projecting cells that provide a direct synaptic input to LC-spinal cord (SC) projection neurons. The PAG-LC projection neurons in wild-type mice turned quiescent in response to opiates, but remained active in the PLCβ4 mutant, suggesting a possibility that an increased adrenergic function induced by the persistent PAG-LC activity underlies the enhanced opioid analgesia in the mutant. Indeed, the enhanced analgesia in the mutant was reversed by blocking α2-noradrenergic receptors. These findings indicate that opioids suppress descending analgesia through the PAG-LC pathway, while enhancing it through the PAG-RVM pathway, i.e., two distinct pathways with opposing effects on opioid analgesia. These results point to a therapeutic target in pain control.
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http://dx.doi.org/10.1073/pnas.1806082115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205495PMC
October 2018

Observational fear behavior in rodents as a model for empathy.

Genes Brain Behav 2019 01 12;18(1):e12521. Epub 2018 Oct 12.

Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, Republic of Korea.

Empathy enables social mammals to recognize and share emotion with others and is well-documented in non-human primates. During the past few years, systematic observations have showed that a primal form of empathy also exists in rodents, indicating that empathy has an evolutionary continuity. Now, using rodents exhibiting emotional empathy, the molecular and cellular study of empathy in animals has begun in earnest. In this article, we will review recent reports that indicate that rodents can share states of fear with others, and will try to highlight new understandings of the neural circuitry, biochemistry and genetics of empathic fear. We hope that the use of rodent models will enhance understanding of the mechanisms of human empathy and provide insights into how to treat social deficits in neuropsychiatric disorders characterized by empathy impairment.
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http://dx.doi.org/10.1111/gbb.12521DOI Listing
January 2019

The Possible Role of Neurobeachin in Extinction of Contextual Fear Memory.

Sci Rep 2018 09 13;8(1):13752. Epub 2018 Sep 13.

Center for Cognition and Sociality, Institute for Basic Science, Daejeon, 34047, Republic of Korea.

Established fear memory becomes vulnerable to disruption after memory retrieval and extinction; this labile state is critical for inhibiting the return of fear memory. However, the labile state has a very narrow time window after retrieval, and underlying molecular mechanisms are not well known. To that end, we isolated the hippocampus immediately after fear memory retrieval and performed proteomics. We identified Neurobeachin (NBEA), an autism-related regulator of synaptic protein trafficking, to be upregulated after contextual fear memory retrieval. NBEA protein expression was rapid and transient after fear memory retrieval at the synapse. Nbea mRNA was enriched at the synapses, and the rapid induction of NBEA expression was blocked by inhibition of the mammalian target of rapamycin (mTOR)-dependent signaling pathway. Mice with cornu ammonis 1 (CA1)-specific Nbea shRNA knockdown showed normal fear acquisition and contextual fear memory but impaired extinction, suggesting an important role of Nbea in fear memory extinction processes. Consistently, Nbea heterozygotes showed normal fear acquisition and fear memory recall but showed impairment in extinction. Our data suggest that NBEA is necessary either for induction of memory lability or for the physiological process of memory extinction.
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http://dx.doi.org/10.1038/s41598-018-30589-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137154PMC
September 2018

Characteristic Signs on T2*-Based Imaging and Their Relationship with Results of Reperfusion Therapy for Acute Ischemic Stroke: A Systematic Review and Evidence to Date.

Neurointervention 2018 Sep 31;13(2):90-99. Epub 2018 Aug 31.

Department of Radiology, Kyung Hee University Hospital, School of Medicine, Kyung Hee University, Seoul, Korea.

Purpose: Characteristic signs - the susceptibility vessel sign (SVS) and the prominent hypointense vessel sign (PHVS) - on T2*-based magnetic resonance imaging (T2*MRI) can be seen for acute ischemic stroke with large artery occlusion. In this study, we investigated the evidence to support our hypothesis that these findings may help to predict outcomes after reperfusion therapy.

Materials And Methods: We searched for papers describing SVS and PHVS in patients treated with reperfusion therapy for acute ischemic stroke, and their functional/radiologic outcomes were systematically reviewed.

Results: Nine studies on the SVS and six studies on the PHVS were included. The pooled odds ratio (OR) of recanalization after intravenous thrombolysis or mechanical thrombectomy was not significantly different with the presence of SVS (OR, 0.615; 95% confidence interval [CI], 0.335-1.131 and OR, 0.993; 95% CI, 0.629-1.567). The OR of favorable functional outcome after reperfusion therapy in terms of the presence of PHVS varied (0.083 to 1.831) by study.

