Pub Date : 2023-07-18DOI: 10.1186/s13041-023-01049-3
Daniel F Martins, Victor Sorrentino, Leidiane Mazzardo-Martins, William R Reed, Adair R S Santos, Vinícius M Gadotti, Gerald W Zamponi
The present study was undertaken to explore the relative contributions of Cav3.2 T-type channels to mediating the antihyperalgesic activity of joint manipulation (JM) therapy. We used the chronic constriction injury model (CCI) to induce peripheral neuropathy and chronic pain in male mice, followed by JM. We demonstrate that JM produces long-lasting mechanical anti-hyperalgesia that is abolished in Cav3.2 null mice. Moreover, we found that JM displays a similar analgesic profile as the fatty acid amide hydrolase inhibitor URB597, suggesting a possible converging mechanism of action involving endocannabinoids. Overall, our findings advance our understanding of the mechanisms through which JM produces analgesia.
{"title":"Antihyperalgesic effect of joint mobilization requires Cav3.2 calcium channels.","authors":"Daniel F Martins, Victor Sorrentino, Leidiane Mazzardo-Martins, William R Reed, Adair R S Santos, Vinícius M Gadotti, Gerald W Zamponi","doi":"10.1186/s13041-023-01049-3","DOIUrl":"https://doi.org/10.1186/s13041-023-01049-3","url":null,"abstract":"<p><p>The present study was undertaken to explore the relative contributions of Cav3.2 T-type channels to mediating the antihyperalgesic activity of joint manipulation (JM) therapy. We used the chronic constriction injury model (CCI) to induce peripheral neuropathy and chronic pain in male mice, followed by JM. We demonstrate that JM produces long-lasting mechanical anti-hyperalgesia that is abolished in Cav3.2 null mice. Moreover, we found that JM displays a similar analgesic profile as the fatty acid amide hydrolase inhibitor URB597, suggesting a possible converging mechanism of action involving endocannabinoids. Overall, our findings advance our understanding of the mechanisms through which JM produces analgesia.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10355051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9918607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-12DOI: 10.1186/s13041-023-01047-5
Siyao Li, Koki Sakurai, Masahiro Ohgidani, Takahiro A Kato, Takatoshi Hikida
Schizophrenia is a psychiatric disorder that affects around 1% of the population in widespread populations, with severe cases leading to long-term hospitalization and necessitation of lifelong treatment. Recent studies on schizophrenia have highlighted the involvement of inflammatory and immunoregulatory mechanisms with the onset of symptoms, and the usage of anti-inflammatory treatments are being tested against periods of rapid psychosis. In the central nervous system, microglia are the innate immune population which are activated in response to a wide range of physical and psychological stress factors and produce proinflammatory mediators such as cytokines. Microglial activation and neuroinflammation has been associated to numerous psychiatric disorders including schizophrenia, especially during psychotic episodes. Thus, novel treatments which dampen microglial activation may be of great relevance in the treatment of psychiatric disorders. Fingolimod (FTY720) is a drug used as an immunosuppressive treatment to multiple sclerosis. Recent clinical trials have focused on FTY720 as a treatment for the behavioral symptoms in schizophrenia. However, the mechanisms of Fingolimod in treating the symptoms of schizophrenia are not clear. In this study we use a recently developed neuroinflammatory psychosis model in mice: cuprizone short-term exposure, to investigate the effects of FTY720 administration. FTY720 administration was able to completely alleviate methamphetamine hypersensitivity caused by cuprizone exposure. Moreover, administration of FTY720 improved multiple measures of neuroinflammation (microglial activation, cytokine production, and leucocyte infiltration). In conclusion, our results highlight the future use of FTY720 as a direct anti-inflammatory treatment against microglial activation and psychosis.
