研究者詳細 - 田中　謙二

論文 - 田中　謙二

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Transformation of Astrocytes to a Neuroprotective Phenotype by Microglia via P2Y₁ Receptor Downregulation

Shinozaki Youichi, Shibata Keisuke, Yoshida Keitaro, Shigetomi Eiji, Gachet Christian, Ikenaka Kazuhiro, Tanaka Kenji F., Koizumi Schuichi

Cell Reports 19 （ 6 ） 1151 - 1164 2017年05月

ISSN 2211-1247

Microglia and astrocytes become reactive following traumatic brain injury (TBI). However, the coordination of this reactivity and its relation to pathophysiology are unclear. Here, we show that microglia transform astrocytes into a neuroprotective phenotype via downregulation of the P2Y₁ purinergic receptor. TBI initially caused microglial activation in the injury core, followed by reactive astrogliosis in the peri-injured region and formation of a neuroprotective astrocyte scar. Equivalent changes to astrocytes were observed in vitro after injury. This change in astrocyte phenotype resulted from P2Y₁ receptor downregulation, mediated by microglia-derived cytokines. In mice, astrocyte-specific P2Y₁ receptor overexpression (Astro-P2Y₁OE) counteracted scar formation, while astrocyte-specific P2Y₁ receptor knockdown (Astro-P2Y₁KD) facilitated scar formation, suggesting critical roles of P2Y₁ receptors in the transformation. Astro-P2Y₁OE and Astro-P2Y₁KD mice showed increased and reduced neuronal damage, respectively. Altogether, our findings indicate that microglia-astrocyte interaction, involving a purinergic signal, is essential for the formation of neuroprotective astrocytes.

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Ventrolateral striatal medium spiny neurons positively regulate food-incentive, goal-directed behavior independently of D1 and D2 selectivity

Natsubori Akiyo, Tsutsui-Kimura Iku, Nishida Hiroshi, Bouchekioua Youcef, Sekiya Hiroshi, Uchigashima Motokazu, Watanabe Masahiko, De Kerchove D’Exaerde Alban, Mimura Masaru, Takata Norio, Tanaka Kenji F.

Journal of Neuroscience 37 （ 10 ） 2723 - 2733 2017年03月

ISSN 0270-6474

The ventral striatum is involved in motivated behavior. Akin to the dorsal striatum, the ventral striatum contains two parallel pathways: the striatomesencephalic pathway consisting of dopamine receptor Type 1-expressing medium spiny neurons (D1-MSNs) and the striatopallidal pathway consisting of D2-MSNs. These two genetically identified pathways are thought to encode opposing functions in motivated behavior. It has also been reported that D1/D2 genetic selectivity is not attributed to the anatomical discrimination of two pathways. We wanted to determine whether D1-and D2-MSNs in the ventral striatum functioned in an opposing manner as previous observations claimed, and whether D1/D2 selectivity corresponded to a functional segregation in motivated behavior of mice. To address this question, we focused on the lateral portion of ventral striatum as a region implicated in food-incentive, goal-directed behavior, and recorded D1 or D2-MSN activity by using a gene-encoded ratiometric Ca²⁺ indicator and by constructing a fiberphotometry system, and manipulated their activities via optogenetic inhibition during ongoing behaviors. We observed concurrent event-related compound Ca²⁺ elevations in ventrolateral D1-and D2-MSNs, especially at trial start cue-related and first lever press-related times. D1 or D2 selective optogenetic inhibition just after the trial start cue resulted in a reduction of goal-directed behavior, indicating a shared coding of motivated behavior by both populations at this time. Only D1-selective inhibition just after the first lever press resulted in the reduction of behavior, indicating D1-MSN-specific coding at that specific time. Our data did not support opposing encoding by both populations in food-incentive, goal-directed behavior.