Conclusion: Our meta-analysis of the published data showed that a SVS was not a predictive factor for recanalization after reperfusion therapy for acute ischemic stroke. Currently, the data available on T2*MRI are too limited to warrant reperfusion therapy in routine practice. More data are needed from studies with randomized treatment allocation to determine the role of T2*MRI.
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http://dx.doi.org/10.5469/neuroint.2018.01039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132033PMC
September 2018

LARGE, an intellectual disability-associated protein, regulates AMPA-type glutamate receptor trafficking and memory.

Proc Natl Acad Sci U S A 2018 07 18;115(27):7111-7116. Epub 2018 Jun 18.

Center for Cognition and Sociality, Institute for Basic Science, 34141 Daejeon, Republic of Korea;

Mutations in the human LARGE gene result in severe intellectual disability and muscular dystrophy. How mutation leads to intellectual disability, however, is unclear. In our proteomic study, LARGE was found to be a component of the AMPA-type glutamate receptor (AMPA-R) protein complex, a main player for learning and memory in the brain. Here, our functional study of LARGE showed that LARGE at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to down-regulated surface and synaptic AMPA-R targeting. In knockdown mice, long-term potentiation (LTP) was occluded by synaptic AMPA-R overloading, resulting in impaired contextual fear memory. These findings indicate that the fine-tuning of AMPA-R trafficking by LARGE at the Golgi is critical for hippocampus-dependent memory in the brain. Our study thus provides insights into the pathophysiology underlying cognitive deficits in brain disorders associated with intellectual disability.
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http://dx.doi.org/10.1073/pnas.1805060115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142281PMC
July 2018

Overcoming Depression by Inhibition of Neural Burst Firing.

Neuron 2018 06;98(5):878-879

Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea. Electronic address:

The N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine has been found to have rapid and long-lasting antidepressive effects. Two elegant studies from Hailan Hu's laboratory (Cui et al., 2018; Yang et al., 2018) showed that ketamine blocks burst firing of neurons in the lateral habenula (LHb), rapidly relieving symptoms of depression.
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http://dx.doi.org/10.1016/j.neuron.2018.05.032DOI Listing
June 2018

A Missense Variant at the Nrxn3 Locus Enhances Empathy Fear in the Mouse.

Neuron 2018 05 19;98(3):588-601.e5. Epub 2018 Apr 19.

Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34047, Republic of Korea; School of Basic Science, University of Science and Technology, Daejeon 34113, Republic of Korea. Electronic address:

Empathy is crucial for our emotional experience and social interactions, and its abnormalities manifest in various psychiatric disorders. Observational fear is a useful behavioral paradigm for assessing affective empathy in rodents. However, specific genes that regulate observational fear remain unknown. Here we showed that 129S1/SvImJ mice carrying a unique missense variant in neurexin 3 (Nrxn3) exhibited a profound and selective enhancement in observational fear. Using the CRISPR/Cas9 system, the arginine-to-tryptophan (R498W) change in Nrxn3 was confirmed to be the causative variant. Selective deletion of Nrxn3 in somatostatin-expressing (SST+) interneurons in the anterior cingulate cortex (ACC) markedly increased observational fear and impaired inhibitory synaptic transmission from SST+ neurons. Concordantly, optogenetic manipulation revealed that SST+ neurons in the ACC bidirectionally controlled the degree of socially transmitted fear. Together, these results provide insights into the genetic basis of behavioral variability and the neurophysiological mechanism controlling empathy in mammalian brains.
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http://dx.doi.org/10.1016/j.neuron.2018.03.041DOI Listing
May 2018

The Improving Effect of HL271, a Chemical Derivative of Metformin, a Popular Drug for Type II Diabetes Mellitus, on Aging-induced Cognitive Decline.

Exp Neurobiol 2018 Feb 12;27(1):45-56. Epub 2018 Feb 12.

Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34141, Korea.

In recent years, as the aging population grows, aging-induced cognitive impairments including dementia and Alzheimer's disease (AD) have become the biggest challenges for global public health and social care. Therefore, the development of potential therapeutic drugs for aging-associated cognitive impairment is essential. Metabolic dysregulation has been considered to be a key factor that affects aging and dementia. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a primary sensor of cellular energy states and regulates cellular energy metabolism. Metformin (1,1-dimethylbiguanide hydrochloride) is a well-known AMPK activator and has been widely prescribed for type 2 diabetes mellitus (T2DM). Since the incidence of T2DM and dementia increases with aging, metformin has been considered to be one of the most promising drugs to target dementia and its related disorders. To that end, here, we tested the efficacy of metformin and HL271, a novel metformin derivative, in aging-induced cognitive decline. Water (control), metformin (100 mg/kg) or HL271 (50 mg/kg) were orally administered to aged mice for two months; then, the mice were subjected to behavioral tests to measure their cognitive function, particularly their contextual, spatial and working memory. AMPK phosphorylation was also measured in the drug-treated mouse brains. Our results show that oral treatment with HL271 (50 mg/kg) but not metformin (100 mg/kg) improved cognitive decline in aged mice. AMPK activation was correlated with behavior recovery after aging-induced cognitive decline. Taken together, these results suggest that the newly synthesized AMPK activator, HL271, could be a potential therapeutic agent to treat age-related cognitive decline.
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http://dx.doi.org/10.5607/en.2018.27.1.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840461PMC
February 2018

Relationship between adverse events and antiplatelet drug resistance in neurovascular intervention: a meta-analysis.

