Selective expression of KCNS3 potassium channel α-subunit in parvalbumin-containing GABA neurons in the human prefrontal cortex

The cognitive deficits of schizophrenia appear to be associated with altered cortical GABA neurotransmission in the subsets of inhibitory neurons that express either parvalbumin (PV) or somatostatin (SST). Identification of molecular mechanisms that operate selectively in these neurons is essential for developing targeted therapeutic strategies that do not influence other cell types. Consequently, we sought to identify, in the human cortex, gene products that are expressed selectively by PV and/or SST neurons, and that might contribute to their distinctive functional properties. Based on previously reported expression patterns in the cortex of mice and humans, we selected four genes: KCNS3, LHX6, KCNAB1, and PPP1R2, encoding K+ channel Kv9.3 modulatory α-subunit, LIM homeobox protein 6, K+ channel Kvβ1 subunit, and protein phosphatase 1 regulatory subunit 2, respectively, and examined their colocalization with PV or SST mRNAs in the human prefrontal cortex using dual-label in situ hybridization with 35S- and digoxigenin-labeled antisense riboprobes. KCNS3 mRNA was detected in almost all PV neurons, but not in SST neurons, and PV mRNA was detected in >90% of KCNS3 mRNA-expressing neurons. LHX6 mRNA was detected in almost all PV and >90% of SST neurons, while among all LHX6 mRNA-expressing neurons 50% expressed PV mRNA and >44% expressed SST mRNA. KCNAB1 and PPP1R2 mRNAs were detected in much larger populations of cortical neurons than PV or SST neurons. These findings indicate that KCNS3 is a selective marker of PV neurons, whereas LHX6 is expressed by both PV and SST neurons. KCNS3 and LHX6 might be useful for characterizing cell-type specific molecular alterations of cortical GABA neurotransmission and for the development of novel treatments targeting PV and/or SST neurons in schizophrenia. © 2012 Georgiev et al

統合失調症の治療効果における神経細胞新生の関与に関する研究

【目的】統合失調症の陰性症状、認知機能障害対するD1/D2受容体作動薬であるpergolideの効果を二重盲検比較試験で検討した。【方法】7病院において倫理委員会の承認を得た上で被験者に研究の内容を文書および口頭で説明し、文書での同意を得た。臨床試験はGCPならびにヘルシンキ宣言を遵守した上で行った。選択基準は1)年齢18〜50歳の統合失調症患者、2)risperidoneを2〜6mgの一定用量で8週間以上服用中、3)陽性および陰性症状評価尺度(PANSS)の陰性症状評価尺度が15点以上、4)試験開始前4週間におけるPANSSの点数の変動が20%以内で症状が安定している者である。除外基準は1)認知機能に影響を与えると考えられる既往歴および薬物治療を受けている、2)他の精神疾患の既往歴を持つ者である。被験者に無作為にpergolideまたはプラセボを割り付けた上で8週間で投与を受ける。pergolideは開始時に250μgで1週間投与し、2週目より750μgに増量し、合計8週間の投与した。精神症状の評価にはPANSS、社会機能の評価にはクオリティ・オブ・ライフ評価尺度(QLS)を用いた。錐体外路症状、アカシジア、ディスキネジアの評価はSimpson-Angus Rating Scale for Extrapyramidal Symptoms、 the Barnes Akathisia Scale、 and the Abnormal Involuntary Movement Scaleを用いた。病前の推定知能指数は日本語版NART(JART)を、現在の知能指数はWAIS-R短縮版を使用して測定した。認知機能の評価は神経心理学検査バッテリー(実行機能、空間作動記憶、持続的注意、言語記憶、言語性作動記憶、言語流暢性)を用いた。【結果】pergolide群13名、プラセボ群13名中、22名の被験者が全てのプロトコルを完了した。pergolide群とプラセボ群との間で、性別の割合、年齢、教育年齢、発症年齢、罹病期間、risperidoneの用量、試験開始時でのPANSSのスコアのいずれも差はなかった。試験薬と時間の関連性について二元配置分散分析を用いた解析で、PANSSの総スコア、陽性症状スコア、陰性症状スコア、QLSスコア、神経心理学的検査のいずれに評価項目においても、pergolide群とプラセボ群の間に有意差は見られなかった。Method. Patients were included in the study if they: 1) were age 18-50 years, met the DSM-IV criteria for schizophrenia as assessed with the Structured Clinical Interview for DSM-IV, Research Version (SCID-RV); 2)were treated with a stable-dose of risperidone, raging 2 to 6mg, for more than 8 weeks; 3) had a score 〓15 on negative subscale items in Positive and Negative Syndrome Scale (PANSS), 4)had a minimum period of symptom stability, defined as no more than 20% change on consecutive ratings on PANSS for at lease 4 weeks. Subjects entered a 8-weeks, double-blind treatment phase during which they were randomly assigned to receive either pergolide or placebo, which was added to risperidone treatment. Pergolide was started at a daily dose of 250 μg for I week and increased to 750 μg from the second week, continuing for total of 8 weeks. The study medication and placebo were provided in identically appearing capsules. The PANSS was used to assess the severity of psychiatric symptoms, and the Quality of Life Scale (QLS) abbreviated version was used to measure general social functioning. Extrapyramidal symptoms, akathisia, and dyskinesia, were evaluated by the Simpson-Angus Rating Scale for Extrapyramidal Symptoms, the Barnes Akathisia Scale, and the Abnormal Involuntary Movement Scale. Estimates of premorbid and current intellectual functions were made by Japanese version of National Adult Reading Test(JART)and short form of Wechsler Adult Intelligence Scale-Revised(WAIS-R). Patients were tested on a comprehensive neuropsychological test battery: executive function, spatial working memory, sustained attention, verbal memory, verbal working memory, verbal fluency. Premorbid and current intellectual functions were measured at the baseline. Results. Twenty-six subjects were randomized to either pergolide or placebo (13 pergolide, 13 placebo; mean age t SD, 33.9 t 5.5 in pergolide, 37.2 ± 8.4 in placebo). Twenty-two subjects completed the entire protocol. No significant differences were noted between the PANSS total, positive scale, and negative scale scores between groups at baseline. Repeated-measures ANOVA revealed no significant differences between pergolide and placebo treatment groups during 8 weeks of the study with respect to PANSS total, PANSS positive, PANSS negative, and QLS scores. There were no statistically significant differences in change(from baseline to week 8)on any of the cognitive measures between the placebo and pergolide treated groups.研究課題/領域番号:18390320, 研究期間(年度):2006-2007出典：「統合失調症の治療効果における神経細胞新生の関与に関する研究」研究成果報告書　課題番号18390320 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）)　　　本文データは著者版報告書より作