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Dysfunction of ventrolateral striatal dopamine receptor type 2-expressing medium spiny neurons impairs instrumental motivation

Tsutsui-Kimura Iku, Takiue Hiroyuki, Yoshida Keitaro, Xu Ming, Yano Ryutaro, Ohta Hiroyuki, Nishida Hiroshi, Bouchekioua Youcef, Okano Hideyuki, Uchigashima Motokazu, Watanabe Masahiko, Takata Norio, Drew Michael R., Sano Hiromi, Mimura Masaru, Tanaka Kenji F.

Nature Communications 8 2017年02月

ISSN 2041-1723

Impaired motivation is present in a variety of neurological disorders, suggesting that decreased motivation is caused by broad dysfunction of the nervous system across a variety of circuits. Based on evidence that impaired motivation is a major symptom in the early stages of Huntington's disease, when dopamine receptor type 2-expressing striatal medium spiny neurons (D2-MSNs) are particularly affected, we hypothesize that degeneration of these neurons would be a key node regulating motivational status. Using a progressive, time-controllable, diphtheria toxin-mediated cell ablation/dysfunction technique, we find that loss-of-function of D2-MSNs within ventrolateral striatum (VLS) is sufficient to reduce goal-directed behaviours without impairing reward preference or spontaneous behaviour. Moreover, optogenetic inhibition and ablation of VLS D2-MSNs causes, respectively, transient and chronic reductions of goal-directed behaviours. Our data demonstrate that the circuitry containing VLS D2-MSNs control motivated behaviours and that VLS D2-MSN loss-of-function is a possible cause of motivation deficits in neurodegenerative diseases.

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YAP functions as a mechanotransducer in oligodendrocyte morphogenesis and maturation

Shimizu Takeshi, Osanai Yasuyuki, Tanaka Kenji F., Abe Manabu, Natsume Rie, Sakimura Kenji, Ikenaka Kazuhiro

GLIA 65 （ 2 ） 360 - 374 2017年02月

ISSN 0894-1491

Oligodendrocytes (OLs) are myelinating cells of the central nervous system. Recent studies have shown that mechanical factors influence various cell properties. Mechanical stimuli can be transduced into intracellular biochemical signals through mechanosensors and intracellular mechanotransducers, such as YAP. However, the molecular mechanisms underlying mechanical regulation of OLs by YAP remain unknown. We found that OL morphology and interactions between OLs and neuronal axons were affected by knocking down YAP. Mechanical stretching of OL precursor cells induced nuclear YAP accumulation and assembly of focal adhesion, key platforms for mechanotransduction. Shear stress decreased the number of OL processes, whereas a dominant-negative form of YAP suppressed these effects. To investigate the roles of YAP in postnatal OLs in vivo, we constructed a novel YAP knock-in mouse and found that in vivo overexpression of YAP widely affected OL maturation. These results indicate that YAP regulates OL morphology and maturation in response to mechanical factors. GLIA 2017;65:360–374.

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The balance between cathepsin C and cystatin F controls remyelination in the brain of Plp1-overexpressing mouse, a chronic demyelinating disease model

Shimizu Takahiro, Wisessmith Wilaiwan, Li Jiayi, Abe Manabu, Sakimura Kenji, Chetsawang Banthit, Sahara Yoshinori, Tohyama Koujiro, Tanaka Kenji F., Ikenaka Kazuhiro

GLIA 2017年

ISSN 0894-1491

In demyelinating diseases such as multiple sclerosis (MS), an imbalance between the demyelination and remyelination rates underlies the degenerative processes. Microglial activation is observed in demyelinating lesions; however, the molecular mechanism responsible for the homeostatic/environmental change remains elusive. We previously found that cystatin F (CysF), a cysteine protease inhibitor, is selectively expressed in microglia only in actively demyelinating/remyelinating lesions but ceases expression in chronic lesions, suggesting its role in remyelination. Here, we report the effects of manipulating the expression of CysF and cathepsin C (CatC), a key target of CysF, in a murine model of transgenic demyelinating disease, Plp^4e/-. During the active remyelinating phase, both CysF knockdown (CysFKD) and microglial-selective CatC overexpression (CatCOE) showed a worsening of the demyelination in Plp^4e/- transgenic mice. Conversely, during the chronic demyelinating phase, CatC knockdown (CatCKD) ameliorated the demyelination. Our results suggest that the balance between CatC and CysF expression controls the demyelination and remyelination process.

