研究者基本情報

• 博士（医学）, 北海道大学, 2014年03月

• https://researchmap.jp/itk

• https://orcid.org/0000-0001-7554-4764
• https://jglobal.jst.go.jp/detail?JGLOBAL_ID=202201000293839957

• 80745779

• https://orcid.org/0000-0001-7554-4764

• 202201000293839957

• 恐怖
• 報酬
• 光遺伝学
• 神経薬理
• ドパミン
• 基底核

• ライフサイエンス, 薬理学
• ライフサイエンス, 認知脳科学

• 学士課程, 薬学部
• 修士課程, 生命科学院
• 博士課程, 生命科学院

研究活動情報

• 2023年07月, 日本神経精神薬理学会, 第12回奨励賞
• 2022年07月, FENS-IBRO/PERC Travel Grant
• 2016年02月, 第21回グリアクラブ賞
• 2015年09月, 第45回日本神経精神薬理学会第37回日本生物学的精神医学会合同年会優秀発表賞
• 2015年03月, 第88回日本薬理学会年会優秀発表賞
• 2014年07月, 光操作研究会 トラベルグラント
• 2013年09月, 日本薬理学会北部会, 第64回優秀発表賞
• 2010年, 音羽博次奨学金
• 2009年, 第23回北海道薬物作用談話会優秀発表賞