Identification of an unconventional process of instrumental learning characteristically initiated with outcome devaluation-insensitivity and generalized action selection.

The distinction between goal-directed action and habitual response, particularly with respect to moderate or extended appetitive instrumental training, is well documented; however, the propensity toward instrumental behavior in the early training stage has not been elucidated. In this study, we trained Sprague Dawley rats to press a lever to obtain food as an outcome for various time periods and monitored the changes in their sensitivity to outcome devaluation and choice between the levers they had been trained with and unfamiliar levers. After the extensive training with a random interval schedule, the rats were insensitive to outcome devaluation, and exhibited a typical habit-like phenotype, as previously reported, and the untrained leverpresses were relatively rare and sporadic. During the initial stage of training (≤1 week), the rats exhibited a similar insensitivity to the devaluation; however, in contrast to the overtrained condition, they performed distinctive unbiased leverpresses on both the trained and untrained levers. Thus, we propose a possibility that, contrary to the authentic concept that instrumental learning is initiated with an outcome devaluation-sensitive goal-directed stage, under some conditions, this learning can unconventionally begin with the initial stage that is distinct from both goal-directed action and habitual response. © The Author(s) 2017

Repeated Exposure of Adult Rats to Transient Oxidative Stress Induces Various Long-Lasting Alterations in Cognitive and Behavioral Functions

Exposure of neonates to oxidative stress may increase the risk of psychiatric disorders such as schizophrenia in adulthood. However, the effects of moderate oxidative stress on the adult brain are not completely understood. To address this issue, we systemically administrated 2-cyclohexen-1-one (CHX) to adult rats to transiently reduce glutathione levels. Repeated administration of CHX did not affect the acquisition or motivation of an appetitive instrumental behavior (lever pressing) rewarded by a food outcome under a progressive ratio schedule. In addition, response discrimination and reversal learning were not affected. However, acute CHX administration blunted the sensitivity of the instrumental performance to outcome devaluation, and this effect was prolonged in rats with a history of repeated CHX exposure, representing pro-depression-like phenotypes. On the other hand, repeated CHX administration reduced immobility in forced swimming tests and blunted acute cocaine-induced behaviors, implicating antidepressant-like effects. Multivariate analyses segregated a characteristic group of behavioral variables influenced by repeated CHX administration. Taken together, these findings suggest that repeated administration of CHX to adult rats did not cause a specific mental disorder, but it induced long-term alterations in behavioral and cognitive functions, possibly related to specific neural correlates