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Quantitative temporal changes in DTI values coupled with histological properties in cuprizone-induced demyelination and remyelination

Yano R., Hata J., Abe Y., Seki F., Yoshida K., Komaki Y., Okano H., Tanaka K.

Neurochemistry International （Neurochemistry International） 119 151 - 158 2017年

ISSN 0197-0186

© 2017 Elsevier Ltd Diffusion tensor imaging (DTI) is widely used to evaluate microstructural variations in brain tissue. In particular, fractional anisotropy (FA), reflecting the magnitude and orientation of anisotropic water diffusion, allows us to detect pathological events in white matter. An ex vivo DTI study coupled with histological assessment is an efficient strategy to evaluate the myelination process, i.e. demyelination and remyelination. The relationship between DTI values and myelin content or the individual cellular components such as oligodendrocytes, microglia, and astrocytes during both processes of demyelination and remyelination are not well-understood. To address this issue, we employed a cuprizone-inducible demyelination mouse model. Demyelination can be induced in this model during cuprizone exposure and termination of cuprizone exposure induces remyelination. We fed the mice cuprizone-containing chow for 4 weeks and then normal chow for an additional 4 weeks. The ex vivo DTI was performed to evaluate the white matter profiles observed by FA, mean diffusivity (MD), and radial diffusivity (RD) at both demyelinating and remyelinating time points, and then we evaluated histological properties at the same time points. The results indicated a gradual FA decrease during the cuprizone treatment (0, 2, 3, 4 weeks). A lower peak was seen at 1 week after the normal chow was resumed, with recovery to baseline at 2 and 4 weeks. MD and RD showed an opposing pattern to that of FA. These DTI values were positively or negatively correlated with myelin content regardless of the status of the white matter. The RD value was more sensitive to myelination status than FA and MD. We have clarified the temporal changes in the DTI values coupled with histological properties over both the demyelination and remyelination processes.

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Striatonigral direct pathway activation is sufficient to induce repetitive behaviors

Bouchekioua Y., Tsutsui-Kimura I., Sano H., Koizumi M., Tanaka K., Yoshida K., Kosaki Y., Watanabe S., Mimura M.

Neuroscience Research （Neuroscience Research） 132 53 - 57 2017年

ISSN 0168-0102

© 2017 Pharmacological intervention in the substantia nigra is known to induce repetitive behaviors in rodents, but a direct causal relationship between a specific neural circuit and repetitive behavior has not yet been established. Here we demonstrate that optogenetic activation of dopamine D1 receptor-expressing MSNs terminals in the substantia nigra pars reticulata resulted in sustained and chronic repetitive behaviors. These data show for the first time that activation of the striatonigral direct pathway is sufficient to generate motor stereotypies.

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Physiological effects of a habituation procedure for functional MRI in awake mice using a cryogenic radiofrequency probe

Yoshida Keitaro, Mimura Yu, Ishihara Ryosuke, Nishida Hiroshi, Komaki Yuji, Minakuchi Tomohito, Tsurugizawa Tomokazu, Mimura Masaru, Okano Hideyuki, Tanaka Kenji F., Takata Norio