• Competing valence-related roles of dopamine in the tail of the striatum
  Iku Tsutsui-Kimura; Ryota Tsuruga; Yu Tajika; Masabumi Minami
  2025年10月09日, ［責任著者］
• A hypothalamic circuit underlying the dynamic control of social homeostasis
  Ding Liu; Mostafizur Rahman; Autumn Johnson; Ryunosuke Amo; Iku Tsutsui-Kimura; Zuri A. Sullivan; Nicolai Pena; Mustafa Talay; Brandon L. Logeman; Samantha Finkbeiner; Lechen Qian; Seungwon Choi; Athena Capo-Battaglia; Ishmail Abdus-Saboor; David D. Ginty; Naoshige Uchida; Mitsuko Watabe-Uchida; Catherine Dulac
  Nature, 2025年04月24日
  研究論文（学術雑誌）
• Dopamine in the tail of the striatum facilitates avoidance in threat-reward conflicts.
  Iku Tsutsui-Kimura; Zhiyu Melissa Tian; Ryunosuke Amo; Yizhou Zhuo; Yulong Li; Malcolm G Campbell; Naoshige Uchida; Mitsuko Watabe-Uchida
  Nature neuroscience, 2025年03月10日, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Responding appropriately to potential threats before they materialize is critical to avoiding disastrous outcomes. Here we examine how threat-coping behavior is regulated by the tail of the striatum (TS) and its dopamine input. Mice were presented with a potential threat (a moving object) while pursuing rewards. Initially, the mice failed to obtain rewards but gradually improved in later trials. We found that dopamine in TS promoted avoidance of the threat, even at the expense of reward acquisition. Furthermore, the activity of dopamine D1 receptor-expressing neurons promoted threat avoidance and prediction. In contrast, D2 neurons suppressed threat avoidance and facilitated overcoming the potential threat. Dopamine axon activation in TS not only potentiated the responses of dopamine D1 receptor-expressing neurons to novel sensory stimuli but also boosted them acutely. These results demonstrate that an opponent interaction of D1 and D2 neurons in the TS, modulated by dopamine, dynamically regulates avoidance and overcoming potential threats.
• Dopamine dynamics are dispensable for movement but promote reward responses
  Xintong Cai; Changliang Liu; Iku Tsutsui-Kimura; Joon-Hyuk Lee; Chong Guo; Aditi Banerjee; Jinoh Lee; Ryunosuke Amo; Yudi Xie; Tommaso Patriarchi; Yulong Li; Mitsuko Watabe-Uchida; Naoshige Uchida; Pascal S. Kaeser
  Nature, 2024年11月14日
  研究論文（学術雑誌）
• Inhibition of the dorsomedial striatal direct pathway is essential for the execution of action sequences.
  Anna Kono; Yu Shikano; Kenji F Tanaka; Katsunori Yamaura; Iku Tsutsui-Kimura
  Neuropsychopharmacology reports, 43, 3, 414, 424, 2023年09月, ［責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Contrary to the previous notion that the dorsomedial striatum (DMS) is crucial for acquiring new learning, accumulated evidence has suggested that the DMS also plays a role in the execution of already learned action sequences. Here, we examined how the direct and indirect pathways in the DMS regulate action sequences using a task that requires animals to press a lever consecutively. Cell-type-specific bulk Ca2+ recording revealed that the direct pathway was inhibited at the time of sequence execution. The sequence-related response was blunted in trials where the sequential behaviors were disrupted. Optogenetic activation at the sequence start caused distraction of action sequences without affecting motor function or memory of the task structure. By contrast with the direct pathway, the indirect pathway was slightly activated at the start of the sequence, but the optogenetic suppression of such sequence-related signaling did not impact the behaviors. These results suggest that the inhibition of the DMS direct pathway promotes sequence execution potentially by suppressing the formation of a new association.
• Striatal dopamine explains novelty-induced behavioral dynamics and individual variability in threat prediction.
  Korleki Akiti; Iku Tsutsui-Kimura; Yudi Xie; Alexander Mathis; Jeffrey E Markowitz; Rockwell Anyoha; Sandeep Robert Datta; Mackenzie Weygandt Mathis; Naoshige Uchida; Mitsuko Watabe-Uchida
  Neuron, 110, 22, 3789, 3804, 2022年11月16日, ［国際誌］
  英語, 研究論文（学術雑誌）, Animals both explore and avoid novel objects in the environment, but the neural mechanisms that underlie these behaviors and their dynamics remain uncharacterized. Here, we used multi-point tracking (DeepLabCut) and behavioral segmentation (MoSeq) to characterize the behavior of mice freely interacting with a novel object. Novelty elicits a characteristic sequence of behavior, starting with investigatory approach and culminating in object engagement or avoidance. Dopamine in the tail of the striatum (TS) suppresses engagement, and dopamine responses were predictive of individual variability in behavior. Behavioral dynamics and individual variability are explained by a reinforcement-learning (RL) model of threat prediction in which behavior arises from a novelty-induced initial threat prediction (akin to "shaping bonus") and a threat prediction that is learned through dopamine-mediated threat prediction errors. These results uncover an algorithmic similarity between reward- and threat-related dopamine sub-systems.
• Dynamical management of potential threats regulated by dopamine and direct- and indirect-pathway neurons in the tail of the striatum
  Iku Tsutsui-Kimura; Naoshige Uchida; Mitsuko Watabe-Uchida
  bioRxiv, Cold Spring Harbor Laboratory, 2022年02月07日, ［筆頭著者］
  研究論文（学術雑誌）
• How does risk preference change under the stress of COVID-19? Evidence from Japan.
  Yoshiro Tsutsui; Iku Tsutsui-Kimura
  Journal of risk and uncertainty, 64, 2, 191, 212, 2022年, ［国際誌］
  英語, 研究論文（学術雑誌）, UNLABELLED: In this study, we investigated whether the risk preference systematically changed during the spread of COVID-19 in Japan. Traditionally, risk preference is assumed to be stable over one's life, though it differs among individuals. While recent studies have reported that it changes with a large event like natural disasters and financial crisis, they have not reached a consensus on its direction, risk aversion, or tolerance. We collected panel data of Japanese individuals in five waves from March to June 2020, which covered the period of the first cycle when COVID-19 spread rapidly and then dwindled. We measured risk preference through questions on the willingness to pay for insurance. The main results are as follows: First, people became more risk tolerant throughout the period; and second, people were more averse to mega risk than moderate risk, with the former correlating more strongly with the individual's perception of COVID-19. The first result may be interpreted as "habituation" to repeated stress, as is understood in neuroscience. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11166-022-09374-z.
• Mice with reduced glutamate transporter GLT1 expression exhibit behaviors related to attention-deficit/hyperactivity disorder.
  Yuichi Hiraoka; Kaori Sugiyama; Daiki Nagaoka; Iku Tsutsui-Kimura; Kenji F Tanaka; Kohichi Tanaka
  Biochemical and biophysical research communications, 567, 161, 165, 2021年08月27日, ［国際誌］
  英語, 研究論文（学術雑誌）, Attention-deficit/hyperactivity disorder (ADHD) is a common neuropsychiatric disorder in children. Although animal models and human brain imaging studies indicate a significant role for glutamatergic dysfunction in ADHD, there is no direct evidence that glutamatergic dysfunction is sufficient to induce ADHD-like symptoms. The glial glutamate transporter GLT1 plays a critical role in glutamatergic neurotransmission. We report here the generation of mice expressing only 20% of normal levels of the GLT1. Unlike conventional GLT1 knockout mice, these mice survive to adulthood and exhibit ADHD-like phenotypes, including hyperactivity, impulsivity and impaired memory. These findings indicate that glutamatergic dysfunction due to GLT1 deficiency, a mechanism distinct from the dopaminergic deficit hypothesis of ADHD, underlies ADHD-like symptoms.
• Spatial inference without a cognitive map: the role of higher-order path integration.
  Youcef Bouchekioua; Aaron P Blaisdell; Yutaka Kosaki; Iku Tsutsui-Kimura; Paul Craddock; Masaru Mimura; Shigeru Watanabe
  Biological reviews of the Cambridge Philosophical Society, 96, 1, 52, 65, 2021年02月, ［国際誌］
  英語, 研究論文（学術雑誌）, The cognitive map has been taken as the standard model for how agents infer the most efficient route to a goal location. Alternatively, path integration - maintaining a homing vector during navigation - constitutes a primitive and presumably less-flexible strategy than cognitive mapping because path integration relies primarily on vestibular stimuli and pace counting. The historical debate as to whether complex spatial navigation is ruled by associative learning or cognitive map mechanisms has been challenged by experimental difficulties in successfully neutralizing path integration. To our knowledge, there are only three studies that have succeeded in resolving this issue, all showing clear evidence of novel route taking, a behaviour outside the scope of traditional associative learning accounts. Nevertheless, there is no mechanistic explanation as to how animals perform novel route taking. We propose here a new model of spatial learning that combines path integration with higher-order associative learning, and demonstrate how it can account for novel route taking without a cognitive map, thus resolving this long-standing debate. We show how our higher-order path integration (HOPI) model can explain spatial inferences, such as novel detours and shortcuts. Our analysis suggests that a phylogenetically ancient, vector-based navigational strategy utilizing associative processes is powerful enough to support complex spatial inferences.
• Distinct temporal difference error signals in dopamine axons in three regions of the striatum in a decision-making task.
  Iku Tsutsui-Kimura; Hideyuki Matsumoto; Korleki Akiti; Melissa M Yamada; Naoshige Uchida; Mitsuko Watabe-Uchida
  eLife, 9, 2020年12月21日, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Different regions of the striatum regulate different types of behavior. However, how dopamine signals differ across striatal regions and how dopamine regulates different behaviors remain unclear. Here, we compared dopamine axon activity in the ventral, dorsomedial, and dorsolateral striatum, while mice performed a perceptual and value-based decision task. Surprisingly, dopamine axon activity was similar across all three areas. At a glance, the activity multiplexed different variables such as stimulus-associated values, confidence, and reward feedback at different phases of the task. Our modeling demonstrates, however, that these modulations can be inclusively explained by moment-by-moment changes in the expected reward, that is the temporal difference error. A major difference between areas was the overall activity level of reward responses: reward responses in dorsolateral striatum were positively shifted, lacking inhibitory responses to negative prediction errors. The differences in dopamine signals put specific constraints on the properties of behaviors controlled by dopamine in these regions.