Pre-stress performance in an instrumental training predicts post-stress behavioral alterations in chronically stressed rats

Stress is a major factor in the development of major depressive disorder (MDD), but few studies have assessed individual risk based on pre-stress behavioral and cognitive traits. To address this issue, we employed appetitive instrumental lever pressing with a progressive ratio (PR) schedule to assess these traits in experimentally naive Sprague-Dawley rats. Based on four distinct traits that were identified by hierarchical cluster analysis, the animals were classified into the corresponding four subgroups (Low Motivation, Quick Learner, Slow Learner, and Hypermotivation), and exposed to chronic unpredictable stress (CUS) before monitoring their post-stress responses for 4 weeks. The four subgroups represented the following distinct behavioral phenotypes after CUS: the Low Motivation subgroup demonstrated weight loss and a late-developing paradoxical enhancement in PR performance that may be related to inappropriate decision-making in human MDD. The Quick Learner subgroup exhibited a transient loss of motivation and the habituation of serum corticosterone (CORT) response to repeated stress. The Slow Learner subgroup displayed resistance to demotivation and a suppressed CORT response to acute stress. Finally, the Hypermotivation subgroup exhibited resistance to weight loss, habituated CORT response to an acute stress, and a long-lasting amotivation. Overall, we identified causal relationships between pre-stress traits in the performance of the instrumental training and post-stress phenotypes in each subgroup. In addition, many of the CUS-induced phenotypes in rats corresponded to or had putative relationships with representative symptoms in human MDD. We concluded that the consequences of stress may be predictable before stress exposure by determining the pre-stress behavioral or cognitive traits of each individual in rats. ©2015 Iguchi, Kosugi, Lin, Nishikawa, Minabe and Toda

Association Between Magnetoencephalographic Interictal Epileptiform Discharge and Cognitive Function in Young Children With Typical Development and With Autism Spectrum Disorders

Electroencephalograms of individuals with autism spectrum disorders (ASD) show higher rates of interictal epileptiform discharges (IEDs), which are known to have an inverse association with cognitive function in typically developed (TD) children. Nevertheless, that phenomenon has not been investigated adequately in children with ASD. From university and affiliated hospitals, 163 TD children (84 male, 79 female, aged 32–89 months) and 107 children (85 male, 22 female, aged 36–98 months) with ASD without clinical seizure were recruited. We assessed their cognitive function using the Kaufman Assessment Battery for Children (K-ABC) and recorded 10 min of MEG. Original waveforms were visually inspected. Then a linear regression model was applied to evaluate the association between the IED frequency and level of their cognitive function. Significantly higher rates of IEDs were found in the ASD group than in the TD group. In the TD group, we found significant negative correlation between mental processing scale scores (MPS) and the IED frequency. However, for the ASD group, we found significant positive correlation between MPS scores and the IED frequency. In terms of the achievement scale, correlation was not significant in either group. Although we found a correlative rather than a causal effect, typically developed children with higher IED frequency might better be followed up carefully. Furthermore, for children with ASD without clinical seizure, clinicians might consider IEDs as less harmful than those observed in TD children

Developmental Trajectory of Infant Brain Signal Variability: A Longitudinal Pilot Study

The infant brain shows rapid neural network development that considerably influences cognitive and behavioral abilities in later life. Reportedly, this neural development process can be indexed by estimating neural signal complexity. However, the precise developmental trajectory of brain signal complexity during infancy remains elusive. This study was conducted to ascertain the trajectory of magnetoencephalography (MEG) signal complexity from 2 months to 3 years of age in five infants using multiscale entropy (MSE), which captures signal complexity at multiple temporal scales. Analyses revealed scale-dependent developmental trajectories. Specifically, signal complexity predominantly increased from 5 to 15 months of age at higher temporal scales, whereas the complexity at lower temporal scales was constant across age, except in one infant who showed decreased complexity. Despite a small sample size limiting this study’s power, this is the first report of a longitudinal investigation of changes in brain signal complexity during early infancy and is unique in its application of MSE analysis of longitudinal MEG data during infancy. The results of this pilot study may serve to further our understanding of the longitudinal changes in the neural dynamics of the developing infant brain