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1.
Yakugaku Zasshi ; 139(10): 1327-1332, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31582618

RESUMO

The dosage of cisplatin is adjusted according to creatinine clearance (Ccr) estimated by the Cockcroft-Gault formula, which is commonly used as a marker for renal function. It is known that different serum creatinine (Scr) levels are reported depending on the analytical methods utilized such as the Scr level by the enzyme method being lower than that by the Jaffe method. Although the enzyme method is used in Japan, most drug dosages, including cisplatin, are adjusted according to the estimated Ccr using the Jaffe method-based Scr level. The purpose of this study was to investigate whether assessment of renal function with or without Scr adjustment affects cisplatin-based chemotherapy in cervical cancer patients. The patients were divided into two groups, normal (Ccr≥60 mL/min with adjusted Scr) and false normal (Ccr<60 mL/min with adjusted Scr, but Ccr≥60 mL/min with non-adjusted Scr). The false normal group had significantly higher rates of cisplatin dose reduction after the second course than the normal group (p<0.05). Leukocytopenia and Grade 2 or higher neutropenia were significantly more common in the false normal group than in the normal group (p<0.05). These results suggest that evaluation of renal function using the adjusted Scr is important for the accurate dosage of cisplatin and that it helps to improve the patient's quality of life. Further investigations may provide useful information for accurate and safe cisplatin-based chemotherapy for cancer patients.

3.
Neurosci Res ; 147: 39-47, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31446906

RESUMO

Perinatal virus infection is an environmental risk factor for neurodevelopmental disorders such as schizophrenia. We previously demonstrated that neonatal treatment with a viral mimetic, polyriboinosinic-polyribocytidilic acid (polyI:C), in mice leads to emotional and cognitive deficits in adolescence. Here, we investigated the effects of antipsychotics on polyI:C-induced behavioral abnormalities. We also performed a proteomic analysis in the hippocampus of polyI:C-treated adult mice using two-dimensional electrophoresis to understand the changes in protein expression following neonatal immune activation. Neonatal mice were subcutaneously injected with polyI:C for 5 days (postnatal day 2-6). At 10 weeks, sensorimotor gating, emotional and cognitive function were analyzed in behavioral tests. Clozapine improved PPI deficit and emotional and cognitive dysfunction in polyI:C-treated mice. However, haloperidol improved only PPI deficit. Proteomic analysis revealed that two candidate proteins were obtained in the hippocampus of polyI:C-treated mice, including aldehyde dehydrogenase family 1 member L1 (ALDH1L1) and collapsin response mediator protein 5 (CRMP5). These data suggest that the neonatal polyI:C-treated mouse model may be useful for evaluating antipsychotic activity of compounds. Moreover, changes in the protein expression of ALDH1L1 and CRMP5 support our previous findings that astrocyte-neuron interaction plays a role in the pathophysiology of neurodevelopmental disorders induced by neonatal immune activation.

4.
Eur Neuropsychopharmacol ; 29(8): 914-924, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31303267

RESUMO

Alterations of the glutamatergic system components, including N-methyl-d-aspartate (NMDA) receptors are relevant to the pathophysiology of schizophrenia. Repeated phencyclidine (PCP) administration induces several schizophrenia-like psychobehavioral abnormalities and decreases extracellular glutamate levels, which are associated with increased levels of glial glutamate and aspartate transporter (GLAST) in the prefrontal cortex (PFC) of mice. In the present study, we investigated the functional roles of GLAST in the emotional and cognitive abnormalities in mice following repeated PCP administration by using GLAST heterozygous (+/-) mice, since GLAST mutant mice are a useful tool for elucidating the contribution of glutamate dysfunction to the pathophysiology of schizophrenia. PCP-administered GLAST wild-type (+/+) mice showed enhancement of immobility in a forced swimming test, impairments of visual recognition memory in a novel object recognition test, decrease in high potassium (K+)-induced extracellular glutamate release, and overexpression of GLAST and S100 proteins in the PFC, compared to saline-administered GLAST+/+ mice. Such behavioral and neurochemical abnormalities were not observed in PCP-administered GLAST+/- mice. In conclusion, these results clearly suggest that genetic GLAST dysfunction and glial activation play important roles in the development of emotional and cognitive abnormalities in PCP-administered GLAST+/+ mice.

