Ana Maria Ichim, Harald Barzan, Vasile Vlad Moca, Adriana Nagy-Dabacan, Andrei Ciuparu, Adela Hapca, Koen Vervaeke, Raul Cristian Muresan
Gamma oscillations in brain activity (30-150 Hz) have been studied for over 80 years. Although in the past three decades significant progress has been made to try to understand their functional role, a definitive answer regarding their causal implication in perception, cognition, and behavior still lies ahead of us. Here, we first review the basic neural mechanisms that give rise to gamma oscillations and then focus on two main pillars of exploration. The first pillar examines the major theories regarding their functional role in information processing in the brain, also highlighting critical viewpoints. The second pillar reviews a novel research direction that proposes a therapeutic role for gamma oscillations, namely the gamma entrainment using sensory stimulation (GENUS). We extensively discuss both the positive findings and the issues regarding reproducibility of GENUS. Going beyond the functional and therapeutic role of gamma, we propose a third pillar of exploration, where gamma, generated endogenously by cortical circuits, is essential for maintenance of healthy circuit function. We propose that four classes of interneurons, namely those expressing parvalbumin (PV), vasointestinal peptide (VIP), somatostatin (SST), and nitric oxide synthase (NOS) take advantage of endogenous gamma to perform active vasomotor control that maintains homeostasis in the neuronal tissue. According to this hypothesis, which we call GAMER (GAmma MEdiated ciRcuit maintenance), gamma oscillations act as a 'servicing' rhythm that enables efficient translation of neural activity into vascular responses that are essential for optimal neurometabolic processes. GAMER is an extension of GENUS, where endogenous rather than entrained gamma plays a fundamental role. Finally, we propose several critical experiments to test the GAMER hypothesis.
对大脑活动中伽马振荡(30-150 赫兹)的研究已有 80 多年的历史。尽管在过去的三十年里,人们在试图理解伽马振荡的功能作用方面取得了重大进展,但关于伽马振荡在感知、认知和行为中的因果关系,我们仍未得到明确的答案。在这里,我们首先回顾了产生伽马振荡的基本神经机制,然后重点探讨两大支柱。第一部分探讨了有关伽马振荡在大脑信息处理过程中的功能作用的主要理论,并强调了一些重要观点。第二部分回顾了提出伽马振荡治疗作用的新研究方向,即使用感官刺激的伽马诱导(GENUS)。我们广泛讨论了GENUS的积极发现和可重复性问题。除了伽马振荡的功能和治疗作用之外,我们还提出了第三个探索方向,即由大脑皮层回路内生的伽马振荡对于维持健康的回路功能至关重要。我们提出,四类中间神经元,即那些表达副阀素(PV)、血管收缩肽(VIP)、体生长抑素(SST)和一氧化氮合酶(NOS)的中间神经元,利用内源性伽马来执行主动的血管运动控制,从而维持神经元组织的平衡。根据我们称之为 GAMER(GAmma MEdiated ciRcuit maintenance)的这一假说,γ 振荡作为一种 "服务 "节律,能够将神经活动有效地转化为血管反应,而血管反应对于优化神经代谢过程至关重要。GAMER 是 GENUS 的延伸,在 GENUS 中,内源性伽马振荡而不是夹带伽马振荡起着根本性的作用。最后,我们提出了几个关键实验来验证伽马假说。
{"title":"The gamma rhythm as a guardian of brain health.","authors":"Ana Maria Ichim, Harald Barzan, Vasile Vlad Moca, Adriana Nagy-Dabacan, Andrei Ciuparu, Adela Hapca, Koen Vervaeke, Raul Cristian Muresan","doi":"10.7554/eLife.100238","DOIUrl":"https://doi.org/10.7554/eLife.100238","url":null,"abstract":"<p><p>Gamma oscillations in brain activity (30-150 Hz) have been studied for over 80 years. Although in the past three decades significant progress has been made to try to understand their functional role, a definitive answer regarding their causal implication in perception, cognition, and behavior still lies ahead of us. Here, we first review the basic neural mechanisms that give rise to gamma oscillations and then focus on two main pillars of exploration. The first pillar examines the major theories regarding their functional role in information processing in the