研究者詳細 - 田中　謙二

論文 - 田中　謙二

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Enriched environment alleviates stress-induced dry-eye through the BDNF axis

Sano K., Kawashima M., Imada T., Suzuki T., Nakamura S., Mimura M., Tanaka K.F., Tsubota K.

Scientific Reports （Scientific Reports） 9 （ 1 ） 3422 2019年12月

© 2019, The Author(s). The number of patients with dry eye disease (DED) is increasing, and DED has become an urgent public health problem. A comorbidity of mental disorders has been reported in DED patients. We hypothesized that physical and psychological stressors impair tear secretion. To examine the relationship between stress loading and decreased tear secretion, we established a stress-induced DED mouse model, which permitted us to address the underlying mechanism of pathogenesis and resilience. Enriched environment (EE) was an effective intervention to prevent and alleviate stress-induced decreased tear secretion. Because stress loading resulted in decreased brain-derived neurotrophic factor (BDNF) expression while EE resulted in increased expression, we focused on the role of BDNF in tear secretion. Using two distinct Bdnf gene knockdown mice, we evaluated whether BDNF was a deterministic factor in regulating tear secretion in healthy and stressed conditions. Bdnf knockdown mice showed decreased basal tear secretion and loss of stress tolerance by EE for tear secretion. These results suggest that BDNF expression is related to tear secretion and to the pathology of DED.

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The physiology and pathophysiology of basal ganglia: From signal transduction to circuits

Chuhma N., Tanaka K.F., Nagai T.

Neurochemistry International （Neurochemistry International） 131 104544 2019年12月

ISSN 01970186

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Neuroprotective effects of microglial P2Y<inf>1</inf> receptors against ischemic neuronal injury

Fukumoto Y., Tanaka K.F., Parajuli B., Shibata K., Yoshioka H., Kanemaru K., Gachet C., Ikenaka K., Koizumi S., Kinouchi H.

Journal of Cerebral Blood Flow and Metabolism （Journal of Cerebral Blood Flow and Metabolism） 39 （ 11 ） 2144 - 2156 2019年11月

ISSN 0271678X

© The Author(s) 2018. Extracellular ATP, which is released from damaged cells after ischemia, activates P2 receptors. P2Y1 receptors (P2Y1R) have received considerable attention, especially in astrocytes, because their activation plays a central role in the regulation of neuron-to-glia communication. However, the functions or even existence of P2Y1R in microglia remain unknown, despite the fact that many microglial P2 receptors are involved in several brain diseases. Herein, we demonstrate the presence and functional capability of microglial P2Y1R to provide neuroprotective effects following ischemic stress. Cerebral ischemia resulted in increased microglial P2Y1R expression. The number of injured hippocampal neurons was significantly higher in P2Y1 R knockout (KO) mice than wildtype mice after forebrain ischemia. Propidium iodide (PI) uptake, a marker for dying cells, was significantly higher in P2Y1R KO hippocampal slices compared with wildtype hippocampal slices at 48 h after 40-min oxygen–glucose deprivation (OGD). Furthermore, increased PI uptake following OGD was rescued by ectopic overexpression of P2Y1R in microglia. In summary, these data suggest that microglial P2Y1R mediate neuroprotective effects against ischemic stress and OGD insult.

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Translational approach to apathy-like behavior in mice: From the practical point of view

Tanaka K.F., Hamaguchi T.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 73 （ 11 ） 685 - 689 2019年11月

ISSN 13231316

© 2019 The Authors. Psychiatry and Clinical Neurosciences © 2019 Japanese Society of Psychiatry and Neurology Apathy is a pervasive clinical phenomenon that deserves more attention at the translational and pre-clinical levels. To study apathy-like behavior in mice, we relied on an operational definition of apathy: the quantitative reduction of voluntary, goal-directed behaviors. We recently found that the chronic loss of function of a specific cell type (striatal dopamine receptor type 2-expressing medium spiny neurons, D2-MSN) in a restricted region (the ventrolateral striatum, VLS) was sufficient to induce apathy-like behavior in a food-seeking operant task. We further showed that VLS D2-MSN are activated at the preparatory period, and that optogenetic inhibition of VLS D2-MSN during that period resulted in transient decreases in instrumental motivation, strengthening the hypothesis that VLS D2-MSN mediate apathy-like behavior in mice. Mice bearing VLS D2-MSN dysfunction can thus be regarded as an apathy model for future translational studies.