• A Unified Framework for Dopamine Signals across Timescales.
  HyungGoo R Kim; Athar N Malik; John G Mikhael; Pol Bech; Iku Tsutsui-Kimura; Fangmiao Sun; Yajun Zhang; Yulong Li; Mitsuko Watabe-Uchida; Samuel J Gershman; Naoshige Uchida
  Cell, 183, 6, 1600, 1616, 2020年12月10日, ［国際誌］
  英語, 研究論文（学術雑誌）, Rapid phasic activity of midbrain dopamine neurons is thought to signal reward prediction errors (RPEs), resembling temporal difference errors used in machine learning. However, recent studies describing slowly increasing dopamine signals have instead proposed that they represent state values and arise independent from somatic spiking activity. Here we developed experimental paradigms using virtual reality that disambiguate RPEs from values. We examined dopamine circuit activity at various stages, including somatic spiking, calcium signals at somata and axons, and striatal dopamine concentrations. Our results demonstrate that ramping dopamine signals are consistent with RPEs rather than value, and this ramping is observed at all stages examined. Ramping dopamine signals can be driven by a dynamic stimulus that indicates a gradual approach to a reward. We provide a unified computational understanding of rapid phasic and slowly ramping dopamine signals: dopamine neurons perform a derivative-like computation over values on a moment-by-moment basis.
• Opposing Ventral Striatal Medium Spiny Neuron Activities Shaped by Striatal Parvalbumin-Expressing Interneurons during Goal-Directed Behaviors.
  Keitaro Yoshida; Iku Tsutsui-Kimura; Anna Kono; Akihiro Yamanaka; Kenta Kobayashi; Masahiko Watanabe; Masaru Mimura; Kenji F Tanaka
  Cell reports, 31, 13, 107829, 107829, 2020年06月30日, ［国際誌］
  英語, 研究論文（学術雑誌）, Medium spiny neurons (MSNs) of mice show opposing activities upon the initiation of a food-seeking lever press task. Ventromedial striatal (VMS)-MSNs are inhibited but ventrolateral striatal (VLS)-MSNs are activated; these activities mediate action selection and action initiation, respectively. To understand what input shapes the opposing MSN activities, here, we monitor cortical input activities at the cell population level and artificially reverse them. We demonstrate that the ventral hippocampus (vHP) and the insular cortex (IC) are major inputs to the VMS and VLS, both projections show silencing at the trial start time, and the vHP-VMS and IC-VLS pathways form functionally coupled input-output units during the task. Of note, the upstream IC silencing is converted to the downstream VLS-MSN activation. We find biased localization of striatal parvalbumin-expressing interneurons (PV INs) and verify PV IN-dependent feedforward architecture in the VLS. Our results reveal a distinct mode of cortico-striatal signal conveyance via feedforward disinhibition in behaving animals.
• Different roles of distinct serotonergic pathways in anxiety-like behavior, antidepressant-like, and anti-impulsive effects.
  Yu Ohmura; Iku Tsutsui-Kimura; Hitomi Sasamori; Mao Nebuka; Naoya Nishitani; Kenji F Tanaka; Akihiro Yamanaka; Mitsuhiro Yoshioka
  Neuropharmacology, 167, 107703, 107703, 2020年05月01日, ［国際誌］
  英語, 研究論文（学術雑誌）, Serotonergic agents have been widely used for treatment of psychiatric disorders, but the therapeutic effects are insufficient and these drugs often induce severe side effects. We need to specify the distinct serotonergic pathways underlying each mental function to overcome these problems. Preclinical studies have demonstrated that the central serotonergic system is involved in several emotional/cognitive functions including anxiety, depression, and impulse control, but it remains unclear whether each function is regulated by a different serotonergic system. We used optogenetic strategy to increase central serotonergic activity in mice and evaluated the behavioral consequences. Pharmacological and genetic tools were used to determine the subtype of 5-HT receptors responsible for the observed effects. We demonstrated that the serotonergic activation in the median raphe nucleus enhanced anxiety-like behavior, the serotonergic activation in the dorsal raphe nucleus exerted antidepressant-like effects, and the serotonergic activation in the median or dorsal raphe nucleus suppressed impulsive action. We also found that different serotonergic terminals, ventral hippocampus, ventral tegmental area/substantia nigra, and subthalamic/parasubthalamic nucleus, are involved in regulating anxiety-like behavior, antidepressant-like, and anti-impulsive effects, respectively. Furthermore, we found, using triple-transgenic mice, that the stimulation of the 5-HT2C receptor is required to evoke anxiety-like behavior, but not to exert anti-impulsive effects. These results suggest the need for pathway-specific treatments and provide important insights that will help the development of more effective and safer therapeutics. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
• AppNL-G-F/NL-G-F mice overall do not show impaired motivation, but cored amyloid plaques in the striatum are inversely correlated with motivation.
  Takuya Hamaguchi; Iku Tsutsui-Kimura; Masaru Mimura; Takashi Saito; Takaomi C Saido; Kenji F Tanaka
  Neurochemistry international, 129, 104470, 104470, 2019年10月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 5-HT3 antagonists decrease discounting rate without affecting sensitivity to reward magnitude in the delay discounting task in mice.
  Marina Mori; Iku Tsutsui-Kimura; Masaru Mimura; Kenji F Tanaka
  Psychopharmacology, 235, 9, 2619, 2629, 2018年09月, ［責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Striatonigral direct pathway activation is sufficient to induce repetitive behaviors.
  Youcef Bouchekioua; Iku Tsutsui-Kimura; Hiromi Sano; Miwako Koizumi; Kenji F Tanaka; Keitaro Yoshida; Yutaka Kosaki; Shigeru Watanabe; Masaru Mimura
  Neuroscience research, 132, 53, 57, 2018年07月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Near-infrared deep brain stimulation via upconversion nanoparticle-mediated optogenetics.
  Shuo Chen; Adam Z Weitemier; Xiao Zeng; Linmeng He; Xiyu Wang; Yanqiu Tao; Arthur J Y Huang; Yuki Hashimotodani; Masanobu Kano; Hirohide Iwasaki; Laxmi Kumar Parajuli; Shigeo Okabe; Daniel B Loong Teh; Angelo H All; Iku Tsutsui-Kimura; Kenji F Tanaka; Xiaogang Liu; Thomas J McHugh
  Science (New York, N.Y.), 359, 6376, 679, 684, 2018年02月09日, ［国際誌］
  英語, 研究論文（学術雑誌）, Optogenetics has revolutionized the experimental interrogation of neural circuits and holds promise for the treatment of neurological disorders. It is limited, however, because visible light cannot penetrate deep inside brain tissue. Upconversion nanoparticles (UCNPs) absorb tissue-penetrating near-infrared (NIR) light and emit wavelength-specific visible light. Here, we demonstrate that molecularly tailored UCNPs can serve as optogenetic actuators of transcranial NIR light to stimulate deep brain neurons. Transcranial NIR UCNP-mediated optogenetics evoked dopamine release from genetically tagged neurons in the ventral tegmental area, induced brain oscillations through activation of inhibitory neurons in the medial septum, silenced seizure by inhibition of hippocampal excitatory cells, and triggered memory recall. UCNP technology will enable less-invasive optical neuronal activity manipulation with the potential for remote therapy.
• Hippocampal activity during serotonergic neuronal activity manipulation using optogenetics
  Kondo D; Mitsukura Y; Yoshida K; Tsutsui-Kimura I; Takata N; Tanaka K
  2017 IEEE Signal Processing in Medicine and Biology Symposium, SPMB 2017 - Proceedings, 2018-January, 1, 6, 2017 IEEE Signal Processing in Medicine and Biology Symposium, SPMB 2017 - Proceedings, 2018年01月12日
  © 2017 IEEE. In order to improve brain dysfunction such as mental disease, it is necessary to clarify the mechanism of activity in the brain. To clarify the relationship between the brain region and the neurotransmitter is important for elucidating the brain. Especially investigating the relationship between serotonin and hippocampus leads to elucidate of the mechanism of depression and sleep. The technique called optogenetics enabled only specific cells to be manipulated by light stimulation in recent years. This technique is a useful technique for clarifying the function of the brain. Because instead of stimulating multiple cells such as electrical stimulation, optogenetics can stimulate only specific cells, so that its function can be clarified. This study focused on neurotransmitter serotonin and the brain region called the hippocampus. For these purpose we can clarify the relationship between serotonin and hippocampus by manipulating serotonin neural activity using optogenetics while invasively measuring the ventral hippocampus of the mouse. In addition, identification of pyramidal cell layer is necessary to clarify hippocampal activity. Currently, visual estimation is perfor
• Amplitude and frequency feature extraction of neural activity in mouse ventrolateral striatum under different motivational states using fiber photometric system
  Imai S; Mitsukura Y; Yoshida K; Tsutsui-Kimura I; Takata N; Tanaka K
  2017 IEEE Signal Processing in Medicine and Biology Symposium, SPMB 2017 - Proceedings, 2018-January, 1, 6, 2017 IEEE Signal Processing in Medicine and Biology Symposium, SPMB 2017 - Proceedings, 2018年01月12日
  © 2017 IEEE. In this paper, we focused on the motivation of mice and aimed to extract neural activity features of D2 medium spiny neurons (D2-MSNs) in the ventrolateral striatum of mice under different motivational states. Motivated behavior is defined as the activation of goal-directed behavior, and this enables actions such as ingestion, sleeping and reproduction, which are essential for living. In human society, motivation allows us to participate in society, improving our quality of life. Loss of motivation has been causing problems such as withdrawal from society. If the symptom is heavy, it can even threaten our lives, and treatment is necessary. The mechanisms which lead to loss of motivation are yet to be understood, and an effective treatment does not exist. To solve these problems, we decided to find features in the neural activity which affect motivation, because understanding the mechanism may contribute to the establishment of treatment. In the experiment, the neural activity was recorded using gene-encoded ratio metric calcium ion (Ca2+) indicator and by constructing a fiber photometric system, which enabled recording of neural activity at specific brain region for s