{"title":"Ameliorative effects of Fingolimod (FTY720) on microglial activation and psychosis-related behavior in short term cuprizone exposed mice.","authors":"Siyao Li, Koki Sakurai, Masahiro Ohgidani, Takahiro A Kato, Takatoshi Hikida","doi":"10.1186/s13041-023-01047-5","DOIUrl":"https://doi.org/10.1186/s13041-023-01047-5","url":null,"abstract":"<p><p>Schizophrenia is a psychiatric disorder that affects around 1% of the population in widespread populations, with severe cases leading to long-term hospitalization and necessitation of lifelong treatment. Recent studies on schizophrenia have highlighted the involvement of inflammatory and immunoregulatory mechanisms with the onset of symptoms, and the usage of anti-inflammatory treatments are being tested against periods of rapid psychosis. In the central nervous system, microglia are the innate immune population which are activated in response to a wide range of physical and psychological stress factors and produce proinflammatory mediators such as cytokines. Microglial activation and neuroinflammation has been associated to numerous psychiatric disorders including schizophrenia, especially during psychotic episodes. Thus, novel treatments which dampen microglial activation may be of great relevance in the treatment of psychiatric disorders. Fingolimod (FTY720) is a drug used as an immunosuppressive treatment to multiple sclerosis. Recent clinical trials have focused on FTY720 as a treatment for the behavioral symptoms in schizophrenia. However, the mechanisms of Fingolimod in treating the symptoms of schizophrenia are not clear. In this study we use a recently developed neuroinflammatory psychosis model in mice: cuprizone short-term exposure, to investigate the effects of FTY720 administration. FTY720 administration was able to completely alleviate methamphetamine hypersensitivity caused by cuprizone exposure. Moreover, administration of FTY720 improved multiple measures of neuroinflammation (microglial activation, cytokine production, and leucocyte infiltration). In conclusion, our results highlight the future use of FTY720 as a direct anti-inflammatory treatment against microglial activation and psychosis.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10339554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10192732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-10DOI: 10.1186/s13041-023-01043-9
Dong Cheol Jang, Geehoon Chung, Sun Kwang Kim, Sang Jeong Kim
Intrinsic plasticity of the cerebellar Purkinje cell (PC) plays a critical role in motor memory consolidation. However, detailed changes in their intrinsic properties during memory consolidation are not well understood. Here, we report alterations in various properties involved in intrinsic excitability, such as the action potential (AP) threshold, AP width, afterhyperpolarization (AHP), and sag voltage, which are associated with the long-term depression of intrinsic excitability following the motor memory consolidation process. We analyzed data recorded from PCs before and 1, 4, and 24 h after cerebellum-dependent motor learning and found that these properties underwent dynamic changes during the consolidation process. We further analyzed data from PC-specific STIM1 knockout (STIM1PKO) mice, which show memory consolidation deficits, and derived intrinsic properties showing distinct change patterns compared with those of wild-type littermates. The levels of memory retention in the STIM1PKO mice were significantly different compared to wild-type mice between 1 and 4 h after training, and AP width, fast- and medium-AHP, and sag voltage showed different change patterns during this period. Our results provide information regarding alterations in intrinsic properties during a particular period that are critical for memory consolidation.