brain, also highlighting critical viewpoints. The second pillar reviews a novel research direction that proposes a therapeutic role for gamma oscillations, namely the gamma entrainment using sensory stimulation (GENUS). We extensively discuss both the positive findings and the issues regarding reproducibility of GENUS. Going beyond the functional and therapeutic role of gamma, we propose a third pillar of exploration, where gamma, generated endogenously by cortical circuits, is essential for maintenance of healthy circuit function. We propose that four classes of interneurons, namely those expressing parvalbumin (PV), vasointestinal peptide (VIP), somatostatin (SST), and nitric oxide synthase (NOS) take advantage of endogenous gamma to perform active vasomotor control that maintains homeostasis in the neuronal tissue. According to this hypothesis, which we call GAMER (GAmma MEdiated ciRcuit maintenance), gamma oscillations act as a 'servicing' rhythm that enables efficient translation of neural activity into vascular responses that are essential for optimal neurometabolic processes. GAMER is an extension of GENUS, where endogenous rather than entrained gamma plays a fundamental role. Finally, we propose several critical experiments to test the GAMER hypothesis.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Samyogita Hardikar, Bronte Mckeown, H Lina Schaare, Raven Star Wallace, Ting Xu, Mark Edgar Lauckener, Sofie Louise Valk, Daniel S Margulies, Adam Turnbull, Boris C Bernhardt, Reinder Vos de Wael, Arno Villringer, Jonathan Smallwood
Complex macro-scale patterns of brain activity that emerge during periods of wakeful rest provide insight into the organisation of neural function, how these differentiate individuals based on their traits, and the neural basis of different types of self-generated thoughts. Although brain activity during wakeful rest is valuable for understanding important features of human cognition, its unconstrained nature makes it difficult to disentangle neural features related to personality traits from those related to the thoughts occurring at rest. Our study builds on recent perspectives from work on ongoing conscious thought that highlight the interactions between three brain networks - ventral and dorsal attention networks, as well as the default mode network. We combined measures of personality with state-of-the-art indices of ongoing thoughts at rest and brain imaging analysis and explored whether this 'tri-partite' view can provide a framework within which to understand the contribution of states and traits to observed patterns of neural activity at rest. To capture macro-scale relationships between different brain systems, we calculated cortical gradients to describe brain organisation in a low-dimensional space. Our analysis established that for more introverted individuals, regions of the ventral attention network were functionally more aligned to regions of the somatomotor system and the default mode network. At the same time, a pattern of detailed self-generated thought was associated with a decoupling of regions of dorsal attention from regions in the default mode network. Our study, therefore, establishes that interactions between attention systems and the default mode network are important influences on ongoing thought at rest and highlights the value of integrating contemporary perspectives on conscious experience when understanding patterns of brain activity at rest.