5.
BMC Psychiatry ; 19(1): 190, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221108

RESUMO

BACKGROUND: Postpartum depression (PPD) is a major depressive disorder that occurs after childbirth. Objective diagnostic and predictive methods for PPD are important for early detection and appropriate intervention. DNA methylation has been recognized as a potential biomarker for major depressive disorder. In this study, we used methylation analysis and peripheral blood to search for biomarkers that could to lead to the development a predictive method for PPD. METHODS: Study participants included 36 pregnant women (18 cases and 18 controls determined after childbirth). Genome-wide DNA methylation profiles were obtained by analysis with an Infinium Human Methylation 450BeadChip. The association of DNA methylation status at each DNA methylation site with PPD was assessed using linear regression analysis. We also conducted functional enrichment analysis of PPD using The Database for Annotation, Visualization and Integrated Discovery 6.8 to explore enriched functional-related gene groups for PPD. RESULTS: In the analysis with postpartum depressed state as an independent variable, the difference in methylation frequency between the postpartum non-depressed group and the postpartum depressed group was small, and sites with genome-wide significant differences were not confirmed. After analysis by The Database for Annotation, Visualization and Integrated Discovery 6.8, we revealed four gene ontology terms, including axon guidance, related to postpartum depression. CONCLUSIONS: These findings may help with the development of an objective predictive method for PPD.

6.
Yakugaku Zasshi ; 139(6): 923-929, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31155537

RESUMO

Brain function is controlled by the balance between the excitatory and inhibitory systems. If this balance is disrupted and the excitatory system dominates, convulsions or epileptic seizures are induced. Neuronal hyperexcitability in the brain leads to marked changes in the function of the neurons, which adversely affect the stability of the neural network. Many of the currently used antiepileptic drugs are symptomatic treatments that suppress the electrical hyperexcitability of the cerebrum. Although patients with epilepsy should continuously take antiepileptic drugs to control their seizures, approximately 20% of patients are drug resistant. The brain has the ability to control neuronal functions within acceptable limits while it maintains the amount of synaptic inputs that form the basis of information accumulation. Neuronal self-regulation is known as homeostatic scaling by which the intensity of all excitatory synapses is suppressed when neuronal excitability is increased. However, the molecular mechanisms of homeostatic scaling and their pathophysiological significance in vivo remain unclear. Repeated treatment with a subconvulsive dosage of pentylenetetrazol (PTZ), a γ-aminobutyric acid (GABA)A receptor antagonist, is known to induce kindling in mice, which is a common animal model used to study epilepsy. We found that PTZ-induced kindling was potentiated in mice deficient in the transcription factor neuronal PAS domain protein 4 (Npas4), the expression of which is immediately induced in response to neuronal activity. At this symposium, we will discuss the possibility of Npas4 as a novel target molecule for epilepsy treatment.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Encéfalo/fisiologia , Epilepsia/tratamento farmacológico , Epilepsia/etiologia , Homeostase , Terapia de Alvo Molecular , Neurônios/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Modelos Animais de Doenças , Epilepsia/genética , Humanos , Excitação Neurológica , Camundongos , Sinapses/fisiologia
7.
Nihon Yakurigaku Zasshi ; 153(5): 224-230, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31092755

RESUMO

Decision-making is a key activity process that influences many aspects of daily living and both mental and physical health. In general, healthy participants reveal rational choice, but patients with neuropsychiatric disorders reveal irrational and risky choice in decision-making. Addiction is one of typical diseases revealed risky decision-making, addicts select risky action and options that confer short-term rewards at the cost of long-term disadvantages. Thus, irrational and risky decision-making is recognized as a core problem in patients with neuropsychiatric disorders, and a better understanding of the mechanisms underlying altered decision-making would provide insights into potential therapeutic approaches for these diseases. However, the neural pathway and substrates underlying these deficits are particularly unknown. Recently, we found that insular cortex is one of key regions for risky decision-making in an animal model of methamphetamine addiction, by using the designer receptor exclusively activated by designer drug (DREADD) technology, and that GABAergic dysfunction in insular cortex is involved in evaluating the subjective value of reward and reward prediction error. These brain dysfunctions would be related to risk taking behavior in addiction. In this review, we introduced the possible neural pathway related to risky decision-making and behavioral changes in choice strategy using adeno associated virus (AAV).