{"title":"Dynamic alteration of intrinsic properties of the cerebellar Purkinje cell during the motor memory consolidation.","authors":"Dong Cheol Jang, Geehoon Chung, Sun Kwang Kim, Sang Jeong Kim","doi":"10.1186/s13041-023-01043-9","DOIUrl":"https://doi.org/10.1186/s13041-023-01043-9","url":null,"abstract":"<p><p>Intrinsic plasticity of the cerebellar Purkinje cell (PC) plays a critical role in motor memory consolidation. However, detailed changes in their intrinsic properties during memory consolidation are not well understood. Here, we report alterations in various properties involved in intrinsic excitability, such as the action potential (AP) threshold, AP width, afterhyperpolarization (AHP), and sag voltage, which are associated with the long-term depression of intrinsic excitability following the motor memory consolidation process. We analyzed data recorded from PCs before and 1, 4, and 24 h after cerebellum-dependent motor learning and found that these properties underwent dynamic changes during the consolidation process. We further analyzed data from PC-specific STIM1 knockout (STIM1<sup>PKO</sup>) mice, which show memory consolidation deficits, and derived intrinsic properties showing distinct change patterns compared with those of wild-type littermates. The levels of memory retention in the STIM1<sup>PKO</sup> mice were significantly different compared to wild-type mice between 1 and 4 h after training, and AP width, fast- and medium-AHP, and sag voltage showed different change patterns during this period. Our results provide information regarding alterations in intrinsic properties during a particular period that are critical for memory consolidation.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10334628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9867826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-05DOI: 10.1186/s13041-023-01041-x
Kelly Ceyzériat, Alekos Nicolaides, Quentin Amossé, Christine Fossey, Thomas Cailly, Frédéric Fabis, Valentina Garibotto, Carole Escartin, Benjamin B Tournier, Philippe Millet
The 18 kDa translocator protein (TSPO) is a classical marker of neuroinflammation targeted for in vivo molecular imaging. Microglial cells were originally thought to be the only source of TSPO overexpression but astrocytes, neurons and endothelial cells can also up-regulate TSPO depending on the pathological context. This study aims to determine the cellular origin of TSPO overexpression in a simplified model of neuroinflammation and to identify the molecular pathways involved. This is essential to better interpret TSPO molecular imaging in preclinical and clinical settings. We used lentiviral vectors (LV) to overexpress the ciliary neurotrophic factor (CNTF) in the right striatum of 2-month-old Sprague Dawley rats. A LV encoding for β-Galactosidase (LV-LacZ) was used as control. One month later, TSPO expression was measured by single-photon emission computed tomography (SPECT) imaging using [125I]CLINDE. The fluorescence-activated cell sorting to radioligand-treated tissue (FACS-RTT) method was used to quantify TSPO levels in acutely sorted astrocytes, microglia, neurons and endothelial cells. A second cohort was injected with LV-CNTF and a LV encoding suppressor of cytokine signaling 3 (SOCS3), to inhibit the JAK-STAT3 pathway specifically in astrocytes. GFAP and TSPO expressions were quantified by immunofluorescence. We measured a significant increase in TSPO signal in response to CNTF by SPECT imaging. Using FACS-RTT, we observed TSPO overexpression in reactive astrocytes (+ 153 ± 62%) but also in microglia (+ 2088 ± 500%) and neurons (+ 369 ± 117%), accompanied by an increase in TSPO binding sites per cell in those three cell populations. Endothelial cells did not contribute to TSPO signal increase. Importantly, LV-SOCS3 reduced CNTF-induced astrocyte reactivity and decreased global TSPO immunoreactivity (-71% ± 30%), suggesting that TSPO overexpression is primarily mediated by reactive astrocytes. Overall, this study reveals that CNTF induces TSPO in multiple cell types in the rat striatum, through the JAK2-STAT3 pathway in astrocytes, identifying this cell type as the primary mediator of CNTF effects neuroinflammatory processes. Our results highlight the difficulty to interpret TSPO imaging in term of cellular origin without addition cellular analysis by FACS-RTT or quantitative immunostainings. Consequently, TSPO should only be used as a global marker of neuroinflammation.