Journal of Neuroscience Methods 274 38 - 48 2016年12月

ISSN 0165-0270

Background Functional magnetic resonance imaging (fMRI) in mice is typically performed under anesthesia due to difficulties in holding the head of awake mice stably with a conventional three-point fixation method that uses a tooth-bar and earplugs. Although some studies have succeeded in fMRI in awake mice by attaching a head-post on the skull, this cannot be applied to fMRI using a high signal-to-noise ratio (SNR) cryogenic MRI-detector, CryoProbe, because it covers the head of a mouse closely. New method We developed head-fixation implements for awake mice that are applicable to fMRI using CryoProbe. Results A head-bar was surgically attached to the skull of a mouse that was then habituated to a mock fMRI-environment, two hours/day for eight days with physiological examinations of body-weight, fecal weight, electromyogram (EMG), and electrocardiogram. EMG power decreased with just one day of habituation, whereas heart rate decreased after at least seven days of habituation. Estimated head motions of awake mice during fMRI were significantly smaller than a voxel size. Unexpectedly, temporal SNR of fMRI signals for awake mice was higher than that for anesthetized mice held by a conventional method. Functional connectivity in the brain of both anesthetized and awake mice showed bilateral and unilateral networks. Comparison with existing method(s) fMRI using CryoProbe had been performed on anesthetized mice previously. Our method does not use anesthetics during habituation or fMRI. Conclusion Our method would be beneficial for translational research using fMRI in mice and humans because human fMRI is typically performed without anesthetics.

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Subcellular calcium dynamics during juvenile development in mouse hippocampal astrocytes

Nakayama Ryota, Sasaki Takuya, Tanaka Kenji F., Ikegaya Yuji

European Journal of Neuroscience 43 （ 7 ） 923 - 932 2016年04月

ISSN 0953-816X

Astrocytes generate calcium signals throughout their fine processes, which are assumed to locally regulate neighbouring neurotransmission and blood flow. The intercellular morphological relationships mature during juvenile periods when astrocytes elongate highly ramified processes. In this study, we examined developmental changes in calcium activity patterns of single hippocampal astrocytes using a transgenic mouse line in which astrocytes selectively express a genetically encoded calcium indicator, Yellow Cameleon-Nano50. Compared with postnatal day 7, astrocytes at postnatal day 30 showed larger subcellular calcium events and a greater proportion of somatic events. At both ages, the calcium activity was abolished by removal of extracellular calcium ions. Calcium events in late juvenile astrocytes were not affected by spontaneously occurring sharp waves that trigger synchronized neuronal spikes, implying the independence of astrocyte calcium signals from neuronal synchronization. These results demonstrate that astrocytes undergo dynamic changes in their activity patterns during juvenile development.

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Immune modulation of the T cell response in asthma through Wnt10b

Trischler Jordis, Shiomi Takayuki, Turner Damian L., Sklepkiewicz Piotr L., Goldklang Monica P., Tanaka Kenji F., Xu Ming, Farber Donna L., D'Armiento Jeanine M.

American Journal of Respiratory Cell and Molecular Biology 54 （ 4 ） 584 - 593 2016年04月

ISSN 1044-1549

Asthma is a chronic inflammatory disease, which is characterized by activation of CD4⁺ T helper 2 cells orchestrating an allergic airway response.Whereas the role ofWnt family members in regulating T cell maintenance and maturation is established, their contribution to T cell activation in allergic asthma is not known.We hypothesized that Wnt10b plays a role in the modulation of the allergic airway response and affectsTcell activation and polarization.Using an in vivo house dust mite asthma model, Wnt10b-deficient (Wnt10b^-/-) mice were allergen-sensitized and inflammation, as well as T cell activation, was studied in vivo and in vitro. Wnt10b^-/- mice exhibited an augmented inflammatory phenotype with an increase in eosinophils in the bronchoalveolar lavage and IL-4 and IL-13 in the lungs when compared with wild-type mice. In vitro studies confirmed an increased T helper type 2 polarization and increased T cell activation ofWnt10b^-/- cells. Accordingly, the percentage of naive T cells was elevated by the addition of recombinantWnt10b protein. Finally,Wnt10b^-/- mice exhibited an increase in the percentage of effector T cells in the lungs after house dust mite sensitization, which indicated a heightened activation state, measured by an increased percentage of CD69^hiCD11a^hi cells. These findings suggest thatWnt10b plays an important role in regulating asthmatic airway inflammation through modification of the T cell response and is a prospective target in the disease process.

