Daejong Jeon’s research while affiliated with Seoul National University Hospital and other places

Recent advances in molecular science have significantly enlightened our mechanistic understanding of spinocerebellar ataxia type 7. To further close remaining gaps, we performed a multi-omics analysis using SCA7266Q/5Q mice. Entire brain tissue samples were collected from 12-week-old mice, and RNA sequencing, methylation analysis, and proteomic analysis were performed. Results were integrated to identify genes with identical trends in expression across all three analyses. Data from RNA sequencing and methylation analysis revealed 58 significantly hypomethylated-upregulated genes and 62 hypermethylated-downregulated genes, mostly enriched in GO terms of regulation of axonogenesis, channel activity, and monoamine signaling. In the proteomic analysis, 211 upregulated and 281 downregulated DEPs associated mostly with immune response and cellular mobility were identified. Two genes, Fam107b and Tph2, showed differential expressions in both transcriptomic and proteomic analyses. Findings were validated in RT-qPCR as well as open data source analysis. Our study is the first to perform multi-omics analysis in SCA7 mice and will serve as an important reference for future studies.

We evaluated the efficacy and safety of 1-year treatment with nilotinib (Tasigna®) in patients with autosomal dominant spinocerebellar ataxia (ADSCA) and the factors associated with responsiveness. From an institutional cohort, patients with ADSCA who completed a 1-year treatment with nilotinib (150–300 mg/day) were included. Ataxia severity was assessed using the Scale for the Rating and Assessment of Ataxia (SARA), scores at baseline and 1, 3, 6, and 12 months. A subject was categorized ‘responsive’ when the SARA score reduction at 12 M was > 0. Pretreatment serum proteomic analysis included subjects with the highest (n = 5) and lowest (n = 5) SARA score change at 12 months and five non-ataxia controls. Thirty-two subjects (18 [56.2%] females, median age 42 [30–49.5] years) were included. Although SARA score at 12 M did not significantly improve in overall population, 20 (62.5%) subjects were categorized as responsive. Serum proteomic analysis identified 4 differentially expressed proteins, leucine-rich alpha-2-glycoprotein (LRG1), vitamin-D binding protein (DBP), and C4b-binding protein (C4BP) beta and alpha chain, which are involved in the autophagy process. This preliminary data suggests that nilotinib might improve ataxia severity in some patients with ADSCA. Serum protein markers might be a clue to predict the response to nilotinib. Trial Registration Information: Effect of Nilotinib in Cerebellar Ataxia Patients (NCT03932669, date of submission 01/05/2019).

Purpose: In our previous study, we developed an assay system to evaluate antisocial maltreating behavior of conspecific mice using a perpetrator-victim paradigm. We also generated a mouse model for the maltreating behavior by mimicking child maltreatment or abuse. Here, we further investigate the antisocial behavior using anti-aggressive and antipsychotic drugs. Methods: Model mice sequentially subjected to maternal separation (MS), social defeat (SD), and social isolation (SI) in that order (MS/SD/SI model) were subjected to a maltreating behavioral task. The MS/SD/SI mice were treated with oxytocin (OXY), clozapine (CLZ), haloperidol (HAL), and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Western blotting and enzyme-linked immunosorbent assay were used for protein analysis. Results: A substantial portion of the MS/SD/SI model mice (46% of males and 40% of females) showed a higher number of nose pokes than the control. OXY or 8-OH-DPAT treatment reduced the high number of nose pokes by the MS/SD/SI mice, whereas HAL increased it. CLZ did not affect the number of nose pokes by the MS/SD/SI mice. Interestingly, although the OXY level in the MS/SD/SI mice was similar to that in the control, the amount of OXY receptor was lower in the MS/SD/SI mice. The amount of 5-HT1A receptor was also decreased in the MS/SD/SI mice. Conclusion: Chronic social stress in childhood might predispose a mouse to antisocial behavior. Our maltreating behavior assay system, including the MS/SD/SI model, is a good animal system for research on and drug screening for brain disorders associated with antisocial or psychotic behavior.

PurposeFebrile seizures at a young age can provoke late-onset temporal lobe epilepsy. Since recent evidence has suggested that the gut microbiome affects central nervous system pathology across the blood-brain barrier, we hypothesized that febrile seizures alter the composition of the gut microbiome to provoke epilepsy.Methods Third-generation C57BL/6 mice were separated into two groups (n = 5 each), and hot air was applied to only one group to cause febrile seizures. After two weeks of heat challenge, the fecal pellets acquired from each group were analyzed.ResultsThe gut microbiota of fecal pellets from each group revealed five taxa at the genus level and eight taxa at the species level that were significantly different in proportion between the groups.Conclusion Although there was no significant difference in the overall diversity of the gut microbiota between the two groups, the identified heterogeneity may imply the pathognomonic causative relevance of febrile seizures and the development of epilepsy.

Purpose: Early-life stress can cause brain inflammation and affect social behavior in adulthood. In humans, maltreated (abused or neglected) children often exhibit antisocial behavior, including violent and sadistic behavior, in adulthood. However, it is unknown whether maltreatment behavior occurs in rodents. Here, we developed an assay system to evaluate conspecific maltreatment behavior in the mouse. Methods: To assess maltreatment behavior, we devised a two-chamber apparatus separated by a transparent partition, in which one chamber was provided with a nose-poking hole that would trigger foot shocks onto the other. Lidocaine was used to inhibit neural activity in vivo. Brain oscillations were investigated by electroencephalograph. Enzyme-linked immunosorbent assay was used for protein assay. The mouse model was sequentially subjected to maternal separation (MS), social defeat (SD), and social isolation (SI) in that order (MS/SD/SI model). Results: Inactivation of the anterior cingulate cortex and medial prefrontal cortex increased the level of nose-poking. Maltreatment behavior provoked changes in oxytocin, corticosterone, and brain-derived neurotrophic factor levels. MS/SD/SI mice exhibited more sustained nose-poking behavior during the experiment, resulting in increased foot shocks to the mouse in the opposite chamber. Abnormal brain oscillations were observed in the MS/SD/SI mice. Conclusion: The MS/SD/SI model and maltreatment-behavior assay may be useful not only to study the relationship between social stress in childhood and antisocial behavior in adulthood, but also for study of etiology, pathology, or treatment for brain disorders, such as psychopathy.

