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新谷 勇介大学院医学系研究科 医科学専攻助教
研究活動情報
■ 受賞- 2026年09月 国立大学法人 神戸大学, 令和８年度 優秀若手研究者賞 優秀賞
- 2026年08月 日本薬学会 薬理系薬学部会, 令和８年度 薬理系薬学部会栴檀賞
- 2026年08月 一般社団法人 日本神経化学会, 2026 年度日本神経化学会奨励賞
- 2026年07月 一般財団法人敬愛まちづくり財団, 前之園記念若手優秀論文賞
- 2026年03月 日本薬理学会, 第二回 日本薬理学会100周年記念博士研究奨励賞
- 2024年10月 神戸大学大学院医学研究科, 第八回 神緑会ヤング・インベスティゲーター・アワード発表会 優秀賞
- 2022年08月 日本薬学会薬理系薬学部会, 生体機能と創薬シンポジウム 2022 ポスター発表賞 最優秀賞
- Abstract Stress-related disorders, such as depression and anxiety, have been one of the most important medical issues. Accumulating evidence suggests that the activation of the pituitary adenylate cyclase-activating polypeptide and its receptor PAC1 are involved in the stress axis and the development of stress-related disorders. We recently developed PA-915, a small-molecule, non-peptide, high-affinity PAC1 antagonist, and demonstrated that it significantly suppresses anxiety-like behavior in acute stress-induced mice. In this study, we aimed to investigate the behavioral effects of PA-915 in chronic stress-induced mouse models of depression, which included repeated social defeat stress, repeated corticosterone administration, and social isolation rearing. PA-915 ameliorated the increased immobility time in the forced swim test in these stress-induced mice. In repeated social defeat stress mice, PA-915 improved anxiety-like and depression-like behaviors and cognitive dysfunction, as assessed by the light-dark, open field, elevated plus maze, sucrose preference, forced swim, Y-maze, and novel object recognition tests. In addition, we evaluated the usefulness of PA-915 as an antidepressant and compared it with ketamine and fluoxetine. In the sucrose preference test, an antidepressant-like effect was observed for 8 weeks in mice that received a single dose of PA-915, which was a similar effect observed with ketamine. In non-stressed control mice, PA-915 did not induce behavioral abnormalities, such as hyperlocomotion, cognitive dysfunction, or dependency. The present results show that PA-915 improves anxiety-like behaviors and cognitive impairment and exerts rapid and long-lasting antidepressant effects in chronic stress-induced mouse models of anxiety and depression, proposing a promising treatment option for stress-related disorders.Springer Science and Business Media LLC, 2026年02月, Molecular Psychiatry[査読有り]研究論文（学術雑誌）
- Post-Intensive Care Syndrome (PICS) is a serious condition involving physical weakness, depression, and cognitive impairment that develop during or after an intensive care unit (ICU) stay, often resulting in long-term declines in quality of life. Patients with acute respiratory distress syndrome (ARDS) and severe COVID-19 are at particularly high risk, yet the molecular mechanisms underlying PICS remain poorly understood. Here, we identify impaired Apelin-APJ signaling as a potential contributor to PICS pathogenesis via disruption of inter-organ homeostasis. Using a mouse model combining acute lung injury and hindlimb immobilization, we observed PICS-like features including muscle atrophy, lung inflammation, and neurobehavioral abnormalities such as anxiety-like behavior and special working memory. Single-cell RNA sequencing in brain revealed upregulation of gene programs associated with Alzheimer disease, depression, and neuroinflammation, particularly in endothelial cells and microglia. Concurrently, Apelin-APJ signaling was downregulated in skeletal muscle. These changes were exacerbated in Apelin-deficient mice and attenuated by muscle-specific Apelin overexpression, which also reduced systemic IL-6 and restored circulating Apelin levels. In ARDS survivors with severe COVID-19, ICU-acquired weakness (ICU-AW) was associated with reduced plasma Apelin and elevated IL-6 levels. Transcriptomic profiling of peripheral blood mononuclear cells from ICU-AW patients showed gene expression signatures linked to depression and neurodegeneration, mirroring murine findings. These data suggest that impaired Apelin-APJ signaling may play a role in PICS pathophysiology. While skeletal muscle appears to contribute to systemic Apelin levels, further studies are needed to clarify tissue-specific roles. Modulating this pathway could offer a therapeutic strategy to mitigate long-term outcomes in ICU survivors.2025年09月, American journal of respiratory cell and molecular biology, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Japanese Pharmacological Society, 2024年07月, Folia Pharmacologica Japonica, 159(4) (4), 219 - 224[査読有り]研究論文（学術雑誌）
- Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved pleiotropic neuropeptide, implicated in emotional stress responses and anxiety-related disorders. Here, we examined whether our recently developed small-molecule non-peptide PACAP receptor antagonists could ameliorate anxiety-like behaviors induced by acute restraint stress in mice. The antagonists PA-9 and its derivative PA-915 improved anxiety-like behaviors in mice subjected to restraint stress. An anxiolytic effect was observed with single acute dose, suggesting their fast-acting properties. PA-915 demonstrated a statistically significant anxiolytic effect whereas fluoxetine did not. These results indicate the potential of PAC1 antagonists as a novel treatment for anxiety.2022年11月, Biochemical and biophysical research communications, 631, 146 - 151, 英語, 国際誌研究論文（学術雑誌）
- Mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) display psychomotor abnormalities, most of which are ameliorated by atypical antipsychotics with serotonin (5-HT) 2A receptor (5-HT2A) antagonism. Heterozygous Pacap mutant mice show a significantly higher hallucinogenic response than wild-type mice to a 5-HT2A agonist. Endogenous PACAP may, therefore, affect 5-HT2A signaling; however, the underlying neurobiological mechanism for this remains unclear. Here, we examined whether PACAP modulates 5-HT2A signaling by addressing cellular protein localization. PACAP induced an increase in internalization of 5-HT2A but not 5-HT1A, 5-HT2C, dopamine D2 receptors or metabotropic glutamate receptor 2 in HEK293T cells. This PACAP action was inhibited by protein kinase C inhibitors, β-arrestin2 silencing, the PACAP receptor PAC1 antagonist PACAP6-38, and PAC1 silencing. In addition, the levels of endogenous 5-HT2A were decreased on the cell surface of primary cultured cortical neurons after PACAP stimulation and were increased in frontal cortex cell membranes of Pacap-/- mice. Finally, intracerebroventricular PACAP administration suppressed 5-HT2A agonist-induced head twitch responses in mice. These results suggest that PACAP-PAC1 signaling increases 5-HT2A internalization resulting in attenuation of 5-HT2A-mediated signaling, although further study is necessary to determine the relationship between behavioral abnormalities in Pacap-/- mice and PACAP-induced 5-HT2A internalization.2021年, Frontiers in endocrinology, 12, 732456 - 732456, 英語, 国際誌研究論文（学術雑誌）
- We previously showed that mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) exhibit attenuated light-induced phase shift. To explore the underlying mechanisms, we performed gene expression analysis of laser capture microdissected suprachiasmatic nuclei (SCNs) and found that lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is involved in the impaired response to light stimulation in the late subjective night in PACAP-deficient mice. L-PGDS-deficient mice also showed impaired light-induced phase advance, but normal phase delay and nonvisual light responses. Then, we examined the receptors involved in the response and observed that mice deficient for type 2 PGD2 receptor DP2/CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells) show impaired light-induced phase advance. Concordant results were observed using the selective DP2/CRTH2 antagonist CAY10471. These results indicate that L-PGDS is involved in a mechanism of light-induced phase advance via DP2/CRTH2 signaling.2020年10月, Communications biology, 3(1) (1), 557 - 557, 英語, 国際誌研究論文（学術雑誌）