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Detection of a High-Turnover Serotonin Circuit in the Mouse Brain Using Mass Spectrometry Imaging

Sugiyama E., Guerrini M.M., Honda K., Hattori Y., Abe M., Källback P., Andrén P.E., Tanaka K.F., Setou M., Fagarasan S., Suematsu M., Sugiura Y.

iScience （iScience） 20 359 - 372 2019年10月

© 2019 The Author(s) Monoamine neurotransmitters are released by specialized neurons regulating behavioral, motor, and cognitive functions. Although the localization of monoaminergic neurons in the brain is well known, the distribution and kinetics of monoamines remain unclear. Here, we generated a murine brain atlas of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels using mass spectrometry imaging (MSI). We found several nuclei rich in both 5-HT and a catecholamine (DA or NE) and identified the paraventricular nucleus of the thalamus (PVT), where 5-HT and NE are co-localized. The analysis of 5-HT fluctuations in response to acute tryptophan depletion and infusion of isotope-labeled tryptophan in vivo revealed a close kinetic association between the raphe nuclei, PVT, and amygdala but not the other nuclei. Our findings imply the existence of a highly dynamic 5-HT-mediated raphe to PVT pathway that likely plays a role in the brain monoamine system.

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App<sup>NL-G-F/NL-G-F</sup> mice overall do not show impaired motivation, but cored amyloid plaques in the striatum are inversely correlated with motivation

Hamaguchi T., Tsutsui-Kimura I., Mimura M., Saito T., Saido T.C., Tanaka K.F.

Neurochemistry International （Neurochemistry International） 129 104470 2019年10月

ISSN 01970186

© 2019 Elsevier Ltd Apathy is clinically defined as lack of motivation. Apathy is a frequent symptom in patients with Alzheimer's disease (AD). It is unclear whether amyloid β (Aβ)pathology is associated with apathy. To address this question, we employed the AppNL-G-F/NL-G-F mouse, an Aβ deposition-bearing mouse without neurofibrillary tangles and neuronal cell death throughout the lifespan and used a progressive-ratio (PR)task to monitor instrumental motivation between the ages of 16 and 39 weeks. In the PR task, the number of lever presses to receive one reward increases and the number of active lever presses in the final trial a mouse completes represents a break point, which is an index of motivation. During the observation period, AppNL-G-F/NL-G-F mice overall did not show impaired motivation. However, AppNL-G-F/NL-G-F mice showed a dispersion of the break point at 39 weeks of age within the group. Therefore, we examined the association between the degree of the break point and Aβ pathology; the number of cored amyloid plaques in the striatum was inversely correlated with the degree of motivation. Furthermore, we measured the dopamine transporter (DAT)levels in the subcortical tissues including the striatum using western blot analysis and showed that AppNL-G-F/NL-G-F mice have lower DAT levels than do C57BL/6J mice. Although we could not directly determine the effect of core amyloid plaques on the DAT, the results of this study suggest a pathway through which cored amyloid plaques damage the DAT and cause impaired motivation. These results will draw attention to cored amyloid plaques and will aid researchers searching for new strategies that are effective for the prevention and treatment of impaired motivation.