PurposeChronic social stress is known to induce inflammation in the brain, and early-life stress affects the brain and social behavior in adulthood. To study the relationship between social stress in childhood development and social behavior in adulthood, we subjected mice to a sequential early-life social stresses and characterized their adult behavioral phenotypes.MethodsC57BL/6 mice were sequentially subjected to maternal separation (MS), social defeat (SD), and social isolation (SI) in that order. The body weights of the MS/SD/SI mice were measured. Behavioral tasks related to anxiety, depression, locomotion, learning/memory, and repetitive/compulsive-like behavior were conducted. Social behaviors suggesting sociability, social interaction, aggression, and social fear were investigated. ResultsMS/SD/SI mice weighed less at 7 and 8 weeks of age. These mice displayed normal behaviors in anxiety-, depression-, and learning/memory-related tasks, but they exhibited increased locomotor activity and a low level of repetitive/compulsive-like behavior. Notably, they exhibited increased social interaction, impaired empathy-related fear, reduced predator fear, and increased defensive aggressiveness.Conclusion Social stress during childhood development resulted in behavioral alterations, and MS/SD/SI mice generated by mimicking child abuse or maltreatment showed unique abnormalities in social behaviors. MS/SD/SI mice might be useful not only to study the relationship between social stress and brain inflammation but also psychosocial behaviors observed in individuals with brain disorders, such as psychopaths.

Seizure clustering is a common phenomenon in epilepsy. Protein expression profiles during a seizure cluster might reflect the pathomechanism underlying ictogenesis. We performed proteomic analyses to identify proteins with a specific temporal expression pattern in cluster phases and to demonstrate their potential pathomechanistic role. Pilocarpine epilepsy model mice with confirmed cluster pattern of spontaneous recurrent seizures by long-term video-electroencpehalography were sacrificed at the onset, peak, or end of a seizure cluster or in the seizure-free period. Proteomic analysis was performed in the hippocampus and the cortex. Differentially expressed proteins (DEPs) were identified and classified according to their temporal expression pattern. Among the five hippocampal (HC)-DEP classes, HC-class 1 (66 DEPs) represented disrupted cell homeostasis due to clustered seizures, HC-class 2 (63 DEPs) cluster-onset downregulated processes, HC-class 3 (42 DEPs) cluster-onset upregulated processes, and HC-class 4 (103 DEPs) consequences of clustered seizures. Especially, DEPs in HC-class 3 were hippocampus-specific and involved in axonogenesis, synaptic vesicle assembly, and neuronal projection, indicating their pathomechanistic roles in ictogenesis. Key proteins in HC-class 3 were highly interconnected and abundantly involved in those biological processes. This study described the seizure cluster-associated spatiotemporal regulation of protein expression. HC-class 3 provides insights regarding ictogenesis-related processes.

Purpose: Suicidality can be a serious feature of psychiatric symptoms in encephalitis. Investigating the psychiatric behavior associated with suicidality in animal models of encephalitis is important; thus, determining whether normal laboratory animals are aware of death is necessary. Methods: To examine the behavioral and brain activity changes associated with death of conspecifics, laboratory mice were exposed to a cadaveric mouse or an anesthetized mouse. Behavioral tasks associated with anxiety and locomotion were conducted after repeated exposure. Neural activity in the medial prefrontal cortex during the cadaver exploration was investigated using electroencephalographic recordings. Results: During repeated exposure, mice in the cadaver group showed a gradual decrease in time exploring the cadaver, which was not observed in mice in the anesthesia group. The cadaver group also exhibited increased levels of anxiety in the light/dark transition and elevated plus maze tasks and displayed increased locomotor activity in the open field test. In an electrophysiological study, different brain oscillations were observed when mice were exposed to a cadaveric mouse and an anesthetized mouse. Enhanced delta-band activity and reduced theta- and alpha-band activities were observed during cadaver exploration. Conclusion: The present study results showed that experiences involving dead conspecifics strongly affect mouse behavior and brain activity. These findings may be helpful in treating patients with psychiatric symptoms and aid in understanding the concept of death recognition/awareness in laboratory animals.

[This corrects the article DOI: 10.1371/journal.pone.0194552.].

Introduction Lamotrigine is one of the most widely used antiepileptic drugs, but it has a critical issue of a skin rash if the starting dose is too high or the escalation rate is too rapid. We investigated the efficacy and safety of a novel and rapid titration protocol for lamotrigine that takes only 11 days to reach a daily dose of 200 mg. Methods We prospectively enrolled 33 adult patients (age 18–85) who were diagnosed with epilepsy and started lamotrigine administration for the first time at a single tertiary hospital. Our new protocol starts with a subthreshold dose of the drug and then administer a stepwise-incremental dose until reaching the full therapeutic dose within 11 days. Results Of 29 patients analyzed, only two (6.9%) experienced idiosyncratic skin rash before the first follow-up visit at 2 weeks (±3 days). In addition, a therapeutic concentration was reached in more than 75% of studied patients after 2 weeks of lamotrigine administration Discussion These findings demonstrate the value of the novel tolerance induction protocol for lamotrigine, which could widen the available application of lamotrigine in various situations.