{"title":"Reactive astrocytes mediate TSPO overexpression in response to sustained CNTF exposure in the rat striatum.","authors":"Kelly Ceyzériat, Alekos Nicolaides, Quentin Amossé, Christine Fossey, Thomas Cailly, Frédéric Fabis, Valentina Garibotto, Carole Escartin, Benjamin B Tournier, Philippe Millet","doi":"10.1186/s13041-023-01041-x","DOIUrl":"10.1186/s13041-023-01041-x","url":null,"abstract":"<p><p>The 18 kDa translocator protein (TSPO) is a classical marker of neuroinflammation targeted for in vivo molecular imaging. Microglial cells were originally thought to be the only source of TSPO overexpression but astrocytes, neurons and endothelial cells can also up-regulate TSPO depending on the pathological context. This study aims to determine the cellular origin of TSPO overexpression in a simplified model of neuroinflammation and to identify the molecular pathways involved. This is essential to better interpret TSPO molecular imaging in preclinical and clinical settings. We used lentiviral vectors (LV) to overexpress the ciliary neurotrophic factor (CNTF) in the right striatum of 2-month-old Sprague Dawley rats. A LV encoding for β-Galactosidase (LV-LacZ) was used as control. One month later, TSPO expression was measured by single-photon emission computed tomography (SPECT) imaging using [<sup>125</sup>I]CLINDE. The fluorescence-activated cell sorting to radioligand-treated tissue (FACS-RTT) method was used to quantify TSPO levels in acutely sorted astrocytes, microglia, neurons and endothelial cells. A second cohort was injected with LV-CNTF and a LV encoding suppressor of cytokine signaling 3 (SOCS3), to inhibit the JAK-STAT3 pathway specifically in astrocytes. GFAP and TSPO expressions were quantified by immunofluorescence. We measured a significant increase in TSPO signal in response to CNTF by SPECT imaging. Using FACS-RTT, we observed TSPO overexpression in reactive astrocytes (+ 153 ± 62%) but also in microglia (+ 2088 ± 500%) and neurons (+ 369 ± 117%), accompanied by an increase in TSPO binding sites per cell in those three cell populations. Endothelial cells did not contribute to TSPO signal increase. Importantly, LV-SOCS3 reduced CNTF-induced astrocyte reactivity and decreased global TSPO immunoreactivity (-71% ± 30%), suggesting that TSPO overexpression is primarily mediated by reactive astrocytes. Overall, this study reveals that CNTF induces TSPO in multiple cell types in the rat striatum, through the JAK2-STAT3 pathway in astrocytes, identifying this cell type as the primary mediator of CNTF effects neuroinflammatory processes. Our results highlight the difficulty to interpret TSPO imaging in term of cellular origin without addition cellular analysis by FACS-RTT or quantitative immunostainings. Consequently, TSPO should only be used as a global marker of neuroinflammation.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9806766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-04DOI: 10.1186/s13041-023-01046-6
Bobae Hyeon, Heeyoung Lee, Nury Kim, Won Do Heo
RET (REarranged during Transfection) is a receptor tyrosine kinase that transduces various external stimuli into biological functions, such as survival and differentiation, in neurons. In the current study, we developed an optogenetic tool for modulating RET signaling, termed optoRET, combining the cytosolic region of human RET with a blue-light-inducible homo-oligomerizing protein. By varying the duration of photoactivation, we were able to dynamically modulate RET signaling. Activation of optoRET recruited Grb2 (growth factor receptor-bound protein 2) and stimulated AKT and ERK (extracellular signal-regulated kinase) in cultured neurons, evoking robust and efficient ERK activation. By locally activating the distal part of the neuron, we were able to retrogradely transduce the AKT and ERK signal to the soma and trigger formation of filopodia-like F-actin structures at stimulated regions through Cdc42 (cell division control 42) activation. Importantly, we successfully modulated RET signaling in dopaminergic neurons of the substantia nigra in the mouse brain. Collectively, optoRET has the potential to be developed as a future therapeutic intervention, modulating RET downstream signaling with light.