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Photoactivated adenylyl cyclase (PAC) reveals novel mechanisms underlying cAMP-dependent axonal morphogenesis

Zhou Zhiwen, Tanaka Kenji F., Matsunaga Shigeru, Iseki Mineo, Watanabe Masakatsu, Matsuki Norio, Ikegaya Yuji, Koyama Ryuta

Scientific Reports 5 2016年01月

ISSN 2045-2322

Spatiotemporal regulation of axonal branching and elongation is essential in the development of refined neural circuits. cAMP is a key regulator of axonal growth; however, whether and how intracellular cAMP regulates axonal branching and elongation remain unclear, mainly because tools to spatiotemporally manipulate intracellular cAMP levels have been lacking. To overcome this issue, we utilized photoactivated adenylyl cyclase (PAC), which produces cAMP in response to blue-light exposure. In primary cultures of dentate granule cells transfected with PAC, short-term elevation of intracellular cAMP levels induced axonal branching but not elongation, whereas long-term cAMP elevation induced both axonal branching and elongation. The temporal dynamics of intracellular cAMP levels regulated axonal branching and elongation through the activation of protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac), respectively. Thus, using PAC, our study for the first time reveals that temporal cAMP dynamics could regulate axonal branching and elongation via different signaling pathways.

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Microglial phospholipase D4 deficiency influences myelination during brain development

Chiba Terumasa, Otani Yoshinori, Yamaguchi Yoshihide, Ishibashi Tomoko, Hayashi Akiko, Tanaka Kenji F., Yamazaki Maya, Sakimura Kenji, Baba Hiroko

Proceedings of the Japan Academy Series B: Physical and Biological Sciences 92 （ 7 ） 237 - 254 2016年

ISSN 0386-2208

Phospholipase D4 (PLD4) is expressed in activated microglia that transiently appear in white matter during postnatal brain development. Previous knockdown experiments using cultured microglia showed PLD4 involvement in phagocytosis and proliferation. To elucidate the role of PLD4 in vivo, PLD4-deficient mice were generated and the cerebella were examined at postnatal day 5 (P5) and P7, when PLD4 expression is highest in microglia. Wild type microglia showed strong immunoreactivity for microglial marker CD68 at P5, whereas CD68 signals were weak in PLD4-deficient microglia, suggesting that loss of PLD4 affects microglial activation. At P5 and P7, immunostaining for anti-myelin basic protein (MBP) antibody indicated a mild but significant delay in myelination in PLD4-deficient cerebellum. Similar change was also observed in the corpus callosum at P7. However, this difference was not apparent at P10, suggesting that microglial PLD4-deficiency primarily influences the early myelination stage. Thus, microglia may have a transient role in myelination via a PLD4-related mechanism during development.

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Concentration-Dependent Dual Mode of Zn Action at Serotonin 5-HT1A Receptors

Satała Grzegorz, Duszyńska Beata, Stachowicz Katarzyna, Rafalo Anna, Pochwat Bartlomiej, Luckhart Christine, Albert Paul R., Daigle Mireille, Tanaka Kenji F., Hen René, Lenda Tomasz, Nowak Gabriel, Bojarski Andrzej J., Szewczyk Bernadeta

