Separate optogenetic manipulation of Nerve/glial antigen 2 (NG2) glia and mural cells using the NG2 promoter.

Nerve/glial antigen 2 (NG2) is a protein marker of NG2 glia and mural cells, and NG2 promoter activity is utilized to target these cells. However, the NG2 promoter cannot target NG2 glia and mural cells separately. This has been an obstacle for NG2 glia-specific manipulation. Here, we developed transgenic mice in which either cell type can be targeted using the NG2 promoter. We selected a tetracycline-controllable gene induction system for cell type-specific transgene expression, and generated NG2-tetracycline transactivator (tTA) transgenic lines. We crossed tTA lines with the tetO-ChR2 (channelrhodopsin-2)-EYFP line to characterize tTA-dependent transgene induction. We isolated two unique NG2-tTA mouse lines: one that induced ChR2-EYFP only in mural cells, likely due to the chromosomal position effect of NG2-tTA insertion, and the other that induced it in both cell types. We then applied a Cre-mediated set-subtraction strategy to the latter case and eliminated ChR2-EYFP from mural cells, resulting in NG2 glia-specific transgene induction. We further demonstrated that tTA-dependent ChR2 expression could manipulate cell function. Optogenetic mural cell activation decreased cerebral blood flow, as previously reported, indicating that tTA-mediated ChR2 expression was sufficient to impact cellular function. ChR2-mediated depolarization was observed in NG2 glia in acute hippocampal slices. In addition, ChR2-mediated depolarization of NG2 glia inhibited their proliferation but promoted their differentiation in juvenile mice. Since the tTA-tetO combination is expandable, the mural cell-specific NG2-tTA line and the NG2 glia-specific NG2-tTA line will permit us to conduct observational and manipulation studies to examine in vivo function of these cells separately.

A study on the examination of sense of coherence-related factors in Japanese junior high school students and their mothers.

This study examined the relationship between the sense of coherence (SOC), which is conceptually the ability to successfully cope with stress, of Japanese junior high school students and their mothers, and investigated SOC-related factors among the students. We analyzed self-reported data from 134 junior high school students (aged 12-14 years) and their mothers (average age: 45.5 ± 4.1 years), based in an urban area of Japan. We found a weak correlation between the SOC total scores of female students and their mothers; further, few subscales showed weak correlations. However, the SOC of male students was not correlated with that of their mothers, including the three subcomponents that constitute the SOC. The results of multiple regression analysis indicated that the SOC of female students was negatively associated with ASD-related characteristics, sensitivity to evaluation, and avoidant help-seeking style, and positively associated with a sense of belonging to the school. However, male students' SOC showed a negative relationship with excessive response to evaluation and a strong sense of parental control. To improve SOC in adolescents, it is necessary to consider their gender differences and support them, both at home and school.

Synaptic plasticity in hippocampal CA1 neurons of mice lacking inositol-1,4,5-trisphosphate receptor-binding protein released with IP3 (IRBIT).

In hippocampal CA1 neurons of wild-type mice, a short tetanus (15 or 20 pulses at 100 Hz) or a standard tetanus (100 pulses at 100 Hz) to a naive input pathway induces long-term potentiation (LTP) of the responses. Low-frequency stimulation (LFS; 1000 pulses at 1 Hz) 60 min after the standard tetanus reverses LTP (depotentiation [DP]), while LFS applied 60 min prior to the standard tetanus suppresses LTP induction (LTP suppression). We investigated LTP, DP, and LTP suppression of both field excitatory postsynaptic potentials and population spikes in CA1 neurons of mice lacking the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)-binding protein released with IP3 (IRBIT). The mean magnitudes of LTP induced by short and standard tetanus were not different in mutant and wild-type mice. In contrast, DP and LTP suppression were attenuated in mutant mice, whereby the mean magnitude of responses after LFS or tetanus were significantly greater than in wild-type mice. These results suggest that, in hippocampal CA1 neurons, IRBIT is involved in DP and LTP suppression, but is not essential for LTP. The attenuation of DP and LTP suppression in mice lacking IRBIT indicates that this protein, released during or after priming stimulations, determines the direction of LTP expression after the delivery of subsequent stimulations.