Assuntos
Córtex Cerebral/fisiologia , Tomada de Decisões , Metanfetamina/farmacologia , Assunção de Riscos , Animais , Dependovirus , Neurônios GABAérgicos/citologia , Humanos , Recompensa
8.
Transl Psychiatry ; 9(1): 146, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053702

RESUMO

The original Article required a few updates; one co-author name, which was given as Hiroki Kiumura, has been updated to Hiroki Kimura. Furthermore, supplementary information has been updated, and grant numbers have been added. These updates have been made to both the PDF and HTML versions of this Article.

9.
Transl Psychiatry ; 9(1): 126, 2019 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-31011151

RESUMO

Although a number of studies have identified several convincing candidate genes or molecules, the pathophysiology of schizophrenia (SCZ) has not been completely elucidated. Therapeutic optimization based on pathophysiology should be performed as early as possible to improve functional outcomes and prognosis; to detect useful biomarkers for SCZ, which reflect pathophysiology and can be utilized for timely diagnosis and effective therapy. To explore biomarkers for SCZ, we employed fluorescence two-dimensional differential gel electrophoresis (2D-DIGE) of lymphoblastoid cell lines (LCLs) (1st sample set: 30 SCZ and 30 CON). Differentially expressed proteins were sequenced by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and identified proteins were confirmed by western blotting (WB) (1st and 2nd sample set: 60 SCZ and 60 CON). Multivariate logistic regression analysis was performed to identify an optimal combination of biomarkers to create a prediction model for SCZ. Twenty protein spots were differentially expressed between SCZ and CON in 2D-DIGE analysis and 22 unique proteins were identified by LC-MS/MS. Differential expression of eight of 22 proteins was confirmed by WB. Among the eight candidate proteins (HSPA4L, MX1, GLRX3, UROD, MAPRE1, TBCB, IGHM, and GART), we successfully constructed logistic regression models comprised of 4- and 6-markers with good discriminative ability between SCZ and CON. In both WB and gene expression analysis of LCL, MX1 showed reproducibly significant associations. Moreover, Mx1 and its related proinflamatory genes (Mx2, Il1b, and Tnf) were also up-regulated in poly I:C-treated mice. Differentially expressed proteins might be associated with molecular pathophysiology of SCZ, including dysregulation of immunological reactions and potentially provide diagnostic and prognostic biomarkers.

10.
Neurol Med Chir (Tokyo) ; 59(4): 117-125, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30880307

RESUMO

We aimed to clarify the outcomes of carotid artery stenting (CAS) in the Japanese population. For this purpose, we reviewed data from the Japanese Registry of NeuroEndovascular Therapy 3 (JR-NET3), a retrospective, nation-wide, multi-center, observational study of neuroendovascular treatments in Japan. Of the 9207 patients who underwent CAS between January 2010 and December 2014, 8458 satisfied the inclusion criteria for our analysis. The outcome statistics of this JR-NET3 cohort were compared to those of JR-NET1 and 2 cohorts fitting the same inclusion criteria. Of the 8458 JR-NET3 patients analyzed, 8042 (95.1%) were treated by surgeons with board certification from the Japanese Society for NeuroEndovascular Therapy. Technical success was achieved in 8417 patients (99.5%), whereas 198 patients (2.3%) had clinically significant complications (CSCs). These findings mirrored those obtained for the JR-NET1 and 2 cohorts. On multivariate analysis, risk factors for CAS-associated CSC included symptomatic lesion [odds ratio (OR), 1.91; 95% confidence interval (CI), 1.23-3.00; P = 0.003] and hypoechoic lesion on carotid artery ultrasound (OR, 1.85; 95% CI, 1.21-2.84; P = 0.005), whereas use of closed-cell stents was a predictor of better outcome (OR, 0.53; 95% CI, 0.35-0.79; P = 0.002). The findings of JR-NET3 reflect good outcomes of CAS, but non-modifiable risk factors reflecting lesion characteristics remain of concern. Using closed-cell stents is advisable. Technological advances such as the introduction of new materials may help further improve CAS outcomes in Japanese patients.

