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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. Mlc1 is a causative gene for megalencephalic leukoencephalopathy with subcortical cysts. In the cerebellum, Mlc1 is highly expressed in Bergmann glia (BG), which is one of the astrocyte associated with Purkinje cells (PCs). Here, we found that Mlc1 over‐expression in astrocyte resulted in the BG ectopia and insufficient association with PCs, and we revealed the critical time window inducing BG ectopia. Once BG impairments were established, synaptic wiring on PCs were affected by glutamate spillover via the insufficient BG association. Our results indicated that time course of BG cytodifferentiation is one of the crucial determinant for synaptic wiring on PCs. Cover Image for this issue: doi: 10.1111/jnc.14199. [ABSTRACT FROM AUTHOR]

Background Although sense of coherence ( SOC) moderates parental stress, the relationship between SOC, parental mental health and physical punishment of children with intellectual disabilities remains uncertain. The present authors describe parental physical punishment towards children with intellectual disabilities and investigate its related demographic characteristics, SOC and parental mental health. Materials and Methods With the cooperation of Tokyo's 10 special needs schools, the present authors obtained 648 questionnaire responses from parents of children with intellectual disabilities. Results Of the parents, 69.7% reported having physically punished their children with intellectual disabilities. This was positively associated with parents' younger age, poorer mental health, lower SOC, children's younger age, birth order (firstborns) and disability type (autism/pervasive developmental disorder). Conclusions This is the first study supporting the relationship between SOC, mental health and physical punishment use among parents of children with intellectual disabilities. It may assist the development of strategies to prevent physical abuse of children with disabilities. [ABSTRACT FROM AUTHOR]

The axonal conduction of action potentials in the nervous system is generally considered to be a stable signal for the relaying of information, and its dysfunction is involved in impairment of cognitive function. Recent evidence suggests that the conduction properties and excitability of axons are more variable than traditionally thought. To investigate possible changes in the conduction of action potentials along axons in the central nervous system, we recorded action potentials from granule cells that were evoked and conducted antidromically along unmyelinated mossy fibers in the rat hippocampus. To evaluate changes in axons by eliminating any involvement of changes in the somata, two latency values were obtained by stimulating at two different positions and the latency difference between the action potentials was measured. A conditioning electrical stimulus of 20 pulses at 1 Hz increased the latency difference and this effect, which lasted for approximately 30 s, was inhibited by the application of an α-amino-3-hydroxy-5-methylisoxazole-4-propionate ( AMPA)/kainate receptor antagonist or a GluK1-containing kainate receptor antagonist, but not by an AMPA receptor-selective antagonist or an N-methyl- d-aspartate receptor antagonist. These results indicated that axonal conduction in mossy fibers is modulated in an activity-dependent manner through the activation of GluK1-containing kainate receptors. These dynamic changes in axonal conduction may contribute to the physiology and pathophysiology of the brain. [ABSTRACT FROM AUTHOR]

This study on individuals with type 2 diabetes living in Japan aimed to examine work-related factors that influence self-care and psychological health among people. A cross-sectional survey was conducted among 121 working adults with type 2 diabetes. A self-report questionnaire assessed demographics, work characteristics, self-disclosure of diabetes, support in the workplace, work-related difficulties due to diabetes, and workplace conformity. Dietary self-care, exercise, depression, and emotional distress were also evaluated. The results indicated statistically significant influence of working night shifts, self-disclosure of diabetes, and workplace conformity on dietary self-care. Work-related difficulties due to diabetes had negative effects on depression and emotional distress, and job control and support in the workplace were found to be correlated with emotional distress. These findings suggest that work-related factors have an impact on some forms of self-care activities and psychological health and that it is important to increase understanding of these issues and provide appropriate support for workers through education and counseling and adjustments in the workplace. [ABSTRACT FROM AUTHOR]