• Distinct Roles of Ventromedial versus Ventrolateral Striatal Medium Spiny Neurons in Reward-Oriented Behavior.
  Iku Tsutsui-Kimura; Akiyo Natsubori; Marina Mori; Kenta Kobayashi; Michael R Drew; Alban de Kerchove d'Exaerde; Masaru Mimura; Kenji F Tanaka
  Current biology : CB, 27, 19, 3042, 3048, 2017年10月09日, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, The ventral striatum (VS) is a key brain center regulating reward-oriented behavior [1-4]. The VS can be anatomically divided into medial (VMS) and lateral (VLS) portions based on cortical input patterns. The VMS receives inputs from medial pallium-originated limbic structures (e.g., the medial prefrontal cortex [mPFC]), and the VLS receives inputs from the lateral pallium-originated areas (e.g., the insula) [5, 6]. This anatomical feature led us to hypothesize a functional segregation within the VS in terms of the regulation of reward-oriented behavior. Here, we engineered a fiber photometry system [4] and monitored population-level Ca2+ activities of dopamine D2-receptor-expressing medium spiny neurons (D2-MSNs), one of the major cell types in the striatum, during a food-seeking discrimination task. We found that VLS D2-MSNs were activated at the time of cue presentation. In stark contrast, VMS D2-MSNs were inhibited at this time point. Optogenetic counteraction of those changes in the VLS and VMS impaired action initiation and increased responding toward non-rewarded cues, respectively. During lever-press reversal training, VMS inhibition at the time of cue presentation temporarily ceased and optogenetic activation of VMS D2-MSNs facilitated acquisition of the new contingency. These data indicate that the opposing inhibition and excitation in VMS and VLS are important for selecting and initiating a proper action in a reward-oriented behavior. We propose distinct subregional roles within the VS in the execution of successful reward-oriented behavior.
• Yokukansankachimpihange increased body weight but not food-incentive motivation in wild-type mice.
  Takuya Hamaguchi; Iku Tsutsui-Kimura; Kenji F Tanaka; Masaru Mimura
  Nagoya journal of medical science, 79, 3, 351, 362, 2017年08月, ［国内誌］
  英語, 研究論文（学術雑誌）, Yokukansankachimpihange (YKSCH), a traditional Japanese medicine, is widely used for the amelioration of the behavioral and psychological symptoms of dementia with digestive dysfunction. Regardless of its successful use for digestive dysfunction, the effect of YKSCH on body weight was unknown. Furthermore, if YKSCH increased body weight, it might increase motivation according to Kampo medicine theory. Therefore, we investigated whether YKSCH had the potential to increase body weight and enhance motivation in mice. To address this, C57BL/6J mice were used to evaluate the long-term effect of YKSCH on body weight and food-incentive motivation. As part of the evaluation, we optimized an operant test for use over the long-term. We found that feeding mice YKSCH-containing chow increased body weight, but did not increase their motivation to food reward. We propose that YKSCH may be a good treatment option for preventing decrease in body weight in patients with dementia.
• A New Paradigm for Evaluating Avoidance/Escape Motivation.
  Iku Tsutsui-Kimura; Youcef Bouchekioua; Masaru Mimura; Kenji F Tanaka
  The international journal of neuropsychopharmacology, 20, 7, 593, 601, 2017年07月01日, ［筆頭著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Organisms have evolved to approach pleasurable opportunities and to avoid or escape from aversive experiences. These 2 distinct motivations are referred to as approach and avoidance/escape motivations and are both considered vital for survival. Despite several recent advances in understanding the neurobiology of motivation, most studies addressed approach but not avoidance/escape motivation. Here we develop a new experimental paradigm to quantify avoidance/escape motivation and examine the pharmacological validity. METHODS: We set up an avoidance variable ratio 5 task in which mice were required to press a lever for variable times to avoid an upcoming aversive stimulus (foot shock) or to escape the ongoing aversive event if they failed to avoid it. We i.p. injected ketamine (0, 1, or 5 mg/kg) or buspirone (0, 5, or 10 mg/kg) 20 or 30 minutes before the behavioral task to see if ketamine enhanced avoidance/escape behavior and buspirone diminished it as previously reported. RESULTS: We found that the performance on the avoidance variable ratio 5 task was sensitive to the intensity of the aversive stimulus. Treatment with ketamine increased while that with buspirone decreased the probability of avoidance from an aversive stimulus in the variable ratio 5 task, being consistent with previous reports. CONCLUSION: Our new paradigm will prove useful for quantifying avoidance/escape motivation and will contribute to a more comprehensive understanding of motivation.
• Milnacipran affects mouse impulsive, aggressive, and depressive-like behaviors in a distinct dose-dependent manner.
  Iku Tsutsui-Kimura; Yu Ohmura; Takayuki Yoshida; Mitsuhiro Yoshioka
  Journal of pharmacological sciences, 134, 3, 181, 189, 2017年07月, ［筆頭著者］, ［国内誌］
  英語, 研究論文（学術雑誌）, Serotonin/noradrenaline reuptake inhibitors (SNRIs) are widely used for the treatment for major depressive disorder, but these drugs induce several side effects including increased aggression and impulsivity, which are risk factors for substance abuse, criminal involvement, and suicide. To address this issue, milnacipran (0, 3, 10, or 30 mg/kg), an SNRI and antidepressant, was intraperitoneally administered to mice prior to the 3-choice serial reaction time task, resident-intruder test, and forced swimming test to measure impulsive, aggressive, and depressive-like behaviors, respectively. A milnacipran dose of 10 mg/kg suppressed all behaviors, which was accompanied by increased dopamine and serotonin levels in the medial prefrontal cortex (mPFC) but not in the nucleus accumbens (NAc). Although the most effective dose for depressive-like behavior was 30 mg/kg, the highest dose increased aggressive behavior and unaffected impulsive behavior. Increased dopamine levels in the NAc could be responsible for the effects. In addition, the mice basal impulsivity was negatively correlated with the latency to the first agonistic behavior. Thus, the optimal dose range of milnacipran is narrower than previously thought. Finding drugs that increase serotonin and dopamine levels in the mPFC without affecting dopamine levels in the NAc is a potential strategy for developing novel antidepressants.
• The data set describing cognitive performance after varenicline administration in a 3-choice serial reaction time task in rats.
  Yu Ohmura; Hitomi Sasamori; Iku Tsutsui-Kimura; Takeshi Izumi; Takayuki Yoshida; Mitsuhiro Yoshioka
  Data in brief, 11, 507, 509, 2017年04月, ［国際誌］
  英語, 研究論文（学術雑誌）, The data shows attentional function, impulsivity, motivation, motor function, and motor activity in rats treated with varenicline, a stop-smoking aid. The data also shows these parameters in rats treated with varenicline after acute/chronic nicotine administration. Our interpretation and discussion of these data were described in the article "Varenicline Provokes Impulsive Action by Stimulating α4β2 Nicotinic Acetylcholine Receptors in the Infralimbic Cortex in a Nicotine Exposure Status-Dependent Manner" (Ohmura et al., 2017) [1].
• Ventrolateral Striatal Medium Spiny Neurons Positively Regulate Food-Incentive, Goal-Directed Behavior Independently of D1 and D2 Selectivity.
  Akiyo Natsubori; Iku Tsutsui-Kimura; Hiroshi Nishida; Youcef Bouchekioua; Hiroshi Sekiya; Motokazu Uchigashima; Masahiko Watanabe; Alban de Kerchove d'Exaerde; Masaru Mimura; Norio Takata; Kenji F Tanaka
  The Journal of neuroscience : the official journal of the Society for Neuroscience, 37, 10, 2723, 2733, 2017年03月08日, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.SIGNIFICANCE STATEMENT An opposing role of dopamine receptor Type 1 or Type 2-expressing medium spiny neurons (D1-MSNs or D2-MSNs) on striatum-mediated behaviors has been widely accepted. However, this idea has been questioned by recent reports. In the present study, we measured concurrent Ca2+ activity patterns of D1- and D2-MSNs in the ventrolateral striatum during food-incentive, goal-directed behavior in mice. According to Ca2+ activity patterns, we conducted timing-specific optogenetic inhibition of each type of MSN. We demonstrated that both D1- and D2-MSNs in the ventrolateral striatum commonly and positively encoded action initiation, whereas only D1-MSNs positively encoded sustained motivated behavior. These findings led us to reconsider the prevailing notion of a functional segregation of MSN activity in the ventral striatum.
• Varenicline provokes impulsive action by stimulating α4β2 nicotinic acetylcholine receptors in the infralimbic cortex in a nicotine exposure status-dependent manner.
  Yu Ohmura; Hitomi Sasamori; Iku Tsutsui-Kimura; Takeshi Izumi; Takayuki Yoshida; Mitsuhiro Yoshioka
  Pharmacology, biochemistry, and behavior, 154, 1, 10, 2017年03月, ［国際誌］
