論文 - 田中　謙二

Challenge to understand the neurobiology of obsessive-compulsive disorder

Tanaka Kenji

Brain and Nerve 64 （ 8 ） 903 - 909 2012年08月

ISSN  1881-6096

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<p>Obsessive-compulsive disorder (OCD) is characterized by obsession (recurrent intrusive thoughts) and compulsion (repetitive behaviors or mental acts). There is no consensus regarding the pathogenesis of OCD, which could support the idea that this disorder is heterogeneous. However, functional imaging data and surgical findings in humans suggest that the hyperactivity of the specific circuit including the striatum, called the cortico-striato-thalamo- cortical circuit, plays a role in OCD pathogenesis. Recently, validated animal models of OCD have been established, and they provide us the opportunity to address how the altered functional activity of this circuit contributes to the repetitive behavior in OCD. To test the causal relationship between the altered function of the circuit and behavioral abnormalities in animals, cell-type-specific manipulation and detection of changes in the circuit will be required. Optogenetic approaches may be used as tools to dissect the complex circuit. Moreover, mouse functional magnetic resonance imaging may yield data comparable to human imaging data.</p>

Gene induction in mature oligodendrocytes with a PLP-tTA mouse line

Inamura Naoko, Sugio Shouta, Macklin Wendy B., Tomita Koichi, Tanaka Kenji F., Ikenaka Kazuhiro

Genesis 50 （ 5 ） 424 - 428 2012年05月

ISSN  1526-954X

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<p>Mature oligodendrocytes are critical for myelin maintenance. To understand the molecular basis for this, genetic manipulation of mature oligodendrocytes is needed. Here we generated a mature oligodendrocyte tTA (tetracycline-controlled transcriptional activator) mouse line which, in combination with a tTA-dependent promoter line driving the expression of the desired transgene, can be used for gain-of-function studies. We used an oligodendrocyte promoter, the mouse proteolipid protein (PLP) promoter, to express mammalianized tTA, and generated a PLP-mtTA mouse line. In adults, mtTA mRNA was predominantly detected in brain white matter where it co-localized with PLP mRNA. mtTA-mediated gene induction was confirmed by crossing to mice with a tTA-dependent promoter driving expression of yellow fluorescent protein (tetO-YFP mice). YFP induction in PLP-mtTA::tetO-YFP mice was consistent with PLP expression in adult mature oligodendrocytes and premyelinating-stage myelinating oligodendrocytes. This PLP-mtTA mouse line is the first to enable gain-of-function studies in mature oligodendrocytes with the tet system. © 2011 Wiley Periodicals, Inc.</p>

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Mitral cells in the olfactory bulb are mainly excited through a multistep signaling path

Gire David H., Franks Kevin M., Zak Joseph D., Tanaka Kenji F., Whitesell Jennifer D., Mulligan Abigail A., Hen René, Schoppa Nathan E.

Journal of Neuroscience 32 （ 9 ） 2964 - 2975 2012年02月

ISSN  0270-6474

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<p>Within the olfactory system, information flow from the periphery onto output mitral cells (MCs) of the olfactory bulb (OB) has been thought to be mediated by direct synaptic inputs from olfactory sensory neurons (OSNs). Here, we performed patch-clamp measurements in rat and mouse OB slices to investigate mechanisms of OSN signaling onto MCs, including the assumption of a direct path, using electrical and optogenetic stimulation methods that selectively activated OSNs. We found that MCs are in fact not typically activated by direct OSN inputs and instead require a multistep, diffuse mechanism involving another glutamatergic cell type, the tufted cells. The preference for a multistep mechanism reflects the fact that signals arising from direct OSN inputs are drastically shunted by connexin 36-mediated gap junctions on MCs, but not tufted cells. An OB circuit with tufted cells intermediate between OSNs and MCs suggests that considerable processing of olfactory information occurs before its reaching MCs. © 2012 the authors.</p>

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Mitral cells in the olfactory bulb are mainly excited through a multistep signaling path.

田中 謙二

J Neurosci. 32   2964 - 2975 2012年

研究論文（学術雑誌）, 査読有り

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Application of an optogenetic byway for perturbing neuronal activity via glial photostimulation.

田中 謙二

Proc Natl Acad Sci U S A 109   20720 - 20725 2012年

研究論文（学術雑誌）, 共著, 査読有り

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Identification of optogenetically activated striatal medium spiny neurons by npas4 expression.

田中 謙二

PLoS One 7   e52783 2012年

査読有り

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Preinspiratory calcium rise in putative pre-Botzinger complex astrocytes.