Aims: The objectives of this study were to understand the experiences of people with cleft lip and cleft palate (CLCP) and to describe the processes and factors leading to the acquisition of high self-esteem. Methods: Semi-structured interviews were conducted of 19 subjects with CLCP recruited via hospitals and through snowball sampling, and the results were analyzed qualitatively, comparing high and low self-esteem groups. Results: Participants with high self-esteem had gone through the phases of 'noticing their difference from others', 'knowing about and deepening their understanding of CLCP', 'no denial of their life with CLCP' and 'affirmation of life with CLCP'. Seven factor categories including 'received sufficient explanation of CLCP condition (from parents) in the early stage', 'have not received negative messages about CLCP' and 'feeling the presence of someone who accepts their feelings and supports them' were extracted as factors promoting these processes. Conclusions: Knowing about and understanding CLCP enables individuals to acquire a sense of coherence in their lives, which may be related to gaining a feeling of control over their cleft condition, acquiring a sense of autonomy, and finding a meaning for their lives. Thus, medical professionals should provide explanations that enable patients to understand CLCP, and also facilitate interaction between patients with the same condition. [ABSTRACT FROM AUTHOR]

This is the preliminary report of a study to evaluate the effectiveness of the Chronic Disease Self-management Program in Japan by comparing changes in health outcomes at the baseline and 3-month and 6-month follow-ups. The program is a patient-centered educational program for the self-management of chronic conditions. The study's participants were recruited from among the attendees of the program workshops. During the study period (August 2006 to May 2007), 18 workshops were held and 128 attendees agreed to participate in the study. The health outcomes that were measured included health status, self-management behaviors, utilization of health services, self-efficacy, satisfaction with daily living, and clinical indicators. These indicators were further analyzed by disease type: diabetes, rheumatic disease, and cardiovascular disease/dyslipidemia. The findings indicated statistically significant positive changes in health distress, coping with symptoms, stretching exercises, communication with the physician, and satisfaction with daily living. The positive changes were especially remarkable among the groups with diabetes and rheumatic disease. These findings suggest that the Chronic Disease Self-management Program can be effective for Japanese people with chronic conditions. [ABSTRACT FROM AUTHOR]

Hippocampal inhibitory interneurons have a central role in the control of network activity, and excitatory synapses that they receive express Hebbian and anti-Hebbian long-term potentiation (LTP). Because many interneurons in the hippocampus express nicotinic acetylcholine receptors (nAChRs), we explored whether exposure to nicotine promotes LTP induction in these interneurons. We focussed on a subset of interneurons in the stratum oriens/alveus that were continuously activated in the presence of nicotine due to the expression of non-desensitizing non-α7 nAChRs. We found that, in addition to α2 subunit mRNAs, these interneurons were consistently positive for somatostatin and neuropeptide Y mRNAs, and showed morphological characteristics of oriens-lacunosum moleculare cells. Activation of non-α7 nAChRs increased intracellular Ca2+ levels at least in part via Ca2+ entry through their channels. Presynaptic tetanic stimulation induced N-methyl-d-aspartate receptor-independent LTP in voltage-clamped interneurons at −70 mV when in the presence, but not absence, of nicotine. Intracellular application of a Ca2+ chelator blocked LTP induction, suggesting the requirement of Ca2+ signal for LTP induction. The induction of LTP was still observed in the presence of ryanodine, which inhibits Ca2+ -induced Ca2+ release from ryanodine-sensitive intracellular stores, and the L-type Ca2+ channel blocker nifedipine. These results suggest that Ca2+ entry through non-α7 nAChR channels is critical for LTP induction. Thus, nicotine affects hippocampal network activity by promoting LTP induction in oriens-lacunosum moleculare cells via continuous activation of non-α7 nAChRs. [ABSTRACT FROM AUTHOR]