RET (rearrange during Transfection)是一种受体酪氨酸激酶,可将各种外部刺激转化为神经元的生物功能,如存活和分化。在目前的研究中,我们开发了一种光遗传学工具来调节RET信号,称为optoRET,将人类RET的细胞质区域与蓝光诱导的同质寡聚蛋白结合起来。通过改变光激活的持续时间,我们能够动态地调节RET信号。optoRET的激活募集了Grb2(生长因子受体结合蛋白2),刺激了AKT和ERK(细胞外信号调节激酶),在培养的神经元中引起强大和有效的ERK激活。通过局部激活神经元的远端部分,我们能够将AKT和ERK信号逆行转导到体细胞,并通过Cdc42(细胞分裂控制42)激活在受刺激区域触发丝状足样f -肌动蛋白结构的形成。重要的是,我们成功地调节了小鼠大脑黑质多巴胺能神经元的RET信号。总的来说,optoRET有潜力成为未来的治疗干预手段,通过光调节RET下游信号。
{"title":"Optogenetic dissection of RET signaling reveals robust activation of ERK and enhanced filopodia-like protrusions of regenerating axons.","authors":"Bobae Hyeon, Heeyoung Lee, Nury Kim, Won Do Heo","doi":"10.1186/s13041-023-01046-6","DOIUrl":"https://doi.org/10.1186/s13041-023-01046-6","url":null,"abstract":"<p><p>RET (REarranged during Transfection) is a receptor tyrosine kinase that transduces various external stimuli into biological functions, such as survival and differentiation, in neurons. In the current study, we developed an optogenetic tool for modulating RET signaling, termed optoRET, combining the cytosolic region of human RET with a blue-light-inducible homo-oligomerizing protein. By varying the duration of photoactivation, we were able to dynamically modulate RET signaling. Activation of optoRET recruited Grb2 (growth factor receptor-bound protein 2) and stimulated AKT and ERK (extracellular signal-regulated kinase) in cultured neurons, evoking robust and efficient ERK activation. By locally activating the distal part of the neuron, we were able to retrogradely transduce the AKT and ERK signal to the soma and trigger formation of filopodia-like F-actin structures at stimulated regions through Cdc42 (cell division control 42) activation. Importantly, we successfully modulated RET signaling in dopaminergic neurons of the substantia nigra in the mouse brain. Collectively, optoRET has the potential to be developed as a future therapeutic intervention, modulating RET downstream signaling with light.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9800996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-03DOI: 10.1186/s13041-023-01042-w
François-Xavier Michon, Isabel Laplante, Anthony Bosson, Richard Robitaille, Jean-Claude Lacaille
Plasticity of principal cells and inhibitory interneurons underlies hippocampal memory. Bidirectional modulation of somatostatin cell mTORC1 activity, a crucial translational control mechanism in synaptic plasticity, causes parallel changes in hippocampal CA1 somatostatin interneuron (SOM-IN) long-term potentiation and hippocampus-dependent memory, indicating a key role in learning. However, SOM-IN activity changes and behavioral correlates during learning, and the role of mTORC1 in these processes, remain ill-defined. To address these questions, we used two-photon Ca2+ imaging from SOM-INs during a virtual reality goal-directed spatial memory task in head-fixed control mice (SOM-IRES-Cre mice) or in mice with conditional knockout of Rptor (SOM-Rptor-KO mice) to block mTORC1 activity in SOM-INs. We found that control mice learn the task, but SOM-Raptor-KO mice exhibit a deficit. Also, SOM-IN Ca2+ activity became increasingly related to reward during learning in control mice but not in SOM-Rptor-KO mice. Four types of SOM-IN activity patterns related to reward location were observed, "reward off sustained", "reward off transient", "reward on sustained" and "reward on transient", and these responses showed reorganization after reward relocation in control but not SOM-Rptor-KO mice. Thus, SOM-INs develop mTORC1-dependent reward- related activity during learning. This coding may bi-directionally interact with pyramidal cells and other structures to represent and consolidate reward location.