田中 謙二

J Physiol 590   4933 - 4944 2012年

共著, 査読有り

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Shared Synaptic Pathophysiology in Syndromic and Nonsyndromic Rodent Models of Autism.

田中 謙二

Science 338   128 - 132 2012年

研究論文（学術雑誌）, 共著, 査読有り

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Serotonin receptor expression along the dorsal-ventral axis of mouse hippocampus.

田中 謙二

Philos Trans R Soc Lond B Biol Sci 367   2395 - 2401 2012年

研究論文（学術雑誌）, 共著, 査読有り

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Expanding the Repertoire of Optogenetically Targeted Cells with an Enhanced Gene Expression System.

田中 謙二

Cell Rep 2   397 - 406 2012年

研究論文（学術雑誌）, 共著, 査読有り

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Gene induction in mature oligodendrocytes with a PLP-tTA mouse line.

田中 謙二

Genesis 50   424 - 428 2012年

研究論文（学術雑誌）, 共著, 査読有り

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Mammalian Gcm genes induce Hes5 expression by active DNA demethylation and induce neural stem cells

Hitoshi Seiji, Ishino Yugo, Kumar Akhilesh, Jasmine Salma, Tanaka Kenji F., Kondo Takeshi, Kato Shigeaki, Hosoya Toshihiko, Hotta Yoshiki, Ikenaka Kazuhiro

Nature Neuroscience 14 （ 8 ） 957 - 964 2011年08月

ISSN  1097-6256

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<p>Signaling mediated by Notch receptors is crucial for the development of many organs and the maintenance of various stem cell populations. The activation of Notch signaling is first detectable by the expression of an effector gene, Hes5, in the neuroepithelium of mouse embryos at embryonic day (E) 8.0-8.5, and this activation is indispensable for the generation of neural stem cells. However, the molecular mechanism by which Hes5 expression is initiated in stem-producing cells remains unknown. We found that mammalian Gcm1 and Gcm2 (glial cells missing 1 anD₂) are involved in the epigenetic regulation of Hes5 transcription by DNA demethylation independently of DNA replication. Loss of both Gcm genes and subsequent lack of Hes5 upregulation in the neuroepithelium of E7.5-8.5 Gcm1 ^-/-; Gcm2 ^-/- mice resulted in the impaired induction of neural stem cells. Our data suggest that Hes5 expression is serially activated first by Gcms and later by the canonical Notch pathway. © 2011 Nature America, Inc. All rights reserved.</p>

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Microglial cystatin F expression is a sensitive indicator for ongoing demyelination with concurrent remyelination

Ma Jianmei, Tanaka Kenji F., Shimizu Takahiro, Bernard Claude C A, Kakita Akiyoshi, Takahashi Hitoshi, Pfeiffer Steven E., Ikenaka Kazuhiro

Journal of Neuroscience Research 89 （ 5 ） 639 - 649 2011年05月

ISSN  0360-4012

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<p>Demyelination coincides with numerous changes of gene expression in the central nervous system (CNS). Cystatin F, which is a papain-like lysosomal cysteine proteinase inhibitor that is normally expressed by immune cells and not in the brain, is massively induced in the CNS during acute demyelination. We found that microglia, which are monocyte/macrophage-lineage cells in the CNS, express cystatin F only during demyelination. By using several demyelinating animal models and the spinal cord tissues from multiple sclerosis (MS) patients, we examined spatiotemporal expression pattern of cystatin F by in situ hybridization and immunohistochemistry. We found that the timing of cystatin F induction matches with ongoing demyelination, and the places with cystatin F expression overlapped with the remyelinating area. Most interestingly, cystatin F induction ceased in chronic demyelination, in which remyelinating ability was lost. These findings demonstrate that the expression of cystatin F indicates the occurrence of ongoing demyelination/remyelination and the absence of cystatin F expression indicates the cessation of remyelination in the demyelinating area. © 2011 Wiley-Liss, Inc.</p>

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Leptin-dependent serotonin control of appetite

Yadav Vijay K., Oury Franck, Tanaka Kenji F., Thomas Tiffany, Wang Ying, Cremers Serge, Hen Rene, Krust Andree, Chambon Pierre, Karsenty Gerard

Journal of Experimental Medicine 208 （ 2 ） 413 2011年02月

ISSN  0022-1007

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Functional connectome of the striatal medium spiny neuron