Oligodendrocytic Na+-K+-Cl- co-transporter 1 activity facilitates axonal conduction and restores plasticity in the adult mouse brain.

The juvenile brain presents plasticity. Oligodendrocytes are the myelinating cells of the central nervous system and myelination can be adaptive. Plasticity decreases from juvenile to adulthood. The mechanisms involving oligodendrocytes underlying plasticity are unclear. Here, we show Na+-K+-Cl- co-transporter 1 (NKCC1), highly expressed in the juvenile mouse brain, regulates the oligodendrocyte activity from juvenile to adulthood in mice, as shown by optogenetic manipulation of oligodendrocytes. The reduced neuronal activity in adults was restored by Nkcc1 overexpression in oligodendrocytes. Moreover, in adult mice overexpressing Nkcc1, long-term potentiation and learning were facilitated compared to age-matched controls. These findings demonstrate that NKCC1 plays a regulatory role in the age-dependent activity of oligodendrocytes, furthermore inducing activation of NKCC1 in oligodendrocytes can restore neuronal plasticity in the adult mouse brain.

[Development and testing of reliability and validity of a subjective QOL scale for older adults perceiving a dynamic healthy life through the three dimensions of biological life, everyday life, and overall course of life].

Objectives　To develop and assess the reliability and validity of a scale measuring subjective quality of life (QOL), which encompasses the "strength and ability" to live positively through the three dimensions of biological life, everyday life, and overall course of life, in order to support QOL in older adults.Methods　We reviewed related literature and conducted interviews with patients with chronic diseases. Participants rated their QOL on a seven-point scale using the visual analog scale. Interviewer-administered questionnaires were used to collect data from 100 older adults living in their own homes. The participants were between the ages of 70 and 84, and were recruited from comprehensive community support centers or from among hospital outpatients. We assessed scale reliability using Cronbach's α, item-total (I-T) correlation analysis, and calculation of α coefficient-if-item-deleted. We examined content validity by analyzing the content of the free response items. To evaluate construct validity, we carried out a hierarchical multiple regression analysis, examined the semantic content of the factors related to subjective QOL, and confirmed consistency with previous studies.Results　Regarding the reliability analysis of the scale, the α coefficient was 0.898, and both the I-T correlation and α coefficient-if-item-deleted exceeded the minimum value considered reliable. In examining content validity, the categories extracted for each of the three dimensions were found to demonstrate the characteristics of the general ideas of each dimension of QOL. Thus, the scale was confirmed to have overall content validity. As for the assessment of validity of its constitutive concepts, subjective QOL scores were significantly high among participants who had jobs, had role-related or financial capacity, used two or more nursing services, or scored high in perceived health competence, social networking, and sense of coherence (SOC). In addition, "meaningfulness" of SOC, and financial capacity had significant correlations with subjective QOL. These results are consistent with past research and therefore confirm construct validity.Conclusion　This study sufficiently confirmed the reliability and validity of the scale, and consequently its usability.

Related Changes in Personal Recovery, Benefit Finding, and Sense of Coherence among People with Chronic Mental Illness: A Two-Wave Study.

Personal recovery is a process of developing new meaning and purpose in life beyond the catastrophic effects of mental illness. Benefit finding (BF) is conceptualized as finding positive changes or benefits through experiences in adversity. Sense of coherence (SOC) focuses on how people can stay healthy and maintain well-being, even in adversity. This study aimed to examine the relationships among the initial levels and longitudinal changes in personal recovery, BF, and SOC among people with chronic mental illness in Japan. In this longitudinal study, a two-wave self-report questionnaire survey was conducted for service users aged 20 or older with mental illness using convenience sampling method in 2014 and 2015. We applied the Latent Change Score approach. Model fit was evaluated according to the CFI and RMSEA. Among 373 eligible participants at baseline, valid responses in both T1 and T2 from 195 respondents were included in the study (valid response rate = 52.3%). Among them, 65.6% were male, with average age of 45.6. The model of the three constructs at the two time points had good to reasonable fit to the data. The initial levels and changes in personal recovery, BF, and SOC were significantly and positively related to each other.