Rapid activation of nicotinic acetylcholine receptors (nAChRs) at various anatomical and cellular locations in the hippocampus differentially modulates the operation of hippocampal circuits. However, it is largely unknown how the continued presence of nicotine affects the normal operation of hippocampal circuits. Here, we used single and dual whole-cell recordings to address this question. We found that horizontally oriented interneurons in the stratum oriens/alveus continuously discharged action potentials in the presence of nicotine. In these interneurons, bath application of nicotine produced slow inward currents that were well maintained and inhibited by the non-α7 antagonist dihydro-β-erythroidine. Single-cell reverse transcription-polymerase chain reaction analysis showed that nicotine-responding interneurons were consistently positive for the α2 subunit mRNA. These observations suggest that in the presence of nicotine, a subset of interneurons in the stratum oriens/alveus are continuously excited due to the sustained activation of α2* nAChRs. These interneurons were synaptically connected to pyramidal cells, and nicotine increased inhibitory baseline currents at the synapses and suppressed phasic inhibition at the same synapses. Nicotine-induced inhibitory activity increased background noise and masked small phasic inhibition in pyramidal cells, originating from other interneurons in the stratum radiatum. Thus, the continued presence of nicotine alters the normal operation of hippocampal circuits by gating inhibitory circuits through activating a non-desensitizing α2 nAChR subtype on a distinct population of interneurons. [ABSTRACT FROM AUTHOR]

Here, we show that chronic nicotine exposure induces changes in Src signaling for the modulation of N-methyl-d-aspartate receptor (NMDAR) function and LTP induction in CA1 pyramidal cells. Activation of muscarinic receptors normally potentiates NMDAR responses in pyramidal cells via a Gq/protein kinase C (PKC)/proline-rich tyrosine kinase 2/Src signaling cascade. However, muscarinic, PKC and Src stimulation had no effect on NMDAR responses after chronic nicotine treatment. The lack of effect was apparently due to enhanced tyrosine phosphorylation, and therefore further stimulation of the signaling cascade caused no effect on NMDAR responses. Interestingly, another Src-family kinase potentiated NMDAR responses after, but not before, chronic nicotine treatment. In control pyramidal cells, Src inhibitor peptides prevented tetanus-induced long-term potentiation (LTP). Conversely, in chronic nicotine-exposed cells, the inhibitor was ineffective in blocking tetanus-induced LTP. Furthermore, in control pyramidal cells, applying exogenous Src and administration of an endogenous Src-family kinase activator increased α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor (AMPAR)-mediated responses. This increase was blocked by Src inhibitor peptides and occluded tetanus-induced LTP, as reported previously. In contrast, in chronic nicotine-treated pyramidal cells, applying exogenous Src had no effect on AMPAR-mediated responses and a tetanus-induced LTP. Interestingly, however, administration of an endogenous Src-family kinase activator enhanced AMPAR-mediated responses, which occluded tetanus-induced LTP. This enhancement was not prevented by co-application of Src inhibitor peptides. Thus, it appears that chronic nicotine exposure recruits another member of the Src-family for the regulation of NMDAR function and LTP induction. The nicotine-induced distinct signaling cascades may be involved in long-lasting memories of nicotine misuse. [ABSTRACT FROM AUTHOR]

We have previously reported that acute and chronic nicotine exposure lower the threshold for long-term potentiation (LTP) induction in the rat hippocampal CA1 region, and acute application of nicotine in the chronic-nicotine-treated hippocampus further reduces the threshold. However, it is unknown how withdrawal from chronic nicotine exposure affects the induction of LTP. Here, we show that, following nicotine withdrawal, the threshold for LTP induction fluctuates before returning to the basal level and acute nicotine is no longer effective in lowering the threshold at 4 days after withdrawal. Chronic nicotine-induced enhancement of N-methyl-d-aspartate receptor responses slowly diminishes and returns to the control level by 8 days of withdrawal. In 4-day-withdrawn hippocampi, there is functional up-regulation of postsynaptic α7 nicotinic acetylcholine receptors (nAChRs) on interneurons in the stratum radiatum, whereas the release of γ-aminobutyric acid from their terminals is reduced. In both control and chronic nicotine-exposed hippocampi, acute nicotine depresses monosynaptic inhibitory postsynaptic currents recorded in pyramidal cells but has almost no effect at 4 days of withdrawal. The lack of effect is due, at least in part, to the loss of a presynaptic nicotine effect. These withdrawal-induced changes are accompanied by decreases in normal nicotine-induced enhancement of N-methyl-d-aspartate receptor responses, which may be responsible for the lack of acute nicotine-mediated facilitation of LTP induction in 4-day-withdrawn hippocampi. These withdrawal-induced changes may contribute to the cellular basis of unpleasant withdrawal symptoms and, thus, nicotine dependence. [ABSTRACT FROM AUTHOR]