{"title":"mTORC1-mediated acquisition of reward-related representations by hippocampal somatostatin interneurons.","authors":"François-Xavier Michon, Isabel Laplante, Anthony Bosson, Richard Robitaille, Jean-Claude Lacaille","doi":"10.1186/s13041-023-01042-w","DOIUrl":"https://doi.org/10.1186/s13041-023-01042-w","url":null,"abstract":"<p><p>Plasticity of principal cells and inhibitory interneurons underlies hippocampal memory. Bidirectional modulation of somatostatin cell mTORC1 activity, a crucial translational control mechanism in synaptic plasticity, causes parallel changes in hippocampal CA1 somatostatin interneuron (SOM-IN) long-term potentiation and hippocampus-dependent memory, indicating a key role in learning. However, SOM-IN activity changes and behavioral correlates during learning, and the role of mTORC1 in these processes, remain ill-defined. To address these questions, we used two-photon Ca<sup>2+</sup> imaging from SOM-INs during a virtual reality goal-directed spatial memory task in head-fixed control mice (SOM-IRES-Cre mice) or in mice with conditional knockout of Rptor (SOM-Rptor-KO mice) to block mTORC1 activity in SOM-INs. We found that control mice learn the task, but SOM-Raptor-KO mice exhibit a deficit. Also, SOM-IN Ca<sup>2+</sup> activity became increasingly related to reward during learning in control mice but not in SOM-Rptor-KO mice. Four types of SOM-IN activity patterns related to reward location were observed, \"reward off sustained\", \"reward off transient\", \"reward on sustained\" and \"reward on transient\", and these responses showed reorganization after reward relocation in control but not SOM-Rptor-KO mice. Thus, SOM-INs develop mTORC1-dependent reward- related activity during learning. This coding may bi-directionally interact with pyramidal cells and other structures to represent and consolidate reward location.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10318662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10135028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-27DOI: 10.1186/s13041-023-01045-7
Rui Chen, Xiang Xu, Xin-Yue Wang, Wen-Bin Jia, De-Shan Zhao, Na Liu, Zhen Pang, Xiao-Qing Liu, Yan Zhang
Itch is a complex aversive sensory and emotional experience. As a most upsetting symptom in many dermatological and systemic diseases, it lacks efficient treatments. The lateral habenula nucleus (LHb) encodes negative emotions in the epithalamus and has been implicated in pain and analgesia. Nevertheless, the role of the lateral habenula nucleus in the pruritic sensation and emotion remains elusive. Here we defined the crucial role of glutamatergic neurons within the lateral habenula nucleus (GluLHb) in itch modulation in mice. We established histamine-dependent and histamine-independent models of acute pruritus, as well as the acetone-ether-water (AEW) model of chronic pruritus. We first assessed the effects of pruritogen injection on neural activation in both medial and lateral divisions of LHb in vitro. We then demonstrated that the population activity of GluLHb neurons was increased during the acute itch and chronic itch-induced scratching behaviors in vivo. In addition, electrophysiological data showed that the excitability of GluLHb neurons was enhanced by chronic itch. Chemogenetic suppression of GluLHb neurons disrupted both acute and chronic itch-evoked scratching behaviors. Furthermore, itch-induced conditioned place aversion (CPA) was abolished by GluLHb neuronal inhibition. Finally, we dissected the LHb upstream brain regions. Together, these findings reveal the involvement of LHb in processing both the sensational and emotional components of pruritus and may shed new insights into itch therapy.
{"title":"The lateral habenula nucleus regulates pruritic sensation and emotion.","authors":"Rui Chen, Xiang Xu, Xin-Yue Wang, Wen-Bin Jia, De-Shan Zhao, Na Liu, Zhen Pang, Xiao-Qing Liu, Yan Zhang","doi":"10.1186/s13041-023-01045-7","DOIUrl":"https://doi.org/10.1186/s13041-023-01045-7","url":null,"abstract":"<p><p>Itch is a complex aversive sensory and emotional experience. As a most upsetting symptom in many dermatological and systemic diseases, it lacks efficient treatments. The lateral habenula nucleus (LHb) encodes negative emotions in the epithalamus and has been implicated in pain and analgesia. Nevertheless, the role of the lateral habenula nucleus in the pruritic sensation and emotion remains elusive. Here we defined the crucial role of glutamatergic neurons within the lateral habenula nucleus (Glu<sup>LHb</sup>) in itch modulation in mice. We established histamine-dependent and histamine-independent models of acute pruritus, as well as the acetone-ether-water (AEW) model of chronic pruritus. We first assessed the effects of pruritogen injection on neural activation in both medial and lateral divisions of LHb in vitro. We then demonstrated