Changes in Japanese Junior High School Students' Sense of Coherence Before and After the Onset of the COVID-19 Pandemic: A Longitudinal Study of Children and Mothers.

We conducted a longitudinal study to clarify the changes in the sense of coherence (SOC); that is, the ability to cope with stress successfully, of 166 Japanese junior high school students and their mothers before and after the onset of the COVID-19 pandemic. First, we analyzed changes in SOC at three time points for all students and divided them into two groups: Group 1 included students with SOC scores that increased or maintained before and after the onset of the pandemic and Group 2 included students with decreased SOC scores after the onset of the pandemic. Second, we conducted a comparative analysis between the two groups. Overall, results indicated that student's SOC scores increased. Additionally, interpersonal stress scores were lower after the onset of the pandemic than before. There were almost no differences in family relationships, financial conditions, or personality tendencies between the two groups. However, Group 2 did not regain their sense of belonging to school. In this group, the frequency of stress experiences in club activities after the onset of the pandemic, troubles with the opposite gender, and inability to catch up with the contents of the subject lecture were high. The accumulation of small stressors may have hindered the maintenance of a sense of school affiliation. Mothers of students in Group 2 either were full-time employees at baseline or had started a new job after the onset of the pandemic. Their children may have been affected by the household's damaged financial budget and changes in mother's working styles. As COVID-19 reduced the number of days students went to school, students' SOC could have reduced had they not felt a sense of presence or belonging due to the lack of participation in club activities, school events, etc. Teachers and mothers should communicate carefully with their students and children, respectively, to develop a sense of belonging.

Factors Influencing Sense of Coherence: Family Relationships, High School Life and Autism Spectrum Tendency.

Adolescence is marked by significant life stress. Recently, school refusal and dropouts as well as suicide among Japanese adolescents have increased. Sense of coherence (SOC) is recognized as a competency that helps people deal with stress. The purpose of this study was to examine the factors influencing SOC in male and female high school students. We conducted a survey with 203 pairs of high school students and their mothers, in Tokyo, to explore their SOC, family relationships, school belonging, and autistic traits. Analysis of the data revealed a weak relationship between female students' SOC and that of their mothers, and no relationship between male students' SOC and their mothers' SOC. Feelings of acceptance and recognition from teachers improved students' SOC, irrespective of gender. Low SOC in mothers had a negative impact on female students' SOC, and children's lack of imagination (an autism spectrum tendency) had a negative impact on male students' SOC. This study revealed the importance of support at home and school according to the needs of both genders.

The Benefit Finding Questionnaire (BFQ): Scale Development, Validation, and Its Psychometric Properties Among People with Mental Illness.

Benefit finding has been defined as positive life changes that result from a stressful event, such as the diagnosis of chronic illness. The present study aimed to develop a benefit finding questionnaire (BFQ) and examine its psychometric property among people with chronic mental illness in Japan. This study adopted a mixed method composed of three phases, including Phase 1: To draft the item pool and design the BFQ based on literature review and discussion among the authors, Phase 2: To revise and refine the drafted items through feedback from focus group interviews and further consideration, and Phase 3: To examine the psychometric properties of the BFQ following the questionnaire survey for people with chronic mental illness and validation of the questionnaire. In Phase 3, a cross-sectional, self-administered questionnaire survey was conducted for mental health service users. Among the 373 eligible participants, we used data from 265 respondents for the analyses (valid response rate = 71.0%). About 65% were male, and the average age was 45.3 years (SD = 12.9). Around 70% were diagnosed with schizophrenia. Factorial, concurrent, and divergent validities, as well as reliability were explored. The 21-item BFQ demonstrated good factorial validity, concurrent and divergent validities, and sufficient internal consistency reliability among people with chronic mental illness. It appears to be a useful scale to assess experience of benefit finding among people with chronic mental illness. Further large-scale research will ensure verification of the scale among people with other illnesses or difficulties.