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大縫線核セロトニン神経による疼痛抑制の光遺伝学的解析

三橋学, 金丸みつ子, 田中謙二, 吉川輝, 稲垣克記, 久光正, 砂川正隆, 泉崎雅彦

昭和学士会雑誌（昭和大学学士会） 79 （ 4 ） 483 - 491 2019年08月

ISSN 2187-719X

延髄大縫線核のセロトニン(5-hydroxytryptamine、5-HT)神経は、下行性疼痛抑制系として鎮痛作用を発揮する。一方で、痛みを増強させるという報告もあり、セロトニン・ノルアドレナリン再取り込み阻害薬の鎮痛薬としての使用が広まるなか、5-HTの疼痛制御に関する検討が必要である。近年、光遺伝学的手法によって大縫線核の5-HT神経を選択的に刺激することが可能になった。本研究では、5-HT系下行性疼痛抑制系の障害が示唆されている間欠的寒冷ストレス(intermittent cold stress、ICS)モデルのマウスを用い、光遺伝学的手法による大縫線核の5-HT神経の選択的刺激が鎮痛作用を発揮するか検討した。青色光照射で大縫線核の5-HT神経を刺激するため、光感受性チャネルを5-HT神経細胞に発現させた遺伝子改変マウス(Tph2-tTA::tetO-ChR2(C128S))に対し、大縫線核直上に光ファイバーを刺入、留置した。このマウスにICSを与えてICS群とし、青色光照射による大縫線核5-HT神経への刺激が疼痛閾値へ与える効果を行動学的手法で評価した。機械刺激性疼痛試験としてvon Frey test、熱刺激性疼痛試験としてHot plate testを用いた。対照群にはSham ICS処置を行った。ICS群とSham ICS処置によるマウス群を比較検討したところ、ICS処置はvon Frey testによる疼痛閾値を低下させた。しかし、遺伝子改変マウスに青色光照射で刺激をしても、von Frey testによる疼痛閾値の変化は認めなかった。一方、Hot plate testで疼痛閾値を評価すると、Sham ICS処置による疼痛閾値の変化とICS処置による疼痛閾値の変化に有意な差はなかった。しかし、曝露処置(ICS処置か、Sham ICS処置か)と時期(処置前か、処置後か)に関わらず、青色光照射で疼痛閾値が上昇した。つまり、ICS処置は、von Frey testによる疼痛閾値を低下させたが、Hot plate testによる疼痛閾値を変化させなかった。一方、青色光照射による大縫線核5-HT神経への刺激は、Hot plate testによる疼痛閾値を上昇させたが、von Frey testによる疼痛閾値を変化させなかった。以上より、大縫線核の5-HT神経への刺激は、熱刺激性疼痛に対する鎮痛作用を発揮した。一方、ICS処置で機械刺激性疼痛に対する疼痛閾値は低下したが、その機序に大縫線核の5-HT神経の積極的な関与は示唆されなかった。(著者抄録)

Region- and cell type-specific facilitation of synaptic function at destination synapses induced by oligodendrocyte depolarization

Yamazaki Y., Abe Y., Shibata S., Shindo T., Fujii S., Ikenaka K., Tanaka K.F.

Journal of Neuroscience （Journal of Neuroscience） 39 （ 21 ） 4036 - 4050 2019年05月

ISSN 02706474

© 2019 the authors. 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.Wefound 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.

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Serotonin-mediated inhibition of ventral hippocampus is required for sustained goal-directed behavior

Yoshida K., Drew M., Mimura M., Tanaka K.

Nature Neuroscience （Nature Neuroscience） 22 （ 5 ） 770 - 777 2019年05月

ISSN 10976256

© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. The ability to sustain goal-directed action is essential for success in many domains, but little is known about the corresponding neural substrates. Using fiber photometry to monitor population neural activity, we demonstrate that engagement in sustained food- or punishment-motivated behavior is associated with suppression of ventral but not dorsal hippocampal activity. Using optogenetic stimulation, we demonstrate that this suppression is required for goal-directed behavior, whereas optogenetic suppression of the ventral hippocampus (vHP) enhances the ability to sustain goal-directed behavior. Suppression of vHP during sustained goal-directed behavior was accompanied by increased activity in median but not dorsal raphe, implicating serotonergic signaling through Htr3a as a mechanism of vHP suppression during successful goal-directed behavior. Sustainment of goal-directed action may require suppression of vHP because of the structure’s well-documented role in behavioral inhibition.

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Correlative study using structural MRI and super-resolution microscopy to detect structural alterations induced by long-term optogenetic stimulation of striatal medium spiny neurons

Abe Y., Komaki Y., Seki F., Shibata S., Okano H., Tanaka K.F.