11.
World Neurosurg ; 127: e330-e336, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30904795

RESUMO

BACKGROUND AND PURPOSE: Neovascularization (NV) is regarded to be one of the important features of vulnerable plaque. The purpose of this study was to evaluate associations between the presence of NV, detected using optical frequency domain imaging (OFDI), and ischemic events and the progress of carotid artery stenosis. MATERIALS AND METHODS: Carotid artery plaques were evaluated using an OFDI system before angioplasty. NV was defined as no-signal tubuloluminal structures recognized on at least 3 consecutive images. The total number of NVs was compared between symptomatic and asymptomatic plaques and between progressive and nonprogressive plaques. Carotid plaque was diagnosed as "progressive" when peak systolic velocity increased between serial carotid duplex scans. RESULTS: A total of 36 patients (17 symptomatic, 16 progressive) were included. The percentage of patients with smoking habits was significantly higher with progressive carotid plaque than with nonprogressive carotid plaque (P = 0.003). NV was detected in 34 patients (94%), and the total number of NVs was significantly higher with progressive carotid plaque (10.2 ± 4.8 vs. 3.7 ± 2.8; P < 0.0001). There was no relationship between the number of NVs and ischemic events (symptomatic 6.0 ± 5.1 vs. asymptomatic 7.1 ± 5.0; P = 0.47). In multivariate logistic regression analysis, the number of NVs was an independent predictor of progressive carotid plaque (odds ratio 1.64 per 1 increase [95% confidence interval 1.19-2.64]; P = 0.0005). CONCLUSIONS: NV was more frequently observed in progressive carotid plaques. Evaluation of NV using OFDI may be useful in predicting progressive carotid plaques.

12.
J Clin Neurosci ; 63: 95-99, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30732983

RESUMO

Carotid intraplaque hemorrhage (IPH) plays a critical role in the progression of carotid atherosclerotic disease. IPH was associated with high intensity signal (HIS) in the plaque on Maximum intensity projection (MIP) images from routine three dimensional magnetic resonance imaging (3D-TOF MRA). The aim of this study was to evaluate the relationships among HIS, new ipsilateral ischemic stroke and a progression rate in carotid plaques with moderate stenosis. We included 45 carotid plaques with moderate stenosis (50%-69%) in 45 patients who could be followed more than 12 months. Carotid IPH was defined as the presence of HIS on 3DTOF MRA using the criteria previously we published. We analyzed the relation between the presence of HIS and new ischemic strokes and annual progression rate of carotid stenosis. HIS was present in 21 (47%) carotid arteries. Over a follow-up period of 24 ±â€¯9 months, six ischemic strokes occurred in ipsilateral side. New ipsilateral ischemic stroke occurred more frequently in HIS positive group (P group: 6 of 21, 29%) than negative group (N group: 0 of 24, 0%) (p = 0.017). Annual progression rate of carotid stenosis is significantly higher in P group (+3.35%/year) than N group (-0.02%/year) (p = 0.0026). In multivariate regression analysis, HIS positive was an independent predictor for annual progression rate of carotid stenosis (p = 0.003). Evaluation of HIS in asymptomatic moderate carotid stenosis can potentially provide risk stratification of new ipsilateral ischemic strokes.