Depotentiation depends on IP3 receptor activation sustained by synaptic inputs after LTP induction.

In CA1 neurons of guinea pig hippocampal slices, long-term potentiation (LTP) was induced in field excitatory postsynaptic potentials (EPSPs) or population spikes (PSs) by the delivery of high-frequency stimulation (HFS, 100 pulses at 100 Hz) to CA1 synapses, and was reversed by the delivery of a train of low-frequency stimulation (LFS, 1000 pulses at 2 Hz) at 30 min after HFS (depotentiation), and this effect was inhibited when test synaptic stimulation was halted for a 19-min period after HFS or for a 20-min period after LFS or applied over the same time period in the presence of an antagonist of N-methyl-D-aspartate receptors (NMDARs), group I metabotropic glutamate receptors (mGluRs), or inositol 1, 4, 5-trisphosphate receptors (IP3Rs). Depotentiation was also blocked by the application of a Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor or a calcineurin inhibitor applied in the presence of test synaptic input for a 10-min period after HFS or for a 20-min period after LFS. These results suggest that, in postsynaptic neurons, the coactivation of NMDARs and group I mGluRs due to sustained synaptic activity following LTP induction results in the activation of IP3Rs and CaMKII, which leads to the activation of calcineurin after LFS and depotentiation of CA1 synaptic responses.

Oligodendrocyte Physiology Modulating Axonal Excitability and Nerve Conduction.

Oligodendrocytes enable saltatory conduction by forming a myelin sheath around axons, dramatically boosts action potential conduction velocity. In addition to this canonical function of oligodendrocytes, it is now known that oligodendrocytes can respond to neuronal activity and regulate axonal conduction. Importantly, white matter plasticity, including adaptive responses by oligodendrocytes, has been shown to be involved in learning and memory. In this chapter, the role of oligodendrocytes in axonal conduction and axonal excitability will be reviewed. Focus will be paid to the mechanisms through which oligodendrocytes, including perineuronal oligodendrocytes, facilitate and suppress axonal conduction.

Region- and Cell Type-Specific Facilitation of Synaptic Function at Destination Synapses Induced by Oligodendrocyte Depolarization.

The axonal conduction of action potentials affects the absolute time it takes to transmit nerve impulses as well as temporal summation at destination synapses. At the physiological level, oligodendrocyte depolarization facilitates axonal conduction along myelinated fibers in the hippocampus; however, the functional significance of this facilitation is largely unknown. In this study, we examined the physiology of the facilitation of axonal conduction by investigating the changes in synaptic responses at destination synapses using male and female mice in which channelrhodopsin-2 expression was restricted to oligodendrocytes. The subiculum, one of the projection areas of the examined axons at the alveus of the hippocampus, is divided into three regions (proximal, mid, and distal) and contains two types of principal neurons: regular firing and bursting pyramidal cells. We found a significant increase in excitatory synaptic responses following optogenetic oligodendrocyte depolarization in bursting neurons at two of the three regions, but not in regular firing neurons at any region. The long-term potentiation (LTP) induced by theta burst stimulation at the synapses showing a significant increase was also enhanced after oligodendrocyte depolarization. Conversely, the reduction of oligodendrocyte depolarization during theta burst stimulation, which was achieved by photostimulation of archaerhodopsin-T expressed selectively on oligodendrocytes, reduced the magnitude of LTP. These results show that oligodendrocyte depolarization contributes to the fine control of synaptic activity between the axons they myelinate and targets subicular cells in a region- and cell type-specific manner, and suggest that oligodendrocyte depolarization during conditioning of stimuli is involved in the induction of LTP.SIGNIFICANCE STATEMENT All activity in the nervous system depends on the propagation of action potentials. Changes in the axonal conduction of action potentials influence the timing of synaptic transmission and information processing in neural circuits. At the physiological level, oligodendrocyte depolarization facilitates axonal conduction along myelinated fibers. In this study, we investigated the functional significance of the facilitation of axonal conduction induced by physiological oligodendrocyte depolarization. Using optogenetics and electrophysiological recordings, we demonstrated that oligodendrocyte depolarization in mice expressing channelrhodopsin-2 on oligodendrocytes increased excitatory synaptic responses and enhanced the induction of long-term potentiation at destination synapses in a region- and cell type-specific manner. This facilitation may have a hitherto unappreciated influence on the transfer of information between regions in the nervous system.