Neurochemistry International （Neurochemistry International） 125 163 - 174 2019年05月

ISSN 01970186

© 2019 Elsevier Ltd Striatal medium spiny neurons (MSNs) control motor function. Hyper- or hypo-activity of MSNs coincides with basal ganglia-related movement disorders. Based on the assumption that lasting alterations in neuronal activity lead to structural changes in the brain, understanding these structural alterations may be used to infer MSN functional abnormalities. To infer MSN function from structural data, understanding how long-lasting alterations in MSN activity affect brain morphology is essential. To address this, we utilized a simplified model of functional induction by stimulating MSNs expressing channelrhodopsin 2 (ChR2). Subsequent structural alterations which induced long-term activity changes in these MSNs were investigated in the striatal pathway and its associated regions by diffusion tensor imaging (DTI) and histological assessment with super-resolution microscopy. DTI detected changes in the striatum, substantia nigra, and motor cortex. Histological assessment found a reduction in the diameter of myelinated cortical axons as well as MSN dendrites and axons. The structural changes showed a high correlation between DTI parameters and histological data. These results demonstrated that long-term neural activation in the MSNs alters the diameter of MSN and cortical neurons fibers. This study provides a tool for understanding the causal relationship between functional and structural alterations.

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Loss of adult 5-HT1A autoreceptors results in a paradoxical anxiogenic response to antidepressant treatment

Turcotte-Cardin V., Vahid-Ansari F., Luckhart C., Daigle M., Geddes S.D., Tanaka K.F., Hen R., James J., Merali Z., Béïque J.C., Albert P.R.

Journal of Neuroscience （Journal of Neuroscience） 39 （ 8 ） 1334 - 1346 2019年02月

ISSN 02706474

© 2019 the authors. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are first-line antidepressants but require several weeks to elicit their actions. Chronic SSRI treatment induces desensitization of 5-HT1A autoreceptors to enhance 5-HT neurotransmission. Mice (both sexes) with gene deletion of 5-HT1A autoreceptors in adult 5-HT neurons (1AcKO) were tested for response to SSRIs. Tamoxifen-induced recombination in adult 1AcKO mice specifically reduced 5-HT1A autoreceptor levels. The 1AcKO mice showed a loss of 5-HT1A autoreceptor-mediated hypothermia and electrophysiological responses, but no changes in anxiety-or depression-like behavior. Subchronic fluoxetine (FLX) treatment induced an unexpected anxiogenic effect in 1AcKO mice in the novelty suppressed feeding and elevated plus maze tests, as did escitalopram in the novelty suppressed feeding test. No effect was seen in wild-type (WT) mice. Subchronic FLX increased 5-HT metabolism in prefrontal cortex, hippocampus, and raphe of 1AcKO but not WT mice, suggesting hyperactivation of 5-HT release. To detect chronic cellular activation, FosB + cells were quantified. FosB + cells were reduced in entorhinal cortex and hippocampus (CA2/3) and increased in dorsal raphe 5-HT cells of 1AcKO mice, suggesting increased raphe activation. In WT but not 1AcKO mice, FLX reduced FosB + cells in the median raphe, hippocampus, entorhinal cortex, and median septum, which receive rich 5-HT projections. Thus, in the absence of 5-HT1A autoreceptors, SSRIs induce a paradoxical anxiogenic response. This may involve imbalance in activation of dorsal and median raphe to regulate septohippocampal or fimbria-fornix pathways. These results suggest that markedly reduced 5-HT1A autoreceptors may provide a marker for aberrant response to SSRI treatment.

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Cathepsin C modulates myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis

Durose W., Shimizu T., Li J., Abe M., Sakimura K., Chetsawang B., Tanaka K., Suzumura A., Tohyama K., Ikenaka K.