Assuntos
Isquemia Encefálica/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico por imagem , Estenose das Carótidas/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagem , Imagem por Ressonância Magnética , Acidente Vascular Cerebral/diagnóstico por imagem , Idoso , Progressão da Doença , Feminino , Humanos , Imagem Tridimensional , Masculino , Pessoa de Meia-Idade
13.
Neurochem Int ; 124: 106-113, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30611760

RESUMO

Methamphetamine is a widely abused psychostimulant. It reverses transport through the dopamine transporter, thereby increasing the extracellular level of dopamine in the brain, which is associated with the rewarding effect. Repeated intake of methamphetamine leads to drug addiction, a chronically relapsing disorder characterized by compulsive drug taking, inability to limit intake, and intense drug cravings. The molecular and cellular mechanisms of drug addiction are not well understood, but have been proposed to involve neural plasticity and the remodeling of specific brain circuits. Accumulating evidence also indicates that patients addicted to methamphetamine exhibit impaired cognitive functions such as executive function, attention, social cognition, flexibility, and working memory. Furthermore, decision-making is altered in patients with drug addiction, including methamphetamine abusers. Cognitive impairment as well as altered decision-making in methamphetamine abusers may contribute to the high rate of relapse even after long-term withdrawal with psychosocial support. In this article, we review the effect of methamphetamine on cognition and decision-making in rodents. We also discuss possible mechanisms underlying cognition and decision-making impairments, including neuronal circuits, molecular and cellular events, and action control, as well as potential therapeutic targets.

14.
World Neurosurg ; 125: e16-e21, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30593963

RESUMO

BACKGROUND: Numerous reports have described the semi-jailing technique (SJT) using a closed-cell stent for stent-assisted coil embolization, revealing issues including poor expansion and thrombotic complications in curved vessels. This paper reports preliminary experience with SJT using an open-cell stent, a novel type of stent allowing stent placement from a microcatheter. METHODS: First, this research investigated differences between open- and closed-cell types in SJT using silicone vessel models. Next, 43 patients who underwent SJT for the internal carotid artery were divided into 2 groups to investigate treatment outcomes: 24 patients with placement of an open-cell stent (open-cell group) and 19 patients with closed-cell stents (closed-cell group). RESULTS: In the silicone vessel model, coils could be placed with the open-cell stent deployed with a shorter length than the closed-cell stent. No significant differences were found between groups in terms of maximum diameter of the aneurysm or dome-neck ratio. The open-cell group showed a trend toward higher complete embolization immediately after surgery (54.2% vs. 26.3%, P = 0.06), with few cases of stent malapposition (0% vs. 31.6%, P < 0.01). However, 1 case of ischemic complication in the closed-cell group and 1 case of hemorrhagic complication in open-cell group occurred. All cases of modified Rankin Scale scores at discharge were 0-1. CONCLUSIONS: Although the open-cell stent carries the disadvantage of an unresheathable design, coil placement with a shorter stent deployment length may be advantageous during SJT for internal carotid artery aneurysm embolization with favorable consequences for excellent vessel wall apposition.

15.
Neuropharmacology ; 148: 107-116, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30590060

RESUMO

The impairment of social behaviors induced by social defeat stress exposure as juveniles is resistant to some antidepressants and an antipsychotic, although the underlying mechanisms and/or therapeutic target are not yet clear. In this study, we investigated the involvement of the glutamatergic neuronal system in the impairment of social behaviors in this model, as this system is known to be involved in many central pathologies. Acute administration of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and subsequent stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, attenuated the expression of impairment of social behaviors. Lack of the NMDA receptor GluN2A subunit or acute administration of ifenprodil, an NMDA receptor GluN2B subunit antagonist, did not cause an effect. There were no significant changes in NMDA function, as determined by the ratios of phosphorylated NMDA receptor subunits in the prefrontal cortex and hippocampus. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione, a selective AMPA receptor antagonist, prevented the effect of ketamine on the expression of impairment of social behaviors. On the contrary, the ratio of phosphorylated AMPA receptor GluA1 subunit in the hippocampus was significantly increased in the non-tested, defeated group. Ketamine increased the level of total protein, but not the ratio of phosphorylated GluA1 in the hippocampus of the non-tested, defeated group. In conclusion, exposure to social defeat stress as juveniles may induce the expression of impairment of social behaviors in adolescents via functional changes in GluA1. Activators of AMPA receptor signaling, such as ketamine, may constitute a novel treatment strategy for stress-related psychiatric disorders in adolescents with adverse juvenile experiences.

