一般口演（Oral）

Oral Sensory Disorders 一般口演感覚障害

7月28日（日）9:45～10:00　第10会場（万代島ビル　6F　会議室） 4O-10m2-1 アストロサイトのmGluR5再発現による大脳皮質ネットワーク再編と神経障害性疼痛 Yosuke Danjo（檀上洋右）¹，Yukiho J Hirayama（平山 J 幸歩）¹，Eiji Shigetomi（繁冨英治）¹，Keisuke Shibata（柴田圭輔）¹，Kenta Takanashi（高梨健太）¹，Youichi Shinozaki（篠崎陽一）¹，Sun Kwang Kim（金善行）²，Junichi Nabekura（鍋倉淳一）²，Schuichi Koizumi（小泉修一）¹ ¹山梨大院医工薬理 ²生理研発達生理生体恒常機能発達機構 Astrocytes play essential roles for the modulation of neural networks, and also have critical roles for the pathogenesis of neural disorders. Recently, we revealed that astrocytes in the primary somatosensory cortex (S1) have a critical role for the pathogenesis of neuropathic pain after partial sciatic nerve ligation (PSNL). In brief, PSNL generated Ca²⁺ excitation in S1 astrocytes, induced synaptogenesis, thereby resulting in cross-wiring of innocuous and nocuous circuits. mGluR5 looked involved in the pathogenesis of neuropathic allodynia, however, we still do not know whether astrocytic mGluR5 is required or not. Here, we show that astrocytic mGluR5 in S1 is a cause of cortical rewiring and the pathogenesis. Firstly, we found that mGluR5 is almost absent but re-emerged in S1 astrocytes after PSNL. Second, we made brain astrocyte-specific mGluR5 knockout mice (astro-mGluR5-KO) by crossing floxed-Grm5 with Glast-Cre mice and validated them. In the adult Wt, mGluR5 is almost absent but reappears in S1 after PSNL. Such mGluR5 increase was no longer observed in astro-mGluR5-KO. Due to insufficient Cre-recombination, the spinal astrocytes in astro-mGluR5-KO looked intact. Third, PSNL-induced mechanical allodynia was abolished in astro-mGluR5-KO mice, suggesting that up-regulation of mGluR5 in S1 astrocytes should be required for induction of mechanical allodynia. Forth, mechanisms underlying astrocytic mGluR5-mediated allodynia were; (1) increase in Ca²⁺ activity, (2) expression of synaptogenic molecules such as glypican4 and hevin, (3) synapse formation, (4) persistent rewiring of incorrect S1 circuits. Hence, we conclude that astrocytic mGluR5 is a crucial molecule that triggers synaptogenesis in S1 after PSNL, which is the causative event for the pathogenesis of neuropathic pain.		7月28日（日）10:00～10:15　第10会場（万代島ビル　6F　会議室） 4O-10m2-2 BMIによる幻肢痛の治療 Takufumi Yanagisawa（栁澤琢史）¹，Ryohei Fukuma（福間良平）^2,3，Seymour Ben（ベンシーモア）^4,5，Masataka Tanaka（田中将貴）²，Koichi Hosomi（細見晃一）^2,8，Okito Yamashita（山下宙人）^6,7，Haruhiko Kishima（貴島晴彦）²，Yukiyasu Kamitani（神谷之康）^3,9，Youichi Saitoh（齋藤洋一）^2,8 ¹大阪大学高等共創研究院 ²大阪大学大学院医学系研究科脳神経外科 ³ATR脳情報通信総合研 ⁴ケンブリッジ大学 ⁵情報通信研究機構 ⁶理化学研究所 ⁷ATR脳情報通信総合研脳解析研 ⁸大阪大学大学院医学系研究科脳神経機能再生学 ⁹京都大学大学院情報学研究科 Background: Phantom limb pain often follows an amputation or deafferentation of a limb, such as brachial plexus root avulsion, and has a large impact on the patient's life. Our previous study demonstrated that training with a brain-machine interface (BMI) to control a robotic hand changed phantom limb pain by inducing plastic changes in the cortical representation of the phantom hand. However, it has not yet been demonstrated that BMI training has a long-term effect that can reduce pain by a clinically significant amount. Here, we assessed the efficacy of BMI treatment to reduce pain with a three-day training protocol. Methods: Twelve patients with chronic phantom limb pain of an upper limb participated in a randomised crossover trial. Patients in the `real training' group were trained for three days to control a hand image by moving their phantom hands. A real decoder classified intact hand movements from these patients' cortical motor currents estimated by magnetoencephalographic signals. Patients in the `random training' control group were engaged with the same hand image, but the hand image was now controlled by randomly changing values. Pain, the main outcome from this study, was evaluated using the visual analogue scale (VAS) before and after each training session and for a further follow-up period of 17 days. Patients were alternatively assigned to the real training group or the random training group at enrolment. Results: VAS scores (on the 1/100 mm scale) were significantly reduced for the real training group, from a mean [SD] of 45.3 [24.3] before the training session to 20.3 [18.4] after the training session on day 1, and from 34.1 [21.3] before to 17.3 [16.7] after the training session on day 2. The random training group did not experience these effects. Using day 1 as a baseline, VAS scores were significantly reduced after the real training by 41.6% on day 3, by 31.8% on day 4, and by 34.2% on day 8. These reductions in pain were significantly better than scores achieved after the random training. The significant decrease in decoding accuracy of the phantom hand was also correlated with pain reduction at day 4 (R=0.58). Conclusions: BMI training in which patients refocused the movement of their phantom hand to control a hand image for three days significantly reduced pain for at least a week. We suggest that ongoing BMI training may further decrease phantom limb pain by gradually attenuating the phantom hand representation.