The use of nicotine via cigarette smoking forms long-lasting memories that are recalled in response to environmental cues associated with previous nicotine use. However, the changes in brain memory systems that underlie these long-lasting memories are not well understood. The N-methyl-d-aspartate receptor (NMDAR) is critical for long-lasting modifications of synapses. Here we show that in vivo nicotine exposure induces the enhancement of NR2B-containing NMDAR-mediated currents in the hippocampus, a brain region associated with the formation of memories. This nicotine effect is maintained during continued nicotine exposure and is accompanied by increased tyrosine phosphorylation of NR2B. Furthermore, long-term potentiation (LTP), which is considered to be a cellular substrate of learning and memory, induced in nicotine-exposed hippocampi contains a protein synthesis-independent long-lasting component. An NR2B-selective antagonist blocks a long-lasting component of LTP, but not LTP. These results suggest that exposure to nicotine provides conditions that promote the induction of long-lasting modifications of synapses, which may be involved in the formation of memories involving nicotine use. [ABSTRACT FROM AUTHOR]

The social and political environments surrounding patient-physician relationship have been changing in Japan for the last few decades. This paper aims to illustrate social and cultural factors that underlie current situations and problems of patient-physician relationship in Japan through a comparison with those in western countries, and to consider how mutual participation model of patient-physician relationship could be applied and fostered in Japan as well as other Asian cultures. Four major sociocultural factors are discussed in relation to the patient-physician relationship in Japan: (1) individualism versus collectivism; (2) low context versus high context; (3) femininity versus masculinity; and (4) Christianity versus Confucianism. Two key issues in discussing the mutual participation model of patient-physician relationship in Japan have emerged; the family and the communication style. The patient autonomy in Japan should be considered within the context of the triadic relationship of patient, family, and physician. Also, since the communication style might differ between Japan and western countries, communication training programs and interventions for medical professionals as well as for patients should be tailored in a culturally appropriate way in order to improve the communication in medical encounters and to achieve the mutual participation. Beyond mere advocacy of the patient autonomy, the mutual participation model of patient-physician relationship should be pursued within our social and cultural context to be truly fruitful for patients and physicians in Japan. [ABSTRACT FROM AUTHOR]

Nicotine facilitates the induction of long-term potentiation (LTP) in the hippocampal CA1 region. The present study reveals the potential mechanisms underlying this effect of nicotine. Timed ACh-mediated activation of α7 nicotinic acetylcholine receptors (nAChRs) on pyramidal cells is known to promote LTP induction. Nicotine could suppress this timing-dependent mechanism by desensitizing nAChRs. Timed ACh-mediated activation of α7 nAChRs on feedforward interneurons can prevent LTP induction by inhibiting pyramidal cells. Nicotine diminished this ACh-mediated inhibition by desensitizing α7 nAChRs, thereby reducing the inhibitory influence on pyramidal cells. In addition to these desensitizing effects, nicotine activated presynaptic non-α7 nAChRs on feedforward interneurons to decrease the evoked release of γ-aminobutyric acid (GABA) onto pyramidal cells. Furthermore, nicotine increased the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) in pyramidal cells, and concomitantly caused a reduction in the size of responses to focal GABA application onto the dendrites of pyramidal cells, suggesting that the nicotine-induced increase in interneuronal activity leads ultimately to a use-dependent depression of evoked IPSCs in pyramidal cells. These nicotine-induced suppressions of inhibition of pyramidal cells were accompanied by enhanced N-methyl- d-aspartate (NMDA) responses in pyramidal cells. Thus, our results suggest that nicotine promotes the induction of LTP by diminishing inhibitory influences on NMDA responses while suppressing the ACh-mediated mechanisms. These ACh-independent mechanisms probably contribute to the nicotine-induced cognitive enhancement observed in the presence of cholinergic deficits, such as those in Alzheimer's disease patients. [ABSTRACT FROM AUTHOR]