16.
Neurochem Int ; 122: 8-18, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30336179

RESUMO

Medium spiny neurons (MSNs) expressing dopamine D1 receptor (D1R) or D2 receptor (D2R) are major components of the striatum. Stimulation of D1R activates protein kinase A (PKA) through Golf to increase neuronal activity, while D2R stimulation inhibits PKA through Gi. Adenosine A2A receptor (A2AR) coupled to Golf is highly expressed in D2R-MSNs within the striatum. However, how dopamine and adenosine co-operatively regulate PKA activity remains largely unknown. Here, we measured Rap1gap serine 563 phosphorylation to monitor PKA activity and examined dopamine and adenosine signals in MSNs. We found that a D1R agonist increased Rap1gap phosphorylation in striatal slices and in D1R-MSNs in vivo. A2AR agonist CGS21680 increased Rap1gap phosphorylation, and pretreatment with the D2R agonist quinpirole blocked this effect in striatal slices. D2R antagonist eticlopride increased Rap1gap phosphorylation in D2R-MSNs in vivo, and the effect of eticlopride was blocked by the pretreatment with the A2AR antagonist SCH58261. These results suggest that adenosine positively regulates PKA in D2R-MSNs through A2AR, while this effect is blocked by basal dopamine in vivo. Incorporating computational model analysis, we propose that the shift from D1R-MSNs to D2R-MSNs or vice versa appears to depend predominantly on a change in dopamine concentration.

17.
J Neuroinflammation ; 15(1): 295, 2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30348171

RESUMO

BACKGROUND: Polyriboinosinic-polyribocytidylic acid (polyI:C) triggers a strong innate immune response that mimics immune activation by viral infections. Induction of interferon-induced transmembrane protein 3 (Ifitm3) in astrocytes has a crucial role in polyI:C-induced neurodevelopmental abnormalities. Through a quantitative proteomic screen, we previously identified candidate astroglial factors, such as matrix metalloproteinase-3 (Mmp3) and follistatin-like 1 (Fstl1), in polyl:C-induced neurodevelopmental impairment. Here, we characterized the Ifitm3-dependent inflammatory processes focusing on astrocyte-derived Fstl1 following polyI:C treatment to assess the neuropathologic role of Fstl1. METHODS: Astrocytes were treated with PBS (control) or polyI:C (10 µg/mL). The conditioned medium was collected 24 h after the polyI:C treatment and used as astrocyte condition medium (ACM). The expression of Fstl1 mRNA and extracellular Fstl1 protein levels were analyzed by quantitative PCR and western blotting, respectively. For functional studies, neurons were treated with ACM and the effects of ACM on dendritic elongation were assayed. To examine the role of Fstl1, recombinant Fstl1 protein and siRNA for Fstl1 were used. To investigate the expression of Fstl1 in vivo, neonatal mice were treated with vehicle or polyI:C on postnatal day 2 to 6. RESULTS: ACM prepared with polyI:C (polyI:C ACM) contained significantly higher Fstl1 protein than control ACM, but no increase in Fstl1 was observed in polyI:C ACM derived from Ifitm3-deficient astrocytes. We found that the production of Fstl1 involves the inflammatory responsive molecule Ifitm3 in astrocytes and influences neuronal differentiation. In agreement, the levels of Fstl1 increased in the hippocampus of polyI:C-treated neonatal mice. COS7 cells co-transfected with both Fstl1 and Ifitm3 had higher extracellular levels of Fstl1 than the cells transfected with Fstl1 alone. Treatment of primary cultured hippocampal neurons with recombinant Fstl1 impaired dendritic elongation, and the deleterious effect of polyI:C ACM on dendritic elongation was attenuated by knockdown of Fstl1 in astrocytes. CONCLUSIONS: The extracellular level of Fstl1 is regulated by Ifitm3 in astrocytes, which could be involved in polyI:C-induced neurodevelopmental impairment.