Journal of Neurochemistry （Journal of Neurochemistry） 148 （ 3 ） 413 - 425 2019年02月

ISSN 00223042

© 2018 International Society for Neurochemistry Multiple sclerosis (MS) is an autoimmune disease characterized by immune-mediated inflammation, which attacks the myelin sheath. MS pursues a relapsing and remitting course with varying intervals between symptoms. The main clinical pathological features include inflammation, myelin sheath destruction and plaque formation in the central nervous system (CNS). We previously reported that cystatin F (CysF) expression is induced in demyelinating lesions that are accompanied by active remyelination (referred to as shadow plaques) but is down-regulated in chronic demyelinated lesions (plaques) in the spinal cord of MS patients and in several murine models of demyelinating disease. CysF is a cathepsin protease inhibitor whose major target is cathepsin C (CatC), which is co-expressed in demyelinating regions in Plp 4e/− mice, a model of chronic demyelination. Here, we report the time course of CatC and CysF expression and describe the symptoms in a mouse experimental autoimmune encephalomyelitis (EAE) model using CatC knockdown (KD) and CatC over-expression (OE) mice. In myelin oligodendrocyte glycoprotein (MOG)-EAE, CatC positive cells were found to infiltrate the CNS at an early stage prior to any clinical signs, in comparison to WT mice. CysF expression was not observed at this early stage, but appeared later within shadow plaques. CatC expression was found in chronic demyelinated lesions but was not associated with CysF expression, and CatCKD EAE mouse showed delayed demyelination. Whereas, CatCOE in microglia significantly increased severity of demyelination in the MOG-EAE model. Thus, these results demonstrate that CatC plays a major role in MOG-EAE. (Figure presented.).

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Mechanical regulation of oligodendrocyte morphology and maturation by the mechanosensor p130Cas

Shimizu T., Osanai Y., Tanaka K., Thai T., Abe M., Natsume R., Sakimura K., Ikenaka K.

Journal of Neurochemistry （Journal of Neurochemistry） 150 （ 2 ） 158 - 172 2019年

ISSN 00223042

© 2018 International Society for Neurochemistry Oligodendrocytes (OLs) are myelinating cells of the central nervous system. Recent studies have shown that mechanical factors influence various cell properties. Mechanical stimulation can be transduced into intracellular biochemical signals through mechanosensors, such as integrin, p130Cas, talin and vinculin. However, the molecular mechanisms underlying the mechanical regulation of OLs by mechanosensors remain largely unknown. We found that morphology of OL was affected by knockdown of the mechanosensors p130Cas or talin1. Stretching of OL precursor cells induced the phosphorylation of p130Cas and talin-associated assembly of vinculin. Shear stress decreased the number of OL processes, whereas these effects were mechanically suppressed by dominant-negative (DN) p130Cas, but not by DN-talin1. To investigate the roles of p130Cas in post-natal OLs in vivo, we constructed a novel p130Cas knock-in mouse and found overexpression of p130Cas in vivo affected the number of mature OLs in the cortex. These results indicate that the mechanosensor p130Cas controls both OL morphogenesis and maturation. (Figure presented.).

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Reward probability and timing uncertainty alter the effect of dorsal raphe serotonin neurons on patience

Miyazaki K., Miyazaki K., Yamanaka A., Tokuda T., Tanaka K., Doya K.

Nature Communications （Nature Communications） 9 （ 1 ） 2048 2018年12月

© 2018 The Author(s). Recent experiments have shown that optogenetic activation of serotonin neurons in the dorsal raphe nucleus (DRN) in mice enhances patience in waiting for future rewards. Here, we show that serotonin effect in promoting waiting is maximized by both high probability and high timing uncertainty of reward. Optogenetic activation of serotonergic neurons prolongs waiting time in no-reward trials in a task with 75% food reward probability, but not with 50 or 25% reward probabilities. Serotonin effect in promoting waiting increases when the timing of reward presentation becomes unpredictable. To coherently explain the experimental data, we propose a Bayesian decision model of waiting that assumes that serotonin neuron activation increases the prior probability or subjective confidence of reward delivery. The present data and modeling point to the possibility of a generalized role of serotonin in resolving trade-offs, not only between immediate and delayed rewards, but also between sensory evidence and subjective confidence.

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Visualization of myelinated fiber bundles orientation during brain slice preparation by reflection polarized light microscopy

Takata N., Kusayanagi K., Maruyama H., Eitai K., Abo M., Akiyama F., Tajima R., Inaba S., Tanaka K., Mimura M., Sanaka K.