Chuhma Nao, Tanaka Kenji F., Hen René, Rayport Stephen

Journal of Neuroscience 31 （ 4 ） 1183 - 1192 2011年01月

ISSN  0270-6474

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<p>Dopamine system disorders ranging from movement disorders to addiction and schizophrenia involve striatal medium spiny neurons (MSNs), yet their functional connectivity has been difficult to determine comprehensively. We generated a mouse with conditional channelrhodopsin-2 expression restricted to medium spiny neurons and assessed the specificity and strength of their intrinsic connections in the striatum and their projections to the globus pallidus and the substantia nigra. In the striatum, medium spiny neurons connected with other MSNs and tonically active cholinergic interneurons, but not with fast-spiking GABA interneurons. In the globus pallidus, medium spiny neurons connected strongly with one class of electrophysiologically identified neurons, but weakly with the other. In the substantia nigra, medium spiny neurons connected strongly with GABA, but not with dopamine neurons. Projections to the globus pallidus showed solely D2-mediated presynaptic inhibition, whereas projections to the substantia nigra showed solely D1-mediated presynaptic facilitation. This optogenetic approach defines the functional connectome of the striatal medium spiny neuron. Copyright © 2011 the authors.</p>

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Leptin-dependent serotonin control of appetite

Yadav Vijay K., Oury Franck, Tanaka Kenji, Thomas Tiffany, Wang Ying, Cremers Serge, Hen Rene, Krust Andree, Chambon Pierre, Karsenty Gerard

Journal of Experimental Medicine 208 （ 1 ） 41 - 52 2011年01月

ISSN  0022-1007

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<p>Recent evidence indicates that leptin regulates appetite and energy expenditure, at least in part by inhibiting serotonin synthesis and release from brainstem neurons. To demonstrate that this pathway works postnatally, we used a conditional, brainstem-specific mouse CreER^T2 driver to show that leptin signals in brainstem neurons after birth to decrease appetite by inhibiting serotonin synthesis. Cell-specific gene deletion experiments and intracerebroventricular leptin infusions reveal that serotonin signals in arcuate nuclei of the hypothalamus through the Htr1a receptor to favor food intake and that this serotonin function requires the expression of Creb, which regulates the expression of several genes affecting appetite. Accordingly, a specific antagonist of the Htr1a receptor decreases food intake in leptin-deficient but not in Htr1a^-/- mice. Collectively, these results establish that leptin inhibition of serotonin is necessary to inhibit appetite postnatally and provide a proof of principle that selective inhibition of this pathway may be a viable option to treat appetite disorders. © 2011 Yadav et al.</p>

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Increased numbers of oligodendrocyte lineage cells in the optic nerves of cerebroside sulfotransferase knockout mice

Kajigaya Hitoshi, Tanaka Kenji F., Hayashi Akiko, Suzuki Ayaka, Ishibashi Tomoko, Ikenaka Kazuhiro, Baba Hiroko

Proceedings of the Japan Academy Series B: Physical and Biological Sciences 87 （ 7 ） 415 - 424 2011年

ISSN  0386-2208

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<p>Sulfatide is a myelin glycolipid that functions in the formation of paranodal axoglial junctions in vivo and in the regulation of oligodendrocyte differentiation in vitro. Cerebroside sulfotransferase (CST) catalyzes the production of two sulfated glycolipids, sulfatide and proligodendroblast antigen, in oligodendrocyte lineage cells. Recent studies have demonstrated significant increases in oligodendrocytes from the myelination stage through adulthood in brain and spinal cord under CST-deficient conditions. However, whether these result from excess migration or in situ proliferation during development is undetermined. In the present study, CST-deficient optic nerves were used to examine migration and proliferation of oligodendrocyte precursor cells (OPCs) under sulfated glycolipid-deficient conditions. In adults, more NG2-positive OPCs and fully differentiated cells were observed. In developing optic nerves, the number of cells at the leading edge of migration was similar in CST-deficient and wild-type mice. However, BrdUD proliferating OPCs were more abundant in CST-deficient mice. These results suggest that sulfated glycolipids may be involved in proliferation of OPCs in vivo. ©2011 The Japan Academy.</p>

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Flexible Accelerated STOP Tetracycline Operator-Knockin (FAST)

Tanaka Kenji F., Ahmari Susanne E., Leonardo E. David, Richardson-Jones Jesse W., Budreck Elaine C., Scheiffele Peter, Sugio Shouta, Inamura Naoko, Ikenaka Kazuhiro, Hen René