Molecular Neurobiology 1 - 13 2015年12月

ISSN 0893-7648

Recent data has indicated that Zn can modulate serotonergic function through the 5-HT_1A receptor (5-HT_1AR); however, the exact mechanisms are unknown. In the present studies, radioligand binding assays and behavioural approaches were used to characterize the pharmacological profile of Zn at 5-HT_1ARs in more detail. The influence of Zn on agonist binding to 5-HT_1ARs stably expressed in HEK293 cells was investigated by in vitro radioligand binding methods using the agonist [³H]-8-OH-DPAT. The in vivo effects of Zn were compared with those of 8-OH-DPAT in hypothermia, lower lip retraction (LLR), 5-HT behavioural syndrome and the forced swim (FST) tests. In the in vitro studies, biphasic effects, which involved allosteric potentiation of agonist binding at sub-micromolar Zn concentrations and inhibition at sub-millimolar Zn concentrations, were found. The in vivo studies showed that Zn did not induce LLR or elements of 5-HT behavioural syndrome but blocked such effects induced by 8-OH-DPAT. Zn decreased body temperature in rats and mice; however, Zn failed to induce hypothermia in the 5-HT_1A autoreceptor knockout mice. In the FST, Zn potentiated the effect of 8-OH-DPAT. However, in the FST performed with the 5-HT_1A autoreceptor knockout mice, the anti-immobility effect of Zn was partially blocked. Both the binding and behavioural studies suggest a concentration-dependent dual mechanism of Zn action at 5-HT_1ARs, with potentiation at low dose and inhibition at high dose. Moreover, the in vivo studies indicate that Zn can modulate both presynaptic and postsynaptic 5-HT_1ARs; however, Zn’s effects at presynaptic receptors seem to be more potent.

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5-HT1A receptors on mature dentate gyrus granule cells are critical for the antidepressant response

Samuels Benjamin Adam, Anacker Christoph, Hu Alice, Levinstein Marjorie R., Pickenhagen Anouchka, Tsetsenis Theodore, Madroñal Noelia, Donaldson Zoe R., Drew Liam John, Dranovsky Alex, Gross Cornelius T., Tanaka Kenji F., Hen René

Nature Neuroscience 18 （ 11 ） 1606 - 1616 2015年11月

ISSN 1097-6256

Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants, but the mechanisms by which they influence behavior are only partially resolved. Adult hippocampal neurogenesis is necessary for some of the responses to SSRIs, but it is not known whether mature dentate gyrus granule cells (DG GCs) also contribute. We deleted the serotonin 1A receptor (5HT1AR, a receptor required for the SSRI response) specifically from DG GCs and found that the effects of the SSRI fluoxetine on behavior and the hypothalamic-pituitary-adrenal (HPA) axis were abolished. By contrast, mice lacking 5HT1ARs only in young adult-born GCs (abGCs) showed normal fluoxetine responses. Notably, 5HT1AR-deficient mice engineered to express functional 5HT1ARs only in DG GCs responded to fluoxetine, indicating that 5HT1ARs in DG GCs are sufficient to mediate an antidepressant response. Taken together, these data indicate that both mature DG GCs and young abGCs must be engaged for an antidepressant response.

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Neuronal heterotopias affect the activities of distant brain areas and lead to behavioral deficits

Ishii Kazuhiro, Kubo Ken Ichiro, Endo Toshihiro, Yoshida Keitaro, Benner Seico, Ito Yukiko, Aizawa Hidenori, Aramaki Michihiko, Yamanaka Akihiro, Tanaka Kohichi, Takata Norio, Tanaka Kenji F., Mimura Masaru, Tohyama Chiharu, Kakeyama Masaki, Nakajima Kazunori

Journal of Neuroscience 35 （ 36 ） 12432 - 12445 2015年09月

ISSN 0270-6474

Neuronal heterotopia refers to brain malformations resulting from deficits of neuronal migration. Individuals with heterotopias show a high incidence of neurological deficits, such as epilepsy. More recently, it has come to be recognized that focal heterotopiasmayalso show a range of psychiatric problems, including cognitive and behavioral impairments. However, because focal heterotopias are not always located in the brain areas responsible for the symptoms, the causal relationship between the symptoms and heterotopias remains elusive. In this study, we showed that mice with focal heterotopias in the somatosensory cortex generated by in utero electroporation exhibited spatial working memory deficit and low competitive dominance behavior, which have been shown to be closely associated with the activity of the medial prefrontal cortex (mPFC) in rodents. Analysis of the mPFC activity revealed that the immediate-early gene expression was decreased and the local field potentials of the mPFC were altered in the mice with heterotopias compared with the control mice. Moreover, activation of these ectopic and overlying sister neurons using the DREADD (designer receptor exclusively activated by designer drug) system improved the working memory deficits. These findings suggest that cortical regions containing focal heterotopias can affect distant brain regions and give rise to behavioral abnormalities.