J Neurointerv Surg 2018 Oct 19;10(10):942-948. Epub 2018 Jan 19.

Department of Neurology, Kyung Hee University Hospital at Gangdong, School of Medicine, Kyung Hee University, Seoul, South Korea.

Background: This meta-analysis aimed to evaluate the association between antiplatelet resistance and the risk of procedure-related complications in neurovascular interventions.

Methods: We identified relevant articles by searching electronic databases and reviewed the reference lists of selected papers. The risk of adverse events between antiplatelet responders and hyporesponders during neurointervention was compared in eligible clinical studies. Risk ratios (RRs) and 95% CIs were pooled using a random-effects meta-analysis.

Results: Of 2134 potentially relevant studies, our search identified 15 studies enrolling a total of 2365 patients. Pooled RRs showed thromboembolic events (TEE) were more frequent in hyporesponders (RR 2.634, 95% CI 1.465 to 4.734). However, hemorrhagic complications did not differ between the two groups (RR 1.236, 95% CI 0.642 to 2.380). In subgroup analysis, hyporesponders showed a higher prevalence of TEE with standard antiplatelet medication, but there was no obvious difference in TEE between the two arms when using a modified antiplatelet medication (RR 3.645, 95% CI 1.537 to 8.646; and RR 1.877, 95% CI 0.749 to 4.751). Studies using stent placement for aneurysms showed a higher TEE rate in hyporesponders (RR 3.221, 95% CI 1.899 to 5.464).

Conclusion: Antiplatelet resistance was significantly associated with TEE in neurointervention, and this adverse event was associated with individually-intensified antiplatelet medication as well as the type of neurointerventional procedure. Our findings support the use of antiplatelet resistance assays and tailored antiplatelet medications in neurovascular stent placement as a management strategy to reduce thromboembolic risk.
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http://dx.doi.org/10.1136/neurintsurg-2017-013632DOI Listing
October 2018

Targeted knockout of a chemokine-like gene increases anxiety and fear responses.

Proc Natl Acad Sci U S A 2018 01 16;115(5):E1041-E1050. Epub 2018 Jan 16.

Department of Biology, Chungnam National University, 34134 Daejeon, South Korea;

Emotional responses, such as fear and anxiety, are fundamentally important behavioral phenomena with strong fitness components in most animal species. Anxiety-related disorders continue to represent a major unmet medical need in our society, mostly because we still do not fully understand the mechanisms of these diseases. Animal models may speed up discovery of these mechanisms. The zebrafish is a highly promising model organism in this field. Here, we report the identification of a chemokine-like gene family, (), and present functional characterization of one of its members, We show exclusive mRNA expression of s in the CNS, predominantly in the dorsal habenula, telencephalon, and hypothalamus. We found knockout (KO) zebrafish to exhibit altered anxiety-related responses in the tank, scototaxis and shoaling assays, and increased mRNA expression in their hypothalamus compared with wild-type fish. To investigate generalizability of our findings to mammals, we developed a KO mouse and compared it to wild-type littermates. Consistent with zebrafish findings, homozygous KO mice exhibited signs of elevated anxiety. We also found bath application of purified SAM2 protein to increase inhibitory postsynaptic transmission onto CRH neurons of the paraventricular nucleus. Finally, we identified a human homolog of , and were able to refine a candidate gene region encompassing , among 21 annotated genes, which is associated with intellectual disability and autism spectrum disorder in the 12q14.1 deletion syndrome. Taken together, these results suggest a crucial and evolutionarily conserved role of in regulating mechanisms associated with anxiety.
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http://dx.doi.org/10.1073/pnas.1707663115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798319PMC
January 2018

Deficiency of a brain-specific chemokine-like molecule, SAM3, induces cardinal phenotypes of autism spectrum disorders in mice.

Sci Rep 2017 11 28;7(1):16503. Epub 2017 Nov 28.

Center for Cognition and Sociality, Institute for Basic Science, Yuseong-gu, Daejeon, 34141, Republic of Korea.