Microscopy Research and Technique （Microscopy Research and Technique） 81 （ 12 ） 1366 - 1373 2018年12月

ISSN 1059910X

© 2018 Wiley Periodicals, Inc. Polarized light imaging (PLI) enables detecting the orientation of myelinated axon bundles in brain slices at microscopic resolution without histological staining. However, standard PLI requires labor-intensive procedures such as mounting brain cryosections on slide glasses. We developed an optical system that does not require a mounting procedure for PLI. Specifically, we developed an optical system to perform PLI in reflection mode (rPLI) instead of employing transmitted light as in standard PLI. We integrated this rPLI system with a conventional vibratome slicer whose cutting blade surface is a mirror. This combination allowed PLI measurements directly during the slicing procedure at room temperature. Thus, mounting procedure for PLI is not necessary. As a proof-of-concept experiment, a perfusion-fixed brain of a mouse was embedded in gelatin-containing agar and cut serially at 40~200 μm intervals. The slicing procedure was temporarily halted after each cut to capture the PLI images of the slice on the reflecting blade surface while the slice was still held up by the agar block. The orientation of the fiber bundle estimated with this method agreed with the results obtained from previous reports. Combination of a popular vibratome slicer and our rPLI system that uses versatile and inexpensive optical components would increase popularity of PLI and facilitates connectome studies at microscopic resolution. Research Highlights: Polarized light imaging (PLI) of brain slices was realized by using reflected light (rPLI) instead of transmitted light. The rPLI method allows detecting the myelinated fiber bundle orientation during slice preparation.

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

Kikuchihara S., Sugio S., Tanaka K., Watanabe T., Kano M., Yamazaki Y., Watanabe M., Ikenaka K.

Journal of Neurochemistry （Journal of Neurochemistry） 147 （ 3 ） 344 - 360 2018年11月

ISSN 00223042

© 2018 International Society for Neurochemistry 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/. (Figure presented.). Cover Image for this issue: doi: 10.1111/jnc.14199.

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Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships

Zhang P., Lu H., Peixoto R., Pines M., Ge Y., Oku S., Siddiqui T., Xie Y., Wu W., Archer-Hartmann S., Yoshida K., Tanaka K., Aricescu A., Azadi P., Gordon M., Sabatini B., Wong R., Craig A.

Cell （Cell） 174 （ 6 ） 1450 - 1464.e23 2018年09月

ISSN 00928674

© 2018 Elsevier Inc. Synapses are fundamental units of communication in the brain. The prototypical synapse-organizing complex neurexin-neuroligin mediates synapse development and function and is central to a shared genetic risk pathway in autism and schizophrenia. Neurexin's role in synapse development is thought to be mediated purely by its protein domains, but we reveal a requirement for a rare glycan modification. Mice lacking heparan sulfate (HS) on neurexin-1 show reduced survival, as well as structural and functional deficits at central synapses. HS directly binds postsynaptic partners neuroligins and LRRTMs, revealing a dual binding mode involving intrinsic glycan and protein domains for canonical synapse-organizing complexes. Neurexin HS chains also bind novel ligands, potentially expanding the neurexin interactome to hundreds of HS-binding proteins. Because HS structure is heterogeneous, our findings indicate an additional dimension to neurexin diversity, provide a molecular basis for fine-tuning synaptic function, and open therapeutic directions targeting glycan-binding motifs critical for brain development. Neurexins, major synaptic-organizing proteins, are heparan sulfate (HS) proteoglycans, and HS modification is required for neurexin functions in synaptic transmission, development, and behavior.

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5-HT<inf>3</inf> antagonists decrease discounting rate without affecting sensitivity to reward magnitude in the delay discounting task in mice

Mori M., Tsutsui-Kimura I., Mimura M., Tanaka K.