  英語, 研究論文（学術雑誌）, Higher impulsivity is a risk factor for criminal involvement and drug addiction. Because nicotine administration enhances impulsivity, the effects of stop-smoking aids stimulating nicotinic acetylcholine receptors (nAChRs) on impulsivity must be determined in different conditions. Our goals were 1) to confirm the relationship between varenicline, a stop-smoking aid and α4β2 nAChR partial agonist, and impulsivity, 2) to elucidate the mechanisms underlying the effects of varenicline, 3) to examine whether a low dose of varenicline that does not evoke impulsive action could block the stimulating effects of nicotine on impulsive action, 4) to determine whether the route of administration could modulate the effects of varenicline on impulsive action, and 5) to determine whether the effects of varenicline on impulsivity could be altered by smoking status. We used a 3-choice serial reaction time task to assess impulsivity and other cognitive functions in rats. Our findings are as follows: 1) acute subcutaneous (s.c.) injection of varenicline evoked impulsive action in a dose-dependent manner; 2) the effects of varenicline on impulsivity were blocked by the microinjection of dihydro-β-erythroidine, a α4β2 nAChR antagonist, into the infralimbic cortex; 3) the low dose of varenicline did not attenuate the effects of nicotine on impulsive action at all; 4) oral administration of varenicline evoked impulsive action in a similar manner to s.c. injection; and 5) the stimulating effects of varenicline on impulsive action were not observed in rats that received nicotine infusion for 8days or nicotine-abstinent rats after discontinuing infusion. Additionally, we found that oral varenicline administration enhanced attentional function whether nicotine was infused or not. Thus, although varenicline administration could be harmless to heavy smokers or ex-smokers, it could be difficult for non-smokers with respect to impulsivity, whereas it may be beneficial with respect to attentional function.
• Dysfunction of ventrolateral striatal dopamine receptor type 2-expressing medium spiny neurons impairs instrumental motivation.
  Iku Tsutsui-Kimura; Hiroyuki Takiue; Keitaro Yoshida; Ming Xu; Ryutaro Yano; Hiroyuki Ohta; Hiroshi Nishida; Youcef Bouchekioua; Hideyuki Okano; Motokazu Uchigashima; Masahiko Watanabe; Norio Takata; Michael R Drew; Hiromi Sano; Masaru Mimura; Kenji F Tanaka
  Nature communications, 8, 14304, 14304, 2017年02月01日, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Neuronal codes for the inhibitory control of impulsive actions in the rat infralimbic cortex.
  Iku Tsutsui-Kimura; Yu Ohmura; Takeshi Izumi; Toshiya Matsushima; Hidetoshi Amita; Taku Yamaguchi; Takayuki Yoshida; Mitsuhiro Yoshioka
  Behavioural brain research, 296, 361, 372, 2016年01月01日, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Poor impulse control is a debilitating condition observed in various psychiatric disorders and could be a risk factor for drug addiction, criminal involvement, and suicide. The rat infralimbic cortex (IL), located in the ventral portion of the medial prefrontal cortex, has been implicated in impulse control. To elucidate the neurophysiological basis of impulse control, we recorded single unit activity in the IL of a rat performing a 3-choiceserial reaction time task (3-CSRTT) and 2-choice task (2-CT), which are animal models for impulsivity. The inactivation of IL neuronal activity with an injection of muscimol (0.1 μg /side) disrupted impulse control in the 3-CSRTT. More than 60% (38/56) of isolated IL units were linked to impulse control, while approximately 30% of all units were linked to attentional function in the 3-CSRTT. To avoid confounding motor-related units with the impulse control-related units, we further conducted the 2-CT in which the animals' motor activities were restricted during recording window. More than 30% (14/44) of recorded IL units were linked to impulse control in the 2-CT. Several types of impulse control-related units were identified. Only 16% of all units were compatible with the results of the muscimol experiment, which showed a transient decline in the firing rate immediately before the release of behavioral inhibition. This is the first study to elucidate the neurophysiological basis of impulse control in the IL and to propose that IL neurons control impulsive actions in a more complex manner than previously considered.
• Milnacipran remediates impulsive deficits in rats with lesions of the ventromedial prefrontal cortex.
  Iku Tsutsui-Kimura; Takayuki Yoshida; Yu Ohmura; Takeshi Izumi; Mitsuhiro Yoshioka
  The international journal of neuropsychopharmacology, 18, 5, 2014年12月08日, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Deficits in impulse control are often observed in psychiatric disorders in which abnormalities of the prefrontal cortex are observed, including attention-deficit/hyperactivity disorder and bipolar disorder. We recently found that milnacipran, a serotonin/noradrenaline reuptake inhibitor, could suppress impulsive action in normal rats. However, whether milnacipran could suppress elevated impulsive action in rats with lesions of the ventromedial prefrontal cortex, which is functionally comparable with the human prefrontal cortex, remains unknown. METHODS: Selective lesions of the ventromedial prefrontal cortex were made using quinolinic acid in rats previously trained on a 3-choice serial reaction time task. Sham rats received phosphate buffered saline. Following a period of recovery, milnacipran (0 or 10mg/kg/d × 14 days) was orally administered 60 minutes prior to testing on the 3-choice task. After 7 days of drug cessation, Western blotting, immunohistochemistry, electrophysiological analysis, and morphological analysis were conducted. RESULTS: Lesions of the ventromedial prefrontal cortex induced impulsive deficits, and repeated milnacipran ameliorated the impulsive deficit both during the dosing period and after the cessation of the drug. Repeated milnacipran remediated the protein levels of mature brain-derived neurotrophic factor and postsynaptic density-95, dendritic spine density, and excitatory currents in the few surviving neurons in the ventromedial prefrontal cortex of ventromedial prefrontal cortex-lesioned rats. CONCLUSIONS: The findings of this study suggest that milnacipran treatment could be a novel strategy for the treatment of psychiatric disorders that are associated with a lack of impulse control.
• [Anti-impulsivity drugs and their mechanisms of action].
  Yu Ohmura; Iku Tsutsui-Kimura; Mitsuhiro Yoshioka
  Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology, 34, 2, 41, 8, 2014年04月, ［国内誌］
  日本語, 研究論文（学術雑誌）, Higher impulsivity could be a risk factor for drug addiction, criminal involvement, and suicide. Moreover, poor inhibitory control is observed in several psychiatric disorders such as attention-deficit/hyperactivity disorder, schizophrenia, and bipolar disorder. Thus it is preferred that clinical drugs have anti-impulsive effects in addition to the therapeutic effects on the primary disease. At least it is better to use clinical drugs that do not increase impulsivity. We have developed a 3-choice serial reaction time task and examined the effects of clinical drugs on impulsivity in rats using the task. We have found several anti-impulsive drugs (lithium, tandospirone, and milnacipran) and elucidated the mechanism of action in some of these drugs. For example, we demonstrated that milnacipran enhanced the control of impulsive action by activating D1-like receptors in the infralimbic cortex. In this review, we introduce recent advances in this field and suggest future directions to develop anti-impulsive drugs.
• Milnacipran enhances the control of impulsive action by activating D₁-like receptors in the infralimbic cortex.
  Iku Tsutsui-Kimura; Yu Ohmura; Takeshi Izumi; Haruko Kumamoto; Taku Yamaguchi; Takayuki Yoshida; Mitsuhiro Yoshioka
  Psychopharmacology, 225, 2, 495, 504, 2013年01月, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, RATIONALE: Elevated impulsivity is often observed in patients with depression. We recently found that milnacipran, an antidepressant and a serotonin/noradrenaline reuptake inhibitor, could enhance impulse control in rats. However, the neural mechanisms underlying the effects of milnacipran on impulsive action remain unclear. Milnacipran increases not only extracellular serotonin and noradrenaline but also dopamine specifically in the medial prefrontal cortex, which is one of the brain regions responsible for impulsive action. OBJECTIVES: Our goal was to identify whether D(1)- and/or D(2)-like receptors in the infralimbic cortex (IL), the ventral portion of the medial prefrontal cortex, mediates the milnacipran-enhanced impulse control in a three-choice serial reaction time task. METHODS: The rats were bilaterally injected with SCH23390, a selective D(1)-like receptor antagonist (0.3 or 3 ng/side) or eticlopride, a selective D(2)-like receptor antagonist (0.3 or 1 μg/side) into the IL after acute intraperitoneal administration of milnacipran (10 mg/kg). RESULTS: Intra-IL SCH23390 injections reversed the milnacipran-enhanced impulse control, whereas injections of eticlopride into the IL failed to block the effects of milnacipran on impulsive action. CONCLUSIONS: This is the first report that demonstrates a critical role for D(1)-like receptors of the IL in milnacipran-enhanced control of impulsive action.
• Tandospirone suppresses impulsive action by possible blockade of the 5-HT1A receptor.
  Yu Ohmura; Haruko Kumamoto; Iku Tsutsui-Kimura; Masabumi Minami; Takeshi Izumi; Takayuki Yoshida; Mitsuhiro Yoshioka
  Journal of pharmacological sciences, 122, 2, 84, 92, 2013年, ［国内誌］
  英語, 研究論文（学術雑誌）, Higher impulsivity is observed in several psychiatric disorders and could be a risk factor for drug addiction, criminal involvement, and suicide. Although the involvement of the 5-HT1A receptor in impulsive behavior has been indicated, the effects of clinically relevant drugs have been rarely tested. In the present study, we examined whether (3aR,4S,7R,7aS)-rel-hexahydro-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-4,7-methano-1H-isoindole-1,3(2H)-dione hydrochloride (tandospirone), an anxiolytic and a partial agonist of the 5-HT1A receptor, could affect impulsive action in the 3-choice serial reaction time task. Rats were acutely administered tandospirone (0, 0.1, and 1 mg/kg, i.p.). Tandospirone decreased the number of premature responses, an index of impulsive action, in a dose-dependent manner. N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY100635; 0.3 mg/kg, s.c.), a 5-HT1A receptor antagonist, did not reverse the suppressing effects of tandospirone on impulsive action. Moreover, a higher dose of WAY100635 (1 mg/kg, s.c.) suppressed impulsive action without tandospirone. Thus the effects of tandospirone on impulsivity might be due to the antagonistic action. Tandospirone could be a therapeutic candidate for impulsivity-related disorders.
• Lithium, but not valproic acid or carbamazepine, suppresses impulsive-like action in rats.
  Yu Ohmura; Iku Tsutsui-Kimura; Haruko Kumamoto; Masabumi Minami; Takeshi Izumi; Taku Yamaguchi; Takayuki Yoshida; Mitsuhiro Yoshioka
  Psychopharmacology, 219, 2, 421, 32, 2012年01月, ［国際誌］