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Identification of the extent of cortical spreading depression propagation by Npas4 mRNA expression

Yoshida Keitaro, Xu Ming, Natsubori Akiyo, Mimura Masaru, Takata Norio, Tanaka Kenji F.

Neuroscience Research 98 1 - 8 2015年09月

ISSN 0168-0102

Cortical spreading depression (CSD) is a phenomenon associated with a propagating large shift in direct current (DC) potential followed by suppression of electrophysiological activity. For temporal analysis of CSD propagation, electrophysiological recording is the most reliable tool. However, it is difficult to completely identify the spatial area of the brain influenced by CSD, because recording sites are technically limited. Histological post hoc identification of activated neurons by labeling the induction of an immediate early gene (IEG) could determine areas of CSD propagation. We found that cortical application of potassium chloride induced expression of Npas4 IEG mRNA in the ipsilateral dorsal cortex. Interestingly, induction of Npas4 was never observed in the ipsilateral hippocampus and there was a clear boundary to the area of Npas4 expression. To determine whether the boundary of the area of Npas4 mRNA expression was the limit of CSD propagation, we recorded local field potentials from multiple sites that crossed the boundary of Npas4 expression. We found that the area of Npas4 mRNA expression coincided with the area of DC-potential shift propagation. We propose that induction of Npas4 identifies the area influenced by CSD propagation.

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Adult hippocampal neurogenesis modulates fear learning through associative and nonassociative mechanisms

Seo Dong Oh, Carillo Mary Ann, Lim Sean Chih Hsiung, Tanaka Kenji F., Drew Michael R.

Journal of Neuroscience 35 （ 32 ） 11330 - 11345 2015年08月

ISSN 0270-6474

Adult hippocampal neurogenesis is believed to support hippocampus-dependent learning and emotional regulation. These putative functions of adult neurogenesis have typically been studied in isolation, and little is known about how they interact to produce adaptive behavior. We used trace fear conditioning as a model system to elucidate mechanisms through which adult hippocampal neurogenesis modulates processing of aversive experience. To achieve a specific ablation of neurogenesis, we generated transgenic mice that express herpes simplex virus thymidine kinase specifically in neural progenitors and immature neurons. Intracerebroventricular injection of the prodrug ganciclovir caused a robust suppression of neurogenesis without suppressing gliogenesis. Neurogenesis ablation via this method or targeted x-irradiation caused an increase in context conditioning in trace but not delay fear conditioning. Data suggest that this phenotype represents opposing effects of neurogenesis ablation on associative and nonassociative components of fear learning. Arrest of neurogenesis sensitizes mice to nonassociative effects of fear conditioning, as evidenced by increased anxiety-like behavior in the open field after (but not in the absence of) fear conditioning. In addition, arrest of neurogenesis impairs associative trace conditioning, but this impairment can be masked by nonassociative fear. The results suggest that adult neurogenesis modulates emotional learning via two distinct but opposing mechanisms: it supports associative trace conditioning while also buffering against the generalized fear and anxiety caused by fear conditioning.