Chemokines are small secreted signaling proteins produced by a broad range of cells, including immune cells. Several studies have recently suggested potential roles of chemokines and their receptors in the pathophysiology of autism spectrum disorders (ASDs). SAM3 is a novel brain-specific chemokine-like molecule with an unknown physiological function. We explored the relevance of chemokines in the development of ASD in mice, with a focus on SAM3. We generated Sam3 gene knockout (KO) mice and characterized their behavioral phenotypes, with a focus on those relevant to ASD. Sam3-deficient mice displayed all three core phenotypes of ASD: impaired responses to social novelty, defects in social communication, and increased repetitive behavior. In addition, they showed increased anxiety. Interestingly, gender differences were identified for several behaviors: only male Sam3 KO mice exhibited increased anxiety and increased repetitive behaviors. Sam3 KO mice did not exhibit changes in other behaviors, including locomotor activities, fear learning and memory, and object recognition memory. These findings indicate that a deficiency of SAM3, a novel brain-specific chemokine-like molecule, may lead to the pathogenesis of ASDs and suggest the possibility that SAM3, a soluble factor, could be a novel therapeutic target for ASD treatment.
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http://dx.doi.org/10.1038/s41598-017-16769-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705707PMC
November 2017

Mice in social conflict show rule-observance behavior enhancing long-term benefit.

Nat Commun 2017 11 7;8(1):1176. Epub 2017 Nov 7.

Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, 34141, Korea.

Disorderly resolution of conflict is costly, whereas orderly resolution by consent rules enables quick settlement. However, it is unclear whether non-human animals can make and observe rules to resolve conflict without aggression. Here we report a new behavioral paradigm for mice: a modified two-armed maze that uses wireless electrical brain stimulation as reward. First, the mice were individually operant-trained to initiate and then receive the reward at the signaled arm. Next, two mice were coupled and had to cooperate to initiate reward but then to compete over reward allocation. Mice develop and observe a rule of reward zone allocation that increases the total amount of reward and reward equity between the pair. In the mutual rule-observance behavior, positive reciprocity and tolerance to the other's violation are also observed. These findings suggest that rodents can learn to make and observe rules to resolve conflict, enhancing long-term benefit and payoff equity.
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http://dx.doi.org/10.1038/s41467-017-01091-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673895PMC
November 2017

Clinical Manifestations of Isolated Chronic Middle Cerebral Artery Occlusion in Relation to Angiographic Features.

World Neurosurg 2017 Dec 8;108:303-309. Epub 2017 Sep 8.

Department of Neurology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Korea.

Objective: Isolated chronic middle cerebral artery occlusion (ChMCAO) is not a rare condition and is known to cause hemodynamic stroke. The purpose of this study was to evaluate differences in clinical manifestations and prognosis of isolated ChMCAO in relation to angiographic features.

Methods: This retrospective study enrolled 56 patients with isolated ChMCAO. In accordance with degree of anterograde collateral flow (AF) on angiography, patients were categorized into poor and good AF groups. The 2 groups were assessed and compared for the presence and recurrence of neurologic symptoms.

Results: Of 56 patients, 33 were in the poor AF group and 23 were in the good AF group. The prevalence of ischemic symptoms was significantly higher in the poor AF group compared with the good AF group (P < 0.05). During an average follow-up period of 33.8 months, recurrent ipsilateral symptoms occurred in 6 of 45 patients. The hazard ratio conferred by poor AF was 5.36 (95% confidence interval, 1.08-26.57) for recurrent symptoms.

Conclusions: AF through the basal collateral network may be related to clinical manifestations of ChMCAO. Good AF in isolated ChMCAO may play an important role in preventing recurrence of an ischemic event.
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http://dx.doi.org/10.1016/j.wneu.2017.09.003DOI Listing
December 2017

Staged Endovascular Occlusion of a Posterior Communicating Artery-Cavernous Sinus Fistula and a Basilar Artery-Cavernous Sinus Fistula Associated with Traumatic Pseudoaneurysms: Technical Consideration and Literature Review.

World Neurosurg 2017 Nov 24;107:1051.e7-1051.e11. Epub 2017 Aug 24.

Department of Neurosurgery, Kyung Hee University Hospital at Gangdong, Gangdong-gu, Seoul, Korea.

Background: Traumatic injury of the posterior communicating artery or the basilar artery causing arteriovenous fistulae is rare.

Case Description: Here we report an unusual case of the coincidence of a posterior communicating artery-cavernous sinus fistula and a basilar artery-cavernous sinus fistula associated with traumatic pseudoaneurysms of the posterior communicating and basilar arteries. The fistulas and pseudoaneurysms were obliterated completely after staged endovascular surgery via a transarterial and transvenous route.

Conclusions: To our knowledge, this is the first such report worldwide.
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http://dx.doi.org/10.1016/j.wneu.2017.08.070DOI Listing
November 2017
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