  英語, 研究論文（学術雑誌）, RATIONALE: Higher impulsivity is a pathological symptom in several psychiatric disorders, including bipolar disorder, and is a risk factor for suicide. OBJECTIVES: Our goal was to determine whether major mood-stabilizing drugs used for the treatment of bipolar disorder could suppress impulsive-like action in the three-choice serial reaction time task (3-CSRTT). METHODS: Following training for the 3-CSRTT, rats were acutely administered lithium chloride (LiCl; 0, 3.2, 10, and 32 mg/kg, i.p.), valproic acid (0, 10, 32, and 100 mg/kg, i.p.), or carbamazepine (0, 10, 20, and 30 mg/kg, i.p.). To assess the anorexic effects of lithium, a simple food consumption test was conducted. RESULTS: LiCl dose-dependently decreased the number of premature responses, an index of impulsive-like action. A high dose of LiCl (32 mg/kg) decreased food consumption, but its anorexic effects were not correlated with the effects of LiCl on premature responses. A moderate dose of LiCl (20 mg/kg) significantly reduced the number of premature responses without affecting motivation-related measures in the 3-CSRTT or the amount of food consumption. Although carbamazepine prolonged reward latency, an index of motivation for food, neither valproic acid nor carbamazepine significantly affected premature responses. CONCLUSION: It is likely that lithium has a suppressive effect on impulsive action independent of the anorexic effect. Lithium may suppress impulsive behavior and thereby decrease the risk of suicide. The present results could provide an explanation for the antisuicidal effects of lithium and suggest that lithium could be a beneficial treatment for impulsivity-related disorders.
• Impulsive behavior and nicotinic acetylcholine receptors.
  Yu Ohmura; Iku Tsutsui-Kimura; Mitsuhiro Yoshioka
  Journal of pharmacological sciences, 118, 4, 413, 22, 2012年, ［国内誌］
  英語, 研究論文（学術雑誌）, Higher impulsivity is thought to be a risk factor for drug addiction, criminal involvement, and suicide. Excessive levels of impulsivity are often observed in several psychiatric disorders including attention-deficit/hyperactivity disorder and schizophrenia. Previous studies have demonstrated that nicotinic acetylcholine receptors (nAChRs) are involved in impulsive behavior. Here, we introduce recent advances in this field and describe the role of the following nAChR-related brain mechanisms in modulating impulsive behavior: dopamine release in the ventral striatum; α4β2 nAChRs in the infralimbic cortex, which is a ventral part of the medial prefrontal cortex (mPFC); and dopamine release in the mPFC. We also suggest several potential therapeutic drugs to address these mechanisms in impulsivity-related disorders and explore future directions to further elucidate the roles of central nAChRs in impulsive behavior.
• Endogenous acetylcholine modulates impulsive action via alpha4beta2 nicotinic acetylcholine receptors in rats.
  Iku Tsutsui-Kimura; Yu Ohmura; Takeshi Izumi; Taku Yamaguchi; Takayuki Yoshida; Mitsuhiro Yoshioka
  European journal of pharmacology, 641, 2-3, 148, 53, 2010年09月01日, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Nicotine has been well established as an impulsive action-inducing agent, but it remains unknown whether endogenous acetylcholine affects impulsive action via nicotinic acetylcholine receptors. In the present study, the 3-choice serial reaction time task (3-CSRTT), a simple and valid assessment of impulsive action, was employed. Male Wistar/ST rats were trained to detect and respond to 1-s flashes of light presented in one of three holes until stable performance was achieved. Following training on the 3-CSRTT, rats received intracerebroventricular injections of the preferential alpha4beta2 nicotinic acetylcholine receptor antagonist dihydro-beta-erythroidine (DHbetaE; 0, 3, 10, and 30 microg) or the selective alpha7 nicotinic acetylcholine receptor antagonist methyllycaconitine (MLA; 0, 3, 10, and 30 microg) 5 min before test sessions. Injection of 10 microg of DHbetaE significantly suppressed premature responses, an index of impulsive-like action, without changing other behavioral parameters. On the other hand, MLA infusions failed to affect impulsive-like action at any dose. These results suggest that the central alpha4beta2 nicotinic acetylcholine receptors that enable a provoking effect of endogenous acetylcholine play a critical role in impulsive action. Substances that modulate nicotinic acetylcholine receptors, especially the alpha4beta2 subtype, may be beneficial for the treatment of psychiatric disorders characterized by lack of inhibitory control.
• The serotonergic projection from the median raphe nucleus to the ventral hippocampus is involved in the retrieval of fear memory through the corticotropin-releasing factor type 2 receptor.
  Yu Ohmura; Takeshi Izumi; Taku Yamaguchi; Iku Tsutsui-Kimura; Takayuki Yoshida; Mitsuhiro Yoshioka
  Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 35, 6, 1271, 8, 2010年05月, ［国際誌］
  英語, 研究論文（学術雑誌）, Several different studies have separately established that serotonin, corticotropin-releasing factor (CRF) receptors, and the hippocampus are involved in fear memory retrieval. The main aim of this study is to connect these separate studies. To assess the levels of anxiety/fear, we used the contextual fear-conditioning test and the elevated plus maze test as memory-dependent and memory-independent tasks, respectively. We injected CRF receptor antagonists or vehicle into the median raphe nucleus (MRN) 10 min before behavioral tests. As a result, 1000 ng of astressin 2B (CRF(2) receptor antagonist), but not 250 ng of antalarmin (CRF(1) receptor antagonist), significantly suppressed the expression rate of freezing behavior in the contextual fear-conditioning test. However, in the elevated plus maze test, there was no difference between astressin 2B-injected rats and saline-injected rats in the time spent in open arms. Neither the amount of exploratory behavior nor the moving distance in the EPM of astressin 2B-injected rats differed from that of vehicle-injected rats. Moreover, when we assessed the extracellular serotonin release in the ventral hippocampus in freely moving rats through in vivo microdialysis, it was shown that the blockade of the CRF(2) receptor in the MRN suppressed serotonin release in the ventral hippocampus during fear memory retrieval. These results indicated that endogenous CRF and/or related ligands that were released in the MRN could activate the CRF(2) receptor and stimulate serotonin release in the ventral hippocampus, thereby inducing fear memory retrieval.
• Nicotine provokes impulsive-like action by stimulating alpha4beta2 nicotinic acetylcholine receptors in the infralimbic, but not in the prelimbic cortex.
  Iku Tsutsui-Kimura; Yu Ohmura; Takeshi Izumi; Taku Yamaguchi; Takayuki Yoshida; Mitsuhiro Yoshioka
  Psychopharmacology, 209, 4, 351, 9, 2010年05月, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, RATIONALE: Nicotine, a major addictive component of tobacco, has been suggested to provoke impulsivity by activating central alpha4beta2 nicotinic acetylcholine receptors (nAChRs). Although lesion studies have demonstrated the involvement of the medial prefrontal cortex (mPFC) in impulsive action, the precise brain sites responsible for nicotine-induced impulsive action have not been identified. OBJECTIVES: Our goal was to determine whether alpha4beta2 nAChRs in the prelimbic cortex (PL) and/or infralimbic cortex (IL), which are subregions of the mPFC, mediate nicotine-induced impulsive-like action in the three-choice serial reaction time task (3-CSRTT). METHODS: The 3-CSRTT is a simple version of five-choice serial reaction time task and a rodent model of impulsive action in which the animal is required to inhibit the response until a light stimulus is presented randomly in one of three holes. Following the completion of the training, rats were bilaterally injected with dihydro-beta-erythroidine (DHbetaE; 6 and 18 microg/side), a selective alpha4beta2 nAChRs antagonist, into the PL or IL before systemic injection of nicotine (0.2 mg/kg, salt, s.c.). RESULTS: Intra-IL DHbetaE infusions dose-dependently blocked nicotine-induced impulsive-like action, while infusions of DHbetaE into the PL failed to block the effects of nicotine on impulsive-like action. CONCLUSION: The present results suggest a critical role for alpha4beta2 nAChRs in the IL in mediating the effects of nicotine on impulsive-like action in the 3-CSRTT.
• The effects of serotonin and/or noradrenaline reuptake inhibitors on impulsive-like action assessed by the three-choice serial reaction time task: a simple and valid model of impulsive action using rats.
  Iku Tsutsui-Kimura; Yu Ohmura; Takeshi Izumi; Taku Yamaguchi; Takayuki Yoshida; Mitsuhiro Yoshioka
  Behavioural pharmacology, 20, 5-6, 474, 83, 2009年09月, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Impulsivity is a pathological symptom in several psychiatric disorders, underscoring the need for animal models of impulsive action to develop a brief screening method for novel therapeutic agents of impulsive action. The aims of this study were (i) to evaluate whether the three-choice serial reaction time task (3-CSRTT), a simple version of the five-choice serial reaction time task (5-CSRTT), is appropriate for brief assessment of impulsive-like action and (ii) to examine the effects of fluvoxamine, a selective serotonin reuptake inhibitor, and milnacipran, a serotonin/noradrenaline reuptake inhibitor, on impulsive-like action using the 3-CSRTT. After training in the 3-CSRTT, rats were administered nicotine (0, 0.1, 0.2, and 0.4 mg/kg, salt, subcutaneously), atomoxetine [0, 0.01, 0.1, and, 1.0 mg/kg, intraperitoneally (i.p.)], fluvoxamine (0, 2, 4, and 8 mg/kg, i.p.), or milnacipran (0, 3, and 10 mg/kg, i.p.). The training time for the 3-CSRTT was significantly shorter than that for the 5-CSRTT. Nicotine increased, whereas atomoxetine decreased the number of premature responses, an index of impulsive-like action, which is consistent with earlier studies. Milnacipran, but not fluvoxamine, dose-dependently decreased premature responses. These results indicate that the 3-CSRTT could provide an appropriate and simpler rodent model of impulsive-like action and that milnacipran could have some beneficial effects on impulsivity-related disorders.
• [Assessment of attentional function and impulsivity using 5-choice serial reaction time task/3-choice serial reaction time task].
  Yu Ohmura; Iku Tsutsui-Kimura; Mitsuhiro Yoshioka
  Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 134, 3, 137, 41, 2009年09月, ［国内誌］
  日本語, 研究論文（学術雑誌）