Having another child without intellectual disabilities: Comparing mothers of a single child with disability and mothers of multiple children with and without disability.

To investigate how having a child without a disability is related to maternal mental health and its predictors, we compared mothers of a single child with intellectual disabilities (single-child group, n = 117) and mothers of children with and without intellectual disabilities (multiple-children group, n = 457), in Japan. Compared to the multiple-children group, the single-child group had lower hope and social capital and poorer mental health; furthermore, 42.5% of them had decided not to have another child, despite desiring one. Hope was the strongest predictor of mental health in both groups but was more positively related to mental health in the multiple-children group. The fear of the possibility of the next child having a disability and receiving inadequate support were the obstacles for mothers who had decided not to have another child. Thus, greater support and more opportunities for obtaining adequate information about the implications of having another child may be needed.

Reliability and validity of a 12-item medication adherence scale for patients with chronic disease in Japan.

BACKGROUND: To improve and support medication adherence among patients with chronic diseases, especially for long-term medication, it is important to consider both their relationship with healthcare providers and their lifestyle. We tested the reliability and validity of a modified 12-item Medication Adherence Scale. METHODS: We revised a 14-item measure of medication adherence, created in 2009, to a more concise and clear 12-item version, and we verified the reliability and validity of the 12-item scale. We included 328 patients with chronic diseases participating in the Chronic Disease Self-Management Program in Japan from 2011 to 2014. Confirmatory factor analysis was used to assess whether the four factors assessed were the same as the previous 14-item Medication Adherence Scale. Cronbach's coefficient alpha was used to assess internal consistency reliability, and the relationships between patient demographic characteristics and medication adherence were compared with previous studies. RESULTS: The 12 items were categorized into the four factors "medication compliance", "collaboration with healthcare providers", "willingness to access and use information about medication", and "acceptance to take medication and how taking medication fits patient's lifestyle". Confirmatory factor analysis showed χ2/df = 2.6, CFI = 0.94, and RMSEA = 0.069. Cronbach's alpha for the 12-item scale was 0.78. Cronbach's alpha for the four subscales was 0.74, 0.81, 0.67, and 0.45. Higher medication adherence was significantly associated with being a female patient, living with someone else, and age 40-49 years versus age 20-29 years. These relationships were the same as in previous studies. CONCLUSIONS: We modified our original 14-item scale to a 12-item Medication Adherence Scale for patients with chronic diseases, which considers their relationship with healthcare providers and lifestyle. Refinement might be needed because of the relatively low reliability of subscales. However, the modified scale is expected to contribute to more effective self-management of medication and to improving medication adherence, particularly among patients with chronic diseases who require long-term medication not only in Japan but also in other countries.

Ectopic positioning of Bergmann glia and impaired cerebellar wiring in Mlc1-over-expressing mice.

Mlc1 is a causative gene for megalencephalic leukoencephalopathy with subcortical cysts, and is expressed in astrocytes. Mlc1-over-expressing mice represent an animal model of early-onset leukoencephalopathy, which manifests as astrocytic swelling followed by myelin membrane splitting in the white matter. It has been previously reported that Mlc1 is highly expressed in Bergmann glia, while the cerebellar phenotypes of Mlc1-over-expressing mouse have not been characterized. Here, we examined the cerebellum of Mlc1-over-expressing mouse and found that the distribution of Bergmann glia (BG) was normally compacted along the Purkinje cell (PC) layer until postnatal day 10 (P10), while most BG were dispersed throughout the molecular layer by P28. Ectopic BG were poorly wrapped around somatodendritic elements of PCs and exhibited reduced expression of the glutamate transporter glutamate-aspartate transporter. Extraordinarily slow and small climbing fiber (CF)-mediated excitatory post-synaptic currents, which are known to be elicited under accelerated glutamate spillover, emerged at P20-P28 when BG ectopia was severe, but not at P9-P12 when ectopia was mild. Furthermore, maturation of CF wiring, which translocates the site of innervation from somata to proximal dendrites, was also impaired. Manipulations that restricted the Mlc1-over-expressing period successfully generated mice with and without BG ectopia, depending on the over-expressing period. Together, these findings suggest that there is a critical time window for mechanisms that promote the positioning of BG in the PC layer. Once normal positioning of BG is affected, the differentiation of BG is impaired, leading to insufficient glial wrapping, exacerbated glutamate spillover, and aberrant synaptic wiring in PCs. Open Practices Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/ Cover Image for this issue: doi: 10.1111/jnc.14199.