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Unveiling astrocytic control of cerebral blood flow with optogenetics

Masamoto Kazuto, Unekawa Miyuki, Watanabe Tatsushi, Toriumi Haruki, Takuwa Hiroyuki, Kawaguchi Hiroshi, Kanno Iwao, Matsui Ko, Tanaka Kenji F., Tomita Yutaka, Suzuki Norihiro

Scientific Reports 5 2015年06月

Cortical neural activities lead to changes in the cerebral blood flow (CBF), which involves astrocytic control of cerebrovascular tone. However, the manner in which astrocytic activity specifically leads to vasodilation or vasoconstriction is difficult to determine. Here, cortical astrocytes genetically expressing a light-sensitive cation channel, channelrhodopsin-2 (ChR2), were transcranially activated with a blue laser while the spatiotemporal changes in CBF were noninvasively monitored with laser speckle flowgraphy in the anesthetised mouse cortex. A brief photostimulation induced a fast transient increase in CBF. The average response onset time was 0.7 ± 0.7 sec at the activation foci, and this CBF increase spread widely from the irradiation spot with an apparent propagation speed of 0.8-1.1 mm/sec. The broad increase in the CBF could be due to a propagation of diffusible vasoactive signals derived from the stimulated astrocytes. Pharmacological manipulation showed that topical administration of a K + channel inhibitor (BaCl<inf>2</inf>; 0.1-0.5 mM) significantly reduced the photostimulation-induced CBF responses, which indicates that the ChR2-evoked astrocytic activity involves K + signalling to the vascular smooth muscle cells. These findings demonstrate a unique model for exploring the role of the astrocytes in gliovascular coupling using non-invasive, time-controlled, cell-type specific perturbations.

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Observation and manipulation of glial cell function by virtue of sufficient probe expression

Natsubori Akiyo, Takata Norio, Tanaka Kenji F.

Frontiers in Cellular Neuroscience 9 （ MAY ） 2015年05月

ISSN 1662-5102

The development of gene-encoded indicators and actuators to observe and manipulate cellular functions is being advanced and investigated. Expressing these probe molecules in glial cells is expected to enable observation and manipulation of glial cell activity, leading to elucidate the behaviors and causal roles of glial cells. The first step toward understanding glial cell functions is to express the probes in sufficient amounts, and the Knockin-mediated ENhanced Gene Expression (KENGE)-tet system provides a strategy for achieving this. In the present article, three examples of KENGE-tet system application are reviewed: depolarization of oligodendrocytes, intracellular acidification of astrocytes, and observation of intracellular calcium levels in the fine processes of astrocytes.

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Distinct Circuits Underlie the Effects of 5-HT1B Receptors on Aggression and Impulsivity

Nautiyal Katherine M., Tanaka Kenji F., Barr Mary M., Tritschler Laurent, Le Dantec Yannick, David Denis J., Gardier Alain M., Blanco Carlos, Hen René, Ahmari Susanne E.

Neuron 86 （ 3 ） 813 - 827 2015年05月

ISSN 0896-6273

Impulsive and aggressive behaviors are both modulated by serotonergic signaling, specifically through the serotonin 1B receptor (5-HT1BR). 5-HT1BR knockout mice show increased aggression and impulsivity, and 5-HT1BR polymorphisms are associated with aggression and drug addiction in humans. To dissect the mechanisms by which the 5-HT1BR affects these phenotypes, we developed a mouse model to spatially and temporally regulate 5-HT1BR expression. Our results demonstrate that forebrain 5-HT1B heteroreceptors expressed during an early postnatal period contribute to the development of the neural systems underlying adult aggression. However, distinct heteroreceptors acting during adulthood are involved in mediating impulsivity. Correlating with the impulsivity, dopamine inthe nucleus accumbens is elevated in the absence of 5-HT1BRs and normalized following adult rescue of the receptor. Overall, these data show that while adolescent expression of 5-HT1BRs influences aggressive behavior, a distinct set of 5-HT1B receptors modulates impulsive behavior during adulthood. Nautiyal etal. show that serotonin 1B receptors modulate aggressive and impulsive behavior through distinct neural circuits. Adolescent expression of forebrain heteroreceptors influences aggressive behavior, while a separate population affects impulsive behavior during adulthood.

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