• Long-term Effect of Yokukansankachimpihange on Motivation in wild-type mice
  Takuya Hamaguchi; Iku Tsutsui-Kimura; Marina Tsukamoto; Masaru Mimura; Kenji F. Tanaka, INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, 19, 260, 261, 2016年06月
  英語, 研究発表ペーパー・要旨（国際会議）
• Tandospirone suppresses impulsive action in rats
  Yu Ohmura; Haruko Kumamoto; Iku Tsutsui-Kimura; Takeshi Izumi; Takayuki Yoshida; Mitsuhiro Yoshioka, JOURNAL OF PHARMACOLOGICAL SCIENCES, 118, 109P, 109P, 2012年
  英語, 研究発表ペーパー・要旨（国際会議）
• Characterizing therapeutic psychoactive drugs in terms of the effects on impulsivity
  Yu Ohmura; Iku Tsutsui-Kimura; Haruko Kumamoto; Takeshi Izumi; Takayuki Yoshida; Mitsuhiro Yoshioka, JOURNAL OF PHARMACOLOGICAL SCIENCES, 118, 141P, 141P, 2012年
  英語, 研究発表ペーパー・要旨（国際会議）
• Nicotine provokes impulsive-like action by stimulating alpha 4 beta 2 nicotinic acetylcholine receptors in the infralimbic, but not in the prelimbic cortex
  Iku Tsutsui-Kimura; Yu Ohmura; Takeshi Izumi; Taku Yamaguchi; Takayuki Yoshida; Mitsuhiro Yoshioka, FASEB JOURNAL, 24, 2010年04月
  英語, 研究発表ペーパー・要旨（国際会議）
• The serotonergic projection from the median raphe nucleus to the ventral hippocampus is involved in the retrieval of fear memory via the corticotropin-releasing Factor Type 2 receptor
  Yu Ohmura; Takeshi Izumi; Taku Yamaguchi; Iku Tsutsui-Kimura; Takayuki Yoshida; Mitsuhiro Yoshioka, JOURNAL OF PHARMACOLOGICAL SCIENCES, 112, 98P, 98P, 2010年
  英語, 研究発表ペーパー・要旨（国際会議）
• An exploration of therapeutic agents for impulsivity-related disorders using the 3-choice serial reaction time task
  Iku Tsutsui-Kimura; Yu Ohmura; Takeshi Izumi; Taku Yamaguchi; Takayuki Yoshida; Yasunori Kubo; Mitsuhiro Yoshioka, JOURNAL OF PHARMACOLOGICAL SCIENCES, 112, 122P, 122P, 2010年
  英語, 研究発表ペーパー・要旨（国際会議）