- Alterations in pituitary adenylate cyclase-activating polypeptide (PACAP), a multifunctional neuropeptide, and its receptors have been identified as risk factors for certain psychiatric disorders, including schizophrenia. Increasing evidence from human genetic and animal model studies suggest an association between various psychiatric disorders and altered dendritic spine morphology. In the present study, we investigated the role of exogenous and endogenous PACAP in spine formation and maturation. PACAP modified the density and morphology of PSD-95-positive spines in primary cultured hippocampal neurons. Notably, PACAP increased the levels of microRNA (miR)-132 and decreased expression of corresponding miR-132 target genes and protein expression of p250GAP, a miR-132 effector known to be involved in spine morphology regulation. In corroboration, PSD-95-positive spines were reduced in PACAP-deficient (PACAP-/-) mice versus WT mice. Golgi staining of hippocampal CA1 neurons revealed a reduced spine densities and atypical morphologies in the male PACAP-/- mice. Furthermore, viral miR-132 overexpression reversed the reduction in hippocampal spinal density in the male PACAP-/- mice. These results indicate that PACAP signaling plays a critical role in spine morphogenesis possibly via miR-132. We suggest that dysfunction of PACAP signaling may contribute to the pathogenesis of neuropsychiatric disorders, at least partly through its effects on spine formation.SIGNIFICANCE STATEMENT Pituitary adenylate cyclase-activating polypeptide (PACAP) signaling dysfunction and dendritic spine morphology alterations have recently been suggested as important pathophysiological mechanisms underlying several psychiatric and neurological disorders. In this study, we investigated whether PACAP regulates dendritic spine morphogenesis. In a combination of pharmacological and viral gain- and loss-of-function approaches in vitro and in vivo experiments, we found PACAP to increase the size and density of dendritic spines via miR-132 upregulation. Together, our data suggest that a dysfunction of PACAP signaling may contribute to the pathogenesis of neuropsychiatric disorders, at least partly through abnormal spine formation.2019年05月, The Journal of neuroscience : the official journal of the Society for Neuroscience, 39(22) (22), 4208 - 4220, 英語, 国際誌研究論文（学術雑誌）
- Mitochondrial dysfunction in the nigrostriatal dopaminergic system is a critical hallmark of Parkinson's disease (PD). Mitochondrial toxins produce cellular and behavioural dysfunctions resembling those in patients with PD Causative gene products for familial PD play important roles in mitochondrial function. Therefore, targeting proteins that regulate mitochondrial integrity could provide convincing strategies for PD therapeutics. We have recently identified a novel 13-kDa protein (p13) that may be involved in mitochondrial oxidative phosphorylation. In the current study, we examine the mitochondrial function of p13 and its involvement in PD pathogenesis using mitochondrial toxin-induced PD models. We show that p13 overexpression induces mitochondrial dysfunction and apoptosis. p13 knockdown attenuates toxin-induced mitochondrial dysfunction and apoptosis in dopaminergic SH-SY5Y cells via the regulation of complex I. Importantly, we generate p13-deficient mice using the CRISPR/Cas9 system and observe that heterozygous p13 knockout prevents toxin-induced motor deficits and the loss of dopaminergic neurons in the substantia nigra. Taken together, our results suggest that manipulating p13 expression may be a promising avenue for therapeutic intervention in PD.2018年03月, EMBO reports, 19(3) (3), 英語, 国際誌研究論文（学術雑誌）
- A pituitary adenylate cyclase-activating polypeptide (PACAP)-specific receptor, PAC1R, is coupled with multiple signal transduction pathways including stimulation of adenylate cyclase, phospholipase C and extracellular-signal regulated kinase (ERK)1/2. PAC1R has been shown to exert its long-lasting and potent signals via β-arrestin1 and β-arrestin2. However, the precise roles of the two β-arrestin isoforms in PACAP-PAC1R signaling remain unclear. Here we examined the interaction between the two β-arrestin isoforms and PAC1R, β-arrestin-dependent PAC1R subcellular localization and ERK1/2 activation. Upon PACAP stimulation, although PAC1R similarly interacted with β-arrestin1 and β-arrestin2 in HEK293T cells, the complex of PAC1R and β-arrestin2 was translocated from the cell surface into cytosol, but that of β-arrestin1 remained in the cell surface regions in HeLa cells and mouse primary cultured neurons. Silencing of β-arrestin2 blocked PACAP-induced PAC1R internalization and ERK1/2 phosphorylation, but silencing of β-arrestin1 increased ERK1/2 phosphorylation. These results show that β-arrestin1 and β-arrestin2 exert differential actions on PAC1R internalization and PAC1R-dependent ERK1/2 activation, and suggest that the two β-arrestin isoforms may be involved in fine and precise tuning of the PAC1R signaling pathways.2018年, PloS one, 13(5) (5), e0196946, 英語, 国際誌研究論文（学術雑誌）