Public perceptions toward mental illness in Japan.

AIM: The purpose was to characterize public perceptions in Japan of mental illness and how they related to stigma-related attitudes for the same. METHODS: Data were obtained using a vignette survey conducted as a part of the Stigma in Global Context - Mental Health Study and contained a nationally representative sample (n = 994). The survey was conducted using a multi-mode approach (face-to-face interviews, the drop-off-and-pick-up, postal collection) from September to December 2006, with a multi-stage probability sample of Japanese residents aged 18-64 years. Respondents were randomly assigned one of four vignette conditions that described psychiatric disorders meeting the diagnostic criteria for schizophrenia and major depressive disorder (one vignette for each gender exhibiting each diagnosis). We compared respondents' stigma-related attitudes and perceptions toward mental illness between vignettes. RESULTS: Over 80% of Japanese participants believed that depressive disorder or schizophrenia could be cured via treatment. However, Japanese people still had relatively strong vigilance and denial of competency toward schizophrenia. CONCLUSIONS: Participants expressed the belief that mental illnesses are curable, but stigma toward people with schizophrenia was still relatively strong.

Modulatory Effects of Perineuronal Oligodendrocytes on Neuronal Activity in the Rat Hippocampus.

Action potentials are fundamental to relaying information from region to region in the nervous system. Changes in action potential firing patterns in neural circuits influence how the brain processes information. In our previous study, we focused on interneuron/perineuronal astrocyte pairs in the hippocampal CA1 region and reported that direct depolarization of perineuronal astrocytes modulated the firing pattern of interneurons. In the current study, we investigated the morphological and electrophysiological properties of perineuronal oligodendrocytes, and examined their modulatory effects on interneuronal firing in the CA1 region. Perineuronal oligodendrocytes only had a few processes, which were crooked, intricately twisted, and twined around the soma and proximal region of the main processes of adjacent interneurons. Whole-cell current patterns of perineuronal oligodendrocytes were homogenous and the current-voltage relationship showed remarkable outward rectification. Although the K+ channel blockers, tetraethylammonium and 4-aminopyridine, clearly blocked outward currents, Ba2+ did not significantly alter whole-cell currents. Unlike perineuronal astrocytes, the depolarization of perineuronal oligodendrocytes had no effect on interneuronal firing; however, when the interneurons were firing at a higher frequency, the hyperpolarization of perineuronal oligodendrocytes suppressed their action potentials. The suppressive effects of perineuronal oligodendrocytes were inhibited in the presence of a low concentration of tetraethylammonium, which selectively blocked deep and fast afterhyperpolarization. These results suggest that perineuronal oligodendrocytes suppress interneuronal firing through their influence on K+ channels, which are responsible for deep and fast afterhyperpolarization.

Positive change and sense of coherence in Japanese mothers of children with congenital appearance malformation.

The purpose of this study was to clarify the factors related to perceived positive change and sense of coherence in mothers (n = 293) of children with cleft lip and palate. The strongest negative correlation with sense of coherence was stigmatizing words from others; there were positive correlations with social capital and perceived positive change. Multiple regression showed that to be aware of positive changes, mothers share their feelings with mothers in the same position, are rooted in a safe community and do not feel isolated in parenting. People who have experienced adversity may have the opportunity to enhance sense of coherence by obtaining perceived positive change.