• 多様なドパミン予測誤差シグナル
  木村 生
  第47回日本神経科学大会, 2024年07月27日
  ［招待講演］
• 感覚系ドーパミン細胞と忌避行動
  第41回Wako受託Webセミナー, 2023年06月16日
  ［招待講演］
• 目的指向型行動における腹側線条体カルシウム振動の役割
  94 回日本生理学会 大会企画シンポジウム
  2017年03月28日 - 2017年03月30日, ［招待講演］
• 線条体からみつめる、報酬獲得意欲と嫌悪回避意欲の神経回路
  薬物・精神・行動 の会, 2016年04月22日
  ［招待講演］
• Ventrolateral striatum D2 expressing projection neurons and approach/avoidance motivation
  BioPsycho seminar
  ［招待講演］

• 薬理学Ⅳ, 2024年, 学士課程, 薬学部
• 先端生物科学実験法Ⅱ, 2024年, 学士課程, 薬学部
• 物理化学実習, 2024年, 学士課程, 薬学部

• 多様なドパミン予測誤差シグナルの並列処理機構
  戦略的な研究開発の推進 創発的研究支援事業
  2026年 - 2032年
  木村 生
  報酬系においてドパミン神経系が中心的役割を果たすことは良く知られていますが、ドパミン神経系機能の破綻は報酬系の異常に限らず、様々な精神症状を引き起こします。本研究では、報酬性ドパミン神経に加え、多種のドパミン神経亜集団に着目した研究を推進することにより、ドパミン神経系の多様な生理的役割を包括的に理解することで、ドパミン神経機能研究の新たな枠組みを創出することを目指します。
  科学技術振興機構, 北海道大学
• 葛藤の脳内処理機構
  科学研究費助成事業
  2025年04月01日 - 2030年03月31日
  木村 生
  日本学術振興会, 基盤研究(B), 北海道大学, 25K02415
• ストレス適応の新規神経基盤－ストレスホルモンによる感覚系ドパミン回路の調節―
  さきがけ
  2023年04月 - 2026年03月
  JST科学技術振興機構
• 光観察技術が解き明かす意欲を司る神経基盤
  海外特別研究員
  2017年09月 - 2019年08月
  日本学術振興会
• 光遺伝学を用いた衝動性における内側前頭前野腹側部-側坐核経路の役割の解明
  科学研究費助成事業
  2014年04月 - 2017年03月
  木村 生
  最終年度は「内側前頭前野腹側部のD1受容体発現神経細胞は側坐核のドパミン遊離を抑制することで、衝動的行動を制御しているのか？」に取り組んだ。
  まずは、内側前頭前野→側坐核経路が、餌を強化因子としたオペラント行動中にどのような活動パターンを取るのかを、ファイバーフォトメトリー法を用いて調べた。その結果、内側前頭前野腹側部→側坐核経路は試行の開始、行動の出力の際に集合カルシウム活動が増加することが分かった。この結果をもとに、オプトジェネティクス法を用いて内側前頭前野腹側部→側坐核経路を試行の開始、行動の出力のタイミングで抑制したところ、パフォーマンスの変化は認められなかった。この結果から、内側前頭前野腹側部→側坐核経路全体を操作しても衝動的行動への影響がないであろうことが示唆された。この結果は、内側前頭前野腹側部のD1受容体発現神経細胞に限った際に行動変化がみられる期待を高めるものである。
  また、初年度・次年度で取り組んできた、外側側坐核および内側側坐核に分布するD2受容体保持細胞の意欲的行動における役割に関する一連の研究成果を最終年度にNature communications [Tsutsui-Kimura & Takiue et al., Nat Commun. 2017 Feb 1;8:14304. doi: 10.1038/ncomms14304.]および The Journal of Neuroscience[Natsubori & Tsutsui-Kimura et al., J Neurosci. 2017 Mar 8;37(10):2723-2733. doi: 10.1523/JNEUROSCI.3377-16.2017.]で報告することができた。
  日本学術振興会 特別研究員（RPD）, 特別研究員奨励費, 慶應義塾大学, 14J40100
• 衝動性の神経基盤の解明と衝動性抑制薬の探索
  特別研究員（DC1）
  2011年04月 - 2014年03月
  木村 生
  採用二年目に得られた果である「ミルナシランの慢性投与は内側前頭前野腹側部障害動物にみられる衝動性の亢進を抑制する」は現在The international of Neuropsychopharmacologyへ投稿中である(IntJNP-14-0108)。採用三年目における研究計画は「内側前頭前野腹側部による側坐核の神経活動変化および衝動性の制御メカニズムの解明」であった。採用者は採用一年目および二年目までに、内側前頭前野腹側部に分布する神経細胞のおよそ6割が3-選択反応時間課題で測定される衝動的行動の調節に関連していることを覚醒下単一細胞記録法を用いて明らかにし、Neuroscience系の雑誌社に投稿した。しかし、厳しい批判を受けて受理には至らなかった。複数の批判のうち、①内側前頭前野腹側部が衝動性を調節している証拠が示されていない、②basal firingの取り方がおかしい、③衝動性を抑制している間(待機時間)行動の統制がとれていない、という三つが最も深刻であった。採用者はまず批判①を克服するため、ラット内側前頭前野腹側部へGABA_A agonistを微量注入し、内側前頭前野腹側部が衝動性の抑制に関わっていることを確認した。次に批判②および③を克服するために、3-選択時間反応時間課題より待機時間中の行動の統制がとれた新しい課題を確立し、その課題を行っている際の内側前頭前野腹側部のneuron活動を覚醒下単一細胞記録法を用いて測定した。その結果、待てた時と待てなかった時でneuron活動に差があるneuronはおよそ3割以上発見された。この結果は3-選択反応時間課題で得られた結果を支持するものであり、研究の信頼性を上昇させるものである。本研究は現在Behavioural Brain Researchへ投稿準備中である。
  日本学術振興会, 特別研究員奨励費, 北海道大学, 11J04134