- 日本臨床精神神経薬理学会・日本神経精神薬理学会, 2018年11月, 日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集, 28回・48回, 224 - 224, 日本語マウス新生仔へのプロスタグランジンD2受容体DP1作動薬による神経細胞の形態や行動への影響
- 日本臨床精神神経薬理学会・日本神経精神薬理学会, 2018年11月, 日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集, 28回・48回, 224 - 224, 日本語マウス新生仔へのプロスタグランジンD2受容体DP1作動薬による神経細胞の形態や行動への影響
- 日本薬理学会 第２回 100周年記念博士研究奨励賞 受賞講演, 2026年03月新規低分子性PACAP受容体リガンドを用いた脳疾患創薬のための薬理学的研究[招待有り]
- 第９９回日本薬理学会年会, 2026年03月幻覚薬により引き起こされる動的な皮質ネットワークの変化
- The 5th Kobe University-RIKEN BDR Joint Symposium, 2025年02月The role of auditory cortex in dynamic cortical network changes induced by psychedelicポスター発表
- 第13回日本情動学会大会, 2024年11月幻覚薬DOIにより惹起されるマウス幻覚様行動異常における聴覚野の役割ポスター発表
- Neuro 2024, 2024年07月, 英語Behavioral correlation of Rescue-like Behavior in C57BL/6 mouse substrainsポスター発表
- 第144回日本薬理学会近畿部会, 2024年03月幻覚薬DOIを用いた大脳皮質メゾスケールイメージング解析
- 第97回日本薬理学会年会, 2023年11月内側前頭前皮質における PACAP-PAC1 シグナルの遮断が反復社会的敗北ストレスマウスに与える影響
- BPCNPNPPP2022, 2022年11月, 日本語PACAP受容体PAC1の低分子遮断薬の抗うつ効果と関連する脳領域の解析ポスター発表
- VPAC ISBAP 2022, 2022年11月, 英語Fast and lasting antidepressant-like effects of small molecule PACAP receptor PAC1 antagonistシンポジウム・ワークショップパネル（公募）
- VPAC ISBAP 2022, 2022年10月, 英語A single oral administration of small-molecule PAC1 antagonist attenuates repeated stress-induced depressive-like behaviors in miceポスター発表
- 2022年10月, 英語Chemogenetic inhibition of PACAP neurons projecting to the mPFC exerts antidepressant-like effectsポスター発表
- 次世代を担う医療薬理と創薬シンポジウム2022, 2022年08月, 日本語新規ストレス関連障害の治療薬創成を目指した非ペプチドで低分子なPACAP受容体PAC1遮断薬の行 動薬理学研究シンポジウム・ワークショップパネル（指名）
- 生体機能と創薬シンポジウム 2022, 2022年08月, 日本語新規ストレス関連障害の治療薬創成を目指した非ペプチドで低分子なPACAP受容体PAC1遮断薬の行 動薬理学研究ポスター発表
- 第95回日本薬理学会年会, 2022年03月, 日本語新規PACAP受容体PAC1遮断薬による即効性、持続性の抗うつ作用口頭発表（一般）
- 第16回GPCR研究会, 2021年11月, 日本語慢性社会的敗北ストレスモデルマウスにおける新規低分子性PACAP受容体PAC1遮断薬の行動薬理学研究口頭発表（一般）
- CINP2020, 2021年02月, 英語PACAP attenuates 5-HTR2A mediated hallucinations.ポスター発表
- The Akira Arimura Memorial VIP/PACAP and Related Peptides Symposium, 2019年11月, 英語Analysis of PACAP signaling for functional synapse formation in the hippocampal neurons口頭発表（一般）
- The Akira Arimura Memorial VIP/PACAP and Related Peptides Symposium, 2019年11月, 英語Differential regulation of PACAP-PAC1 signaling by two isoforms of β-arrestinポスター発表
- AsCNP2019, 2019年10月, 英語PACAP Increases Functional Synapses In The Primary Hippocampal Neuronsポスター発表
- 次世代を担う創薬・医療薬理シンポジウム 2019, 2019年08月, 日本語神経ペプチドPACAPの機能的シナプス調節機構の解析ポスター発表
- Neuro 2019, 2019年07月, 日本語PACAP-provoked PAC1 receptor signaling and internalization through two isoform of β-arrestins dependent mechanismsポスター発表
- Neuro 2019, 2019年07月, 日本語Prostaglandin D2 modulates neuronal morphological development via activation of DP1 receptorポスター発表
- WCP 2018, 2018年07月, 英語An interaction between PAC1 receptor and serotonin 2A receptor involved in receptor trafficking and signal transductionポスター発表
- International GPCR symposium, 2018年06月, 英語PACAP-provoked PAC1 receptor signaling and internalization through two isoform of β-arrestins dependent mechanismsポスター発表
- 第132回 日本薬理学会 近畿部会, 2017年11月, 日本語プロスタグランジンD2受容体DP1を介したマウス神経細胞の形態変化の解析口頭発表（一般）
- 第131回 日本薬理学会 近畿部会, 2017年06月, 日本語β-アレスチンを介する PACAP-PAC1 シグナルの解析口頭発表（一般）
- 日本学術振興会, 科学研究費助成事業, 特別研究員奨励費, 神戸大学, 2026年04月01日 - 2029年03月31日ミクロ・マクロスケールの蛍光ライブイメージング解析による幻覚の神経基盤の解明
- 日本学術振興会, 科学研究費助成事業, 若手研究, 神戸大学, 2024年04月 - 2027年03月マルチモーダルVR装置を用いた幻覚の神経基盤に関する薬理学研究
- 公益財団法人 先進医薬研究振興財団, 精神薬療分野 若手研究者助成金, 2025年12月 - 2026年11月幻覚の責任領野の同定
- 日本学術振興会, 研究活動スタート支援, 2023年10月 - 2025年03月, 研究代表者大脳皮質マクロイメージング法を用いたうつ病の病態と治療機構に関する検討
- 日本学術振興会, 科学研究費助成事業, 特別研究員奨励費, 大阪大学, 2019年04月 - 2022年03月新規低分子性PACAP受容体リガンドを用いた脳疾患創薬のための薬理学的研究
■ その他