Biological Psychiatry 67 （ 8 ） 770 - 773 2010年04月

ISSN  0006-3223

　概要を見る

<p>We created the Flexible Accelerated STOP Tetracycline Operator (tetO)-knockin (FAST) system, an efficient method for manipulating gene expression in vivo to rapidly screen animal models of disease. A single gene targeting event yields two distinct knockin mice-STOP-tetO and tetO knockin-that permit generation of multiple strains with variable expression patterns: 1) knockout, 2) Cre-mediated rescue, 3) tetracycline-controlled transcriptional activator (tTA)-mediated misexpression, 4) tetracycline-controlled transcriptional activator (tTA)-mediated overexpression, and 5) tetracycline-controlled transcriptional silencer (tTS)-mediated conditional knockout/knockdown. Using the FAST system, multiple gain-of-function and loss-of-function strains can therefore be generated on a time scale not previously achievable. These strains can then be screened for clinically relevant abnormalities. We demonstrate the flexibility and broad applicability of the FAST system by targeting several genes encoding proteins implicated in neuropsychiatric disorders: Mlc1, neuroligin 3, the serotonin 1A receptor, and the serotonin 1B receptor. © 2010 Society of Biological Psychiatry.</p>

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Organotypic tissue culture of adult rodent retina followed by particle-mediated acute gene transfer in vitro

Moritoh Satoru, Tanaka Kenji F., Jouhou Hiroshi, Ikenaka Kazuhiro, Koizumi Amane

PLoS One 5 （ 9 ）  2010年

ISSN  1932-6203

　概要を見る

<p>Background: Organotypic tissue culture of adult rodent retina with an acute gene transfer that enables the efficient introduction of variable transgenes would greatly facilitate studies into retinas of adult rodents as animal models. However, it has been a difficult challenge to culture adult rodent retina. The purpose of this present study was to develop organotypic tissue culture of adult rodent retina followed by particle-mediated acute gene transfer in vitro. Methodology/Principal Findings: We established an interphase organotypic tissue culture for adult rat retinas (&gt;P35 of age) which was optimized from that used for adult rabbit retinas. We implemented three optimizations: a greater volume of Ames' medium (&gt;26 mL) per retina, a higher speed (constant 55 rpm) of agitation by rotary shaker, and a greater concentration (10%) of horse serum in the medium. We also successfully applied this method to adult mouse retina (&gt;P35 of age). The organotypic tissue culture allowed us to keep adult rodent retina morphologically and structurally intact for at least 4 days. However, mouse retinas showed less viability after 4-day culture. Electrophysiologically, ganglion cells in cultured rat retina were able to generate action potentials, but exhibited less reliable light responses. After transfection of EGFP plasmids by particle-mediated acute gene transfer, we observed EGFP-expressing retinal ganglion cells as early as 1 day of culture. We also introduced polarized-targeting fusion proteins such as PSD95-GFP and melanopsin-EYFP (hOPN4-EYFP) into rat retinal ganglion cells. These fusion proteins were successfully transferred into appropriate locations on individual retinal neurons. Conclusions/Significance: This organotypic culture method is largely applicable to rat retinas, but it can be also applied to mouse retinas with a caveat regarding cell viability. This method is quite flexible for use in acute gene transfection in adult rodent retina, replacing molecular biological bioassays that used to be conducted in isolated cultured cells. © 2010 Moritoh et al.</p>

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A Serotonin-Dependent Mechanism Explains the Leptin Regulation of Bone Mass, Appetite, and Energy Expenditure

Yadav Vijay K., Oury Franck, Suda Nina, Liu Zhong Wu, Gao Xiao Bing, Confavreux Cyrille, Klemenhagen Kristen C., Tanaka Kenji F., Gingrich Jay A., Guo X. Edward, Tecott Laurence H., Mann J. John, Hen Rene, Horvath Tamas L., Karsenty Gerard

Cell 138 （ 5 ） 976 - 989 2009年09月

ISSN  0092-8674

　概要を見る

<p>Leptin inhibition of bone mass accrual requires the integrity of specific hypothalamic neurons but not expression of its receptor on these neurons. The same is true for its regulation of appetite and energy expenditure. This suggests that leptin acts elsewhere in the brain to achieve these three functions. We show here that brainstem-derived serotonin (BDS) favors bone mass accrual following its binding to Htr2c receptors on ventromedial hypothalamic neurons and appetite via Htr1a and 2b receptors on arcuate neurons. Leptin inhibits these functions and increases energy expenditure because it reduces serotonin synthesis and firing of serotonergic neurons. Accordingly, while abrogating BDS synthesis corrects the bone, appetite and energy expenditure phenotypes caused by leptin deficiency, inactivation of the leptin receptor in serotonergic neurons recapitulates them fully. This study modifies the map of leptin signaling in the brain and identifies a molecular basis for the common regulation of bone and energy metabolisms. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online. © 2009 Elsevier Inc. All rights reserved.</p>

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