Psychopharmacology （Psychopharmacology） 235 （ 9 ） 2619 - 2629 2018年09月

ISSN 00333158

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Rationale: Impulsive choice has often been evaluated in rodents according to the proportion of choices for the delayed large magnitude reinforcer (%large choice) in a delay-discounting task (DDT). However, because %large choice is influenced by both sensitivity to reinforcer magnitude and sensitivity to delayed reinforcement (i.e., discounting rate), distinctively evaluating such discounting parameters represents a critical issue demanding methods to determine each parameter in rats. The serotonin (5-HT) system is well known to be involved in impulsive choice; nevertheless, only a few studies have distinguished discounting parameters and investigated how 5-HT modulators affect discounting rate. Objective: Here, we performed a discounting parameter analysis in mice and examined the effects of various 5-HT modulators on discounting rate. Methods: We set up DDTs with different delay schedules to determine which schedule could address delay-discounting rates in mice. We examined the effect of the following drugs on impulsive choice: a 5-HT reuptake inhibitor (paroxetine), a 5-HT1A receptor agonist (8-OH-DPAT), and two 5-HT3 receptor antagonists (granisetron and ondansetron). Results: Mice showed typical delay discounting at the shorter delay schedules (up to 4 s delay). The %large choice under shorter, but not longer, schedules followed an exponential function and allowed us to derive discounting rates. We selected a DDT with a 4-s delay schedule for further experiments. Granisetron and ondansetron, but not paroxetine or 8-OH-DPAT, decreased discounting rates without affecting sensitivity to reinforcer magnitude. Conclusion: We found that a method to calculate discounting rates in rats is also applicable to mouse models. We also provided evidence that 5-HT3 antagonism controls impulsive choice in mice.

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Optogenetic astrocyte activation evokes BOLD fMRI response with oxygen consumption without neuronal activity modulation

Takata N., Sugiura Y., Yoshida K., Koizumi M., Hiroshi N., Honda K., Yano R., Komaki Y., Matsui K., Suematsu M., Mimura M., Okano H., Tanaka K.

GLIA （GLIA） 66 （ 9 ） 2013 - 2023 2018年09月

ISSN 08941491

© 2018 Wiley Periodicals, Inc. Functional magnetic resonance imaging (fMRI) based on the blood oxygenation level-dependent (BOLD) signal has been used to infer sites of neuronal activation in the brain. A recent study demonstrated, however, unexpected BOLD signal generation without neuronal excitation, which led us to hypothesize the presence of another cellular source for BOLD signal generation. Collective assessment of optogenetic activation of astrocytes or neurons, fMRI in awake mice, electrophysiological measurements, and histochemical detection of neuronal activation, coherently suggested astrocytes as another cellular source. Unexpectedly, astrocyte-evoked BOLD signal accompanied oxygen consumption without modulation of neuronal activity. Imaging mass spectrometry of brain sections identified synthesis of acetyl-carnitine via oxidative glucose metabolism at the site of astrocyte-, but not neuron-evoked BOLD signal. Our data provide causal evidence that astrocytic activation alone is able to evoke BOLD signal response, which may lead to reconsideration of current interpretation of BOLD signal as a marker of neuronal activation.

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Calcium Transient Dynamics of Neural Ensembles in the Primary Motor Cortex of Naturally Behaving Monkeys

Kondo T., Saito R., Otaka M., Yoshino-Saito K., Yamanaka A., Yamamori T., Watakabe A., Mizukami H., Schnitzer M., Tanaka K., Ushiba J., Okano H.

Cell Reports （Cell Reports） 24 （ 8 ） 2191 - 2195.e4 2018年08月

© 2018 The Authors To understand brain circuits of cognitive behaviors under natural conditions, we developed techniques for imaging neuronal activities from large neuronal populations in the deep layer cortex of the naturally behaving common marmoset. Animals retrieved food pellets or climbed ladders as a miniature fluorescence microscope monitored hundreds of calcium indicator-expressing cortical neurons in the right primary motor cortex. This technique, which can be adapted to other brain regions, can deepen our understanding of brain circuits by facilitating longitudinal population analyses of neuronal representation associated with cognitive naturalistic behaviors and their pathophysiological processes. Kondo et al. demonstrate calcium imaging from neuronal populations using a miniature fluorescence microscope in naturally behaving non-human primates (NHPs), common marmosets. This technique marks an advance beyond methods that use fixed head positioning, which limits the study of complex, self-determined behaviors such as social interactions or fear and anxiety.

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