18.
Sci Rep ; 8(1): 14413, 2018 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-30258218

RESUMO

Medium spiny neurons (MSN) in the nucleus accumbens (NAc) are a fundamental component of various aspects of motivated behavior. Although mitogen-activated protein kinase (MAPK) signaling plays a crucial role in several types of learning, the cell type-specific role of MAPK pathway in stimulus-reward learning and motivation remains unclear. We herein investigated the role of MAPK in accumbal MSNs in reward-associated learning and memory. During the acquisition of Pavlovian conditioning, the number of phosphorylated MAPK1/3-positive cells was increased significantly and exclusively in the NAc core by 7-days of extensive training. MAPK signaling in the respective D1R- and D2R-MSNs was manipulated by transfecting an adeno-associated virus (AAV) plasmid into the NAc of Drd1a-Cre and Drd2-Cre transgenic mice. Potentiation of MAPK signaling shifted the learning curve of Pavlovian conditioning to the left only in Drd1a-Cre mice, whereas such manipulation in D2R-MSNs had negligible effects. In contrast, MAPK manipulation in D2R-MSNs of the NAc core significantly increased motivation for food rewards as found in Drd1a-Cre mice. These results suggest that MAPK signaling in the D1R-MSNs of NAc core plays an important role in stimulus-reward learning, while MAPK signaling in both D1R- and D2R-MSNs is involved in motivation for natural rewards.

19.
Sci Rep ; 8(1): 13046, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158644

RESUMO

Reelin protein (RELN), an extracellular matrix protein, plays multiple roles that range from embryonic neuronal migration to spine formation in the adult brain. Results from genetic studies have suggested that RELN is associated with the risk of psychiatric disorders, including schizophrenia (SCZ). We previously identified a novel exonic deletion of RELN in a patient with SCZ. High-resolution copy number variation analysis revealed that this deletion included exons 52 to 58, which truncated the RELN in a similar manner to the Reln Orleans mutation (Relnrl-Orl). We examined the clinical features of this patient and confirmed a decreased serum level of RELN. To elucidate the pathophysiological role of the exonic deletion of RELN in SCZ, we conducted behavioral and neurochemical analyses using heterozygous Relnrl-Orl/+ mice. These mice exhibited abnormalities in anxiety, social behavior, and motor learning; the deficits in motor learning were ameliorated by antipsychotics. Methamphetamine-induced hyperactivity and dopamine release were significantly reduced in the Relnrl-Orl/+ mice. In addition, the levels of GABAergic markers were decreased in the brain of these mice. Taken together, our results suggest that the exonic deletion of RELN plays a pathological role, implicating functional changes in the dopaminergic and GABAergic systems, in the pathophysiology of SCZ.

20.
World Neurosurg ; 119: 54-57, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30017765

RESUMO

BACKGROUND: Neovascularization (NV) plays an important role in plaque progression and plaque vulnerability. However, visualization of NV is difficult using standard imaging tools. Recently, optical frequency domain imaging (OFDI) has provided images of intraplaque microstructure that could not be visualized by previous imaging modalities. Here we report a rare case of NV in the carotid plaque detected both before carotid artery stenting (CAS) and in an in-stent restenotic lesion using OFDI. CASE DESCRIPTION: A 71-year-old man with asymptomatic severe left carotid artery stenosis was scheduled for CAS. The degree of stenosis had progressed during short-term follow-up. Preoperative magnetic resonance imaging suggested vulnerable plaque. We performed OFDI to evaluate plaque morphology before and after the CAS procedure. Before CAS, OFDI revealed multiple NVs in the carotid plaque, localized around the most stenotic lesion. After CAS, OFDI showed good apposition of the stent to the vascular wall. At 5 months after CAS, in-stent restenosis was detected, which was treated by CAS. Before CAS of the restenotic lesion, OFDI revealed multiple NVs in the restenotic lesion inside the stent struts. After stenting, no ischemic lesions were detected, and restenosis did not occur again over the 1-year follow-up period. CONCLUSIONS: In carotid artery plaque, NV might correlate with plaque progression and in-stent restenosis. OFDI enables advanced evaluation of NVs in the carotid artery plaque.

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