7月28日（日）10:15～10:30　第10会場（万代島ビル　6F　会議室） 4O-10m2-3 病的な痒みにおける脊髄後角GRP産生ニューロンの関与 Norikazu Kiguchi（木口倫一）¹，Daisuke Uta（歌大介）²，Hitoshi Uchida（内田仁司）³，Shinsuke Matsuzaki（松﨑伸介）¹，Shiroh Kishioka（岸岡史郎）¹ ¹和歌山県立医大医薬理 ²富山大院医薬応用薬理 ³新潟大脳研細胞病態 Itch (pruritus) is an uncomfortable sensation that evokes a desire to scratch. Given that itch is a key symptom of numerous systemic disorders, it is imperative to study the mechanisms underlying sensory processing of itch. Accumulating evidence indicate that gastrin-releasing peptide (GRP) receptor-expressing (GRPR⁺) neurons in the spinal dorsal horn (SDH) are itch-responsive, but their regulatory mechanisms are not yet fully understood. Recently, we found that not only GRP but also glutamate directly activate GRPR⁺ neurons through AMPA receptors (AMPAR), and that those transmitters play fundamental roles in the spinal transmission of acute itch. Histaminergic and non-histaminergic acute itch are suppressed by either an antagonist for AMPAR, ablation of GRPR⁺ AMPAR⁺ neurons after bombesin-saporin treatment, or chemogenetic silencing of GRP⁺/Glu⁺ neurons using Cre-dependent Gi- designer receptors exclusively activated by designer drugs (Gi-DREADD). Here, we determined whether such systems play a pivotal role in pathological itch. To induce contact dermatitis or psoriasis, diphenylcyclopropenone (DCP) or imiquimod (IMQ) was applied to C57BL mice after having shaved on the back. The mRNA expression levels of GRP, GRPR, and AMPAR subunits in the cervical SDH were upregulated after DCP or IMQ application. DCP- or IMQ-induced scratching behaviors were significantly prevented by either ablation of GRPR⁺ AMPAR⁺ neurons or chemogenetic silencing of GRP⁺/Glu⁺ neurons. These results suggest that GRP-GRPR system and glutamate-AMPAR system in the SDH might cooperatively regulate not only acute but also pathological itch.		7月28日（日）10:30～10:45　第10会場（万代島ビル　6F　会議室） 4O-10m2-4 脊髄後角アストロサイトの活性化は接触性皮膚炎モデルにおける痒み伝達を増強する Keisuke Koga（古賀啓祐），Ryo Yamagata（山方涼），Miho Shiratori-Hayashi（白鳥美穂），Makoto Tsuda（津田誠）九州大院薬ライフイノベーション Chronic itch is a major symptom in various skin diseases, such as atopic and contact dermatitis, but its mechanism is not determined. We have previously shown that spinal dorsal horn (SDH) astrocytes become activated in mouse models of chronic itch and that astrocyte-derived lipocalin-2 (LCN2) is crucial for maintaining chronic itching. However, how LCN2 enhances spinal itch neurotransmission remains to be understood. In this study, we used Gastrin-releasing peptide receptor (Grpr)-EGFP mice to label itch-specific neurons in the SDH. Electrophysiological and immunohistochemical analyses showed that GRPR⁺ neurons were mainly excitatory and that most of excitatory GRPR⁺ neurons had a vertical cell-like morphology. To examine whether itch transmission in excitatory GRPR⁺ neurons is changed under a chronic itch condition, we used a model of contact dermatitis, in which diphenylcyclopropenone (DCP) was applied to the rostral back skin. According to a previous study, DCP-treated Grpr-EGFP mice exhibited spontaneous repetitive scratching behaviors, dermatitis and astrocytic activation in the cervical SDH. Under such conditions, GRP-induced depolarization of excitatory GRPR⁺ neurons was greatly potentiated. Genetic inhibition of signal transducer and activator transcription 3 (STAT3) in SDH astrocytes ameliorated astrocyte activation and chronic itch, and also normalized enhancement of GRP-induced depolarization of excitatory GRPR⁺ neurons in DCP-treated mice. Furthermore, co-application of LCN2 and GRP also potentiated GRP-induced depolarization of excitatory GRPR⁺ neurons. Our findings indicate that reactive astrocytes facilitate SDH itch transmission via upregulated LCN2 and contribute to chronic itch.