that the population activity of Glu<sup>LHb</sup> neurons was increased during the acute itch and chronic itch-induced scratching behaviors in vivo. In addition, electrophysiological data showed that the excitability of Glu<sup>LHb</sup> neurons was enhanced by chronic itch. Chemogenetic suppression of Glu<sup>LHb</sup> neurons disrupted both acute and chronic itch-evoked scratching behaviors. Furthermore, itch-induced conditioned place aversion (CPA) was abolished by Glu<sup>LHb</sup> neuronal inhibition. Finally, we dissected the LHb upstream brain regions. Together, these findings reveal the involvement of LHb in processing both the sensational and emotional components of pruritus and may shed new insights into itch therapy.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10303242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9718158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-21DOI: 10.1186/s13041-023-01044-8
Shukui Zhang, Jinyue Zhao, Cheng Zhao, Libo Su, Jianwei Jiao
The regulation of neural stem cell (NSC) proliferation and differentiation during brain development is a precisely controlled process, with the production of different neuronal subtypes governed by strict timelines. Glutamate is predominantly used as a neurotransmitter by the subtypes of neurons in the various layers of the cerebral cortex. The expression pattern of BCAT1, a gene involved in glutamate metabolism, in the different layers of neurons has yet to be fully understood. Using single-cell data, we have identified seven different states of NSCs and found that state 4 is closely associated with the development of projection neurons. By inferring the developmental trajectory of different neuronal subtypes from NSC subsets of this state, we discovered that BCAT1 is involved in the regulation of NSC proliferation and differentiation and is specifically highly expressed in layer II/III and IV neurons. Suppression of BCAT1 through shRNA resulted in a reduction in NSC proliferation and an abnormal development of layer II/III and IV neurons. These findings provide new insights into the role of BCAT1 in the regulation of NSC behavior and neuronal development.
{"title":"BCAT1 controls embryonic neural stem cells proliferation and differentiation in the upper layer neurons.","authors":"Shukui Zhang, Jinyue Zhao, Cheng Zhao, Libo Su, Jianwei Jiao","doi":"10.1186/s13041-023-01044-8","DOIUrl":"https://doi.org/10.1186/s13041-023-01044-8","url":null,"abstract":"<p><p>The regulation of neural stem cell (NSC) proliferation and differentiation during brain development is a precisely controlled process, with the production of different neuronal subtypes governed by strict timelines. Glutamate is predominantly used as a neurotransmitter by the subtypes of neurons in the various layers of the cerebral cortex. The expression pattern of BCAT1, a gene involved in glutamate metabolism, in the different layers of neurons has yet to be fully understood. Using single-cell data, we have identified seven different states of NSCs and found that state 4 is closely associated with the development of projection neurons. By inferring the developmental trajectory of different neuronal subtypes from NSC subsets of this state, we discovered that BCAT1 is involved in the regulation of NSC proliferation and differentiation and is specifically highly expressed in layer II/III and IV neurons. Suppression of BCAT1 through shRNA resulted in a reduction in NSC proliferation and an abnormal development of layer II/III and IV neurons. These findings provide new insights into the role of BCAT1 in the regulation of NSC behavior and neuronal development.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10283284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9702043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-13DOI: 10.1186/s13041-023-01037-7
Chiwoo Lee, Jihae Oh, Jae-Hyung Lee, Bong-Kiun Kaang, Hyoung-Gon Ko
Itch is a distinctive sensation that causes a specific affection and scratching reaction. The anterior cingulate cortex (ACC) has been linked to itch sensation in numerous studies; however, its precise function in processing pruritic inputs remains unknown. Distinguishing the precise role of the ACC in itch sensation can be challenging because of its capacity to conduct heterologous neurophysiological activities. Here, we used in vivo calcium imaging to examine how ACC neurons in free-moving mice react to pruritogenic histamine. In particular, we focused on how the activity of the ACC neurons varied before and after the scratching response. We discovered that although the change in neuronal activity was not synchronized with the scratching reaction, the overall activity of itch-responsive neurons promptly decreased after the scratching response. These findings suggest that the ACC does not directly elicit the feeling of itchiness.