Long-distance submarine cable telecommunication systems using low-loss optical fiber have been investigated more and more extensively. They are expected for international digital trunk because of their economical feature brought by smaller diameter cable and longer repeater spacing as well as large transmission capacity. This paper describes a design concept for deep sea optical submarine cable and proposes a three-split metal pipe structure as the pressure-resistant layer against the high water pressure. This structure features good manufacturability of small diameter and thick-wall metal pipe, particularly cable of long run length. A prototype anti-water propagation cable was manufactured using the pipe described above and the mechanical and transmission performance was measured in elevated temperatures, pressures, and tensions in the ocean simulator on the land. Also, test operations of the cable laying, holding and recovery on the 7000-m deep ocean bed were performed. From the results obtained, we find that the estimated loss change is less than 0.02 dB/km, which makes the proposed optical fiber cable structure feasible for deep sea submarine cable system application. [ABSTRACT FROM AUTHOR]

Hippocampal inhibitory interneurons have a central role in the control of network activity, and excitatory synapses that they receive express Hebbian and anti-Hebbian long-term potentiation (LTP). Because many interneurons in the hippocampus express nicotinic acetylcholine receptors (nAChRs), we explored whether exposure to nicotine promotes LTP induction in these interneurons. We focussed on a subset of interneurons in the stratum oriens/alveus that were continuously activated in the presence of nicotine due to the expression of non-desensitizing non-alpha7 nAChRs. We found that, in addition to alpha2 subunit mRNAs, these interneurons were consistently positive for somatostatin and neuropeptide Y mRNAs, and showed morphological characteristics of oriens-lacunosum moleculare cells. Activation of non-alpha7 nAChRs increased intracellular Ca(2+) levels at least in part via Ca(2+) entry through their channels. Presynaptic tetanic stimulation induced N-methyl-D-aspartate receptor-independent LTP in voltage-clamped interneurons at -70 mV when in the presence, but not absence, of nicotine. Intracellular application of a Ca(2+) chelator blocked LTP induction, suggesting the requirement of Ca(2+) signal for LTP induction. The induction of LTP was still observed in the presence of ryanodine, which inhibits Ca(2+) -induced Ca(2+) release from ryanodine-sensitive intracellular stores, and the L-type Ca(2+) channel blocker nifedipine. These results suggest that Ca(2+) entry through non-alpha7 nAChR channels is critical for LTP induction. Thus, nicotine affects hippocampal network activity by promoting LTP induction in oriens-lacunosum moleculare cells via continuous activation of non-alpha7 nAChRs.

Rapid activation of nicotinic acetylcholine receptors (nAChRs) at various anatomical and cellular locations in the hippocampus differentially modulates the operation of hippocampal circuits. However, it is largely unknown how the continued presence of nicotine affects the normal operation of hippocampal circuits. Here, we used single and dual whole-cell recordings to address this question. We found that horizontally oriented interneurons in the stratum oriens/alveus continuously discharged action potentials in the presence of nicotine. In these interneurons, bath application of nicotine produced slow inward currents that were well maintained and inhibited by the non-alpha 7 antagonist dihydro-beta-erythroidine. Single-cell reverse transcription-polymerase chain reaction analysis showed that nicotine-responding interneurons were consistently positive for the alpha2 subunit mRNA. These observations suggest that in the presence of nicotine, a subset of interneurons in the stratum oriens/alveus are continuously excited due to the sustained activation of alpha2* nAChRs. These interneurons were synaptically connected to pyramidal cells, and nicotine increased inhibitory baseline currents at the synapses and suppressed phasic inhibition at the same synapses. Nicotine-induced inhibitory activity increased background noise and masked small phasic inhibition in pyramidal cells, originating from other interneurons in the stratum radiatum. Thus, the continued presence of nicotine alters the normal operation of hippocampal circuits by gating inhibitory circuits through activating a non-desensitizing alpha2 nAChR subtype on a distinct population of interneurons.