{"title":"Loosely synchronized activation of anterior cingulate cortical neurons for scratching response during histamine-induced itch.","authors":"Chiwoo Lee, Jihae Oh, Jae-Hyung Lee, Bong-Kiun Kaang, Hyoung-Gon Ko","doi":"10.1186/s13041-023-01037-7","DOIUrl":"https://doi.org/10.1186/s13041-023-01037-7","url":null,"abstract":"<p><p>Itch is a distinctive sensation that causes a specific affection and scratching reaction. The anterior cingulate cortex (ACC) has been linked to itch sensation in numerous studies; however, its precise function in processing pruritic inputs remains unknown. Distinguishing the precise role of the ACC in itch sensation can be challenging because of its capacity to conduct heterologous neurophysiological activities. Here, we used in vivo calcium imaging to examine how ACC neurons in free-moving mice react to pruritogenic histamine. In particular, we focused on how the activity of the ACC neurons varied before and after the scratching response. We discovered that although the change in neuronal activity was not synchronized with the scratching reaction, the overall activity of itch-responsive neurons promptly decreased after the scratching response. These findings suggest that the ACC does not directly elicit the feeling of itchiness.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10262506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9676661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Angiotensin (Ang)-converting-enzyme (ACE) 2 converts Ang II into Ang (1-7), which in turn acts on MAS receptors (ACE2/Ang (1-7)/MAS receptors pathway). This pathway has neuroprotective properties, making it a potential therapeutic target for psychiatric disorders such as depression. Thus, we examined the effects of diminazene aceturate (DIZE), an ACE2 activator, on depressive-like behavior using behavioral, pharmacological, and biochemical assays. To determine whether DIZE or Ang (1-7) produce antidepressant-like effects, we measured the duration of immobility of mice in the tail suspension test following their intracerebroventricular administration. Next, we measured the levels of ACE2 activation in the cerebral cortex, prefrontal cortex, hippocampus, and amygdala after DIZE injection, and examined which cell types, including neurons, microglia, and astrocytes, express ACE2 in the hippocampus using immunofluorescence. Administration of DIZE or Ang (1-7) significantly shortened the duration of immobility time in the tail suspension test, while this effect was inhibited by the co-administration of the MAS receptor antagonist A779. DIZE activated ACE2 in the hippocampus. ACE2 was localized to neurons, astrocytes, and microglia in the hippocampus. In conclusion, these results suggest that DIZE may act on ACE2-positive cells in the hippocampus where it increases the activity of ACE2, thereby enhancing signaling of the ACE2/Ang (1-7)/MAS receptor pathway and resulting in antidepressant-like effects.
{"title":"Activation of angiotensin-converting enzyme 2 produces an antidepressant-like effect via MAS receptors in mice.","authors":"Osamu Nakagawasai, Kohei Takahashi, Taisei Koyama, Ryota Yamagata, Wataru Nemoto, Koichi Tan-No","doi":"10.1186/s13041-023-01040-y","DOIUrl":"https://doi.org/10.1186/s13041-023-01040-y","url":null,"abstract":"<p><p>Angiotensin (Ang)-converting-enzyme (ACE) 2 converts Ang II into Ang (1-7), which in turn acts on MAS receptors (ACE2/Ang (1-7)/MAS receptors pathway). This pathway has neuroprotective properties, making it a potential therapeutic target for psychiatric disorders such as depression. Thus, we examined the effects of diminazene aceturate (DIZE), an ACE2 activator, on depressive-like behavior using behavioral, pharmacological, and biochemical assays. To determine whether DIZE or Ang (1-7) produce antidepressant-like effects, we measured the duration of immobility of mice in the tail suspension test following their intracerebroventricular administration. Next, we measured the levels of ACE2 activation in the cerebral cortex, prefrontal cortex, hippocampus, and amygdala after DIZE injection, and examined which cell types, including neurons, microglia, and astrocytes, express ACE2 in the hippocampus using immunofluorescence. Administration of DIZE or Ang (1-7) significantly shortened the duration of immobility time in the tail suspension test, while this effect was inhibited by the co-administration of the MAS receptor antagonist A779. DIZE activated ACE2 in the hippocampus. ACE2 was localized to neurons, astrocytes, and microglia in the hippocampus. In conclusion, these results suggest that DIZE may act on ACE2-positive cells in the hippocampus where it increases the activity of ACE2, thereby enhancing signaling of the ACE2/Ang (1-7)/MAS receptor pathway and resulting in antidepressant-like effects.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10262141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9672227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}