{"title":"Macro-scale patterns in functional connectivity associated with ongoing thought patterns and dispositional traits.","authors":"Samyogita Hardikar, Bronte Mckeown, H Lina Schaare, Raven Star Wallace, Ting Xu, Mark Edgar Lauckener, Sofie Louise Valk, Daniel S Margulies, Adam Turnbull, Boris C Bernhardt, Reinder Vos de Wael, Arno Villringer, Jonathan Smallwood","doi":"10.7554/eLife.93689","DOIUrl":"https://doi.org/10.7554/eLife.93689","url":null,"abstract":"<p><p>Complex macro-scale patterns of brain activity that emerge during periods of wakeful rest provide insight into the organisation of neural function, how these differentiate individuals based on their traits, and the neural basis of different types of self-generated thoughts. Although brain activity during wakeful rest is valuable for understanding important features of human cognition, its unconstrained nature makes it difficult to disentangle neural features related to personality traits from those related to the thoughts occurring at rest. Our study builds on recent perspectives from work on ongoing conscious thought that highlight the interactions between three brain networks - ventral and dorsal attention networks, as well as the default mode network. We combined measures of personality with state-of-the-art indices of ongoing thoughts at rest and brain imaging analysis and explored whether this 'tri-partite' view can provide a framework within which to understand the contribution of states and traits to observed patterns of neural activity at rest. To capture macro-scale relationships between different brain systems, we calculated cortical gradients to describe brain organisation in a low-dimensional space. Our analysis established that for more introverted individuals, regions of the ventral attention network were functionally more aligned to regions of the somatomotor system and the default mode network. At the same time, a pattern of detailed self-generated thought was associated with a decoupling of regions of dorsal attention from regions in the default mode network. Our study, therefore, establishes that interactions between attention systems and the default mode network are important influences on ongoing thought at rest and highlights the value of integrating contemporary perspectives on conscious experience when understanding patterns of brain activity at rest.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Clément Mazeaud, Stefan Pfister, Jonathan E Owen, Higor Sette Pereira, Flavie Charbonneau, Zachary E Robinson, Anaïs Anton, Cheyanne L Bemis, Aïssatou Aïcha Sow, Trushar R Patel, Christopher J Neufeldt, Pietro Scaturro, Laurent Chatel-Chaix
Zika virus (ZIKV) infection causes significant human disease that, with no approved treatment or vaccine, constitutes a major public health concern. Its life cycle entirely relies on the cytoplasmic fate of the viral RNA genome (vRNA) through a fine-tuned equilibrium between vRNA translation, replication, and packaging into new virions, all within virus-induced replication organelles (vROs). In this study, with an RNA interference (RNAi) mini-screening and subsequent functional characterization, we have identified insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) as a new host dependency factor that regulates vRNA synthesis. In infected cells, IGF2BP2 associates with viral NS5 polymerase and redistributes to the perinuclear viral replication compartment. Combined fluorescence in situ hybridization-based confocal imaging, in vitro binding assays, and immunoprecipitation coupled to RT-qPCR showed that IGF2BP2 directly interacts with ZIKV vRNA 3' nontranslated region. Using ZIKV sub-genomic replicons and a replication-independent vRO induction system, we demonstrated that IGF2BP2 knockdown impairs de novo vRO biogenesis and, consistently, vRNA synthesis. Finally, the analysis of immunopurified IGF2BP2 complex using quantitative mass spectrometry and RT-qPCR revealed that ZIKV infection alters the protein and RNA interactomes of IGF2BP2. Altogether, our data support that ZIKV hijacks and remodels the IGF2BP2 ribonucleoprotein complex to regulate vRO biogenesis and vRNA neosynthesis.
{"title":"Zika virus remodels and hijacks IGF2BP2 ribonucleoprotein complex to promote viral replication organelle biogenesis.","authors":"Clément Mazeaud, Stefan Pfister, Jonathan E Owen, Higor Sette Pereira, Flavie Charbonneau, Zachary E Robinson, Anaïs Anton, Cheyanne L Bemis, Aïssatou Aïcha Sow, Trushar R Patel, Christopher J Neufeldt, Pietro Scaturro, Laurent Chatel-Chaix","doi":"10.7554/eLife.94347","DOIUrl":"https://doi.org/10.7554/eLife.94347","url":null,"abstract":"<p><p>Zika virus (ZIKV) infection causes significant human disease that, with no approved treatment or vaccine, constitutes a major public health concern. Its life cycle entirely relies on the cytoplasmic fate of the viral RNA genome (vRNA) through a fine-tuned equilibrium between vRNA translation, replication, and packaging into new virions, all within virus-induced replication organelles (vROs). In this study, with an RNA interference (RNAi) mini-screening and subsequent functional characterization, we have identified insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) as a new host dependency factor that regulates vRNA synthesis. In infected cells, IGF2BP2 associates with viral NS5 polymerase and redistributes to the perinuclear viral replication compartment. Combined fluorescence <i>in situ</i> hybridization-based confocal imaging, <i>in vitro</i> binding assays, and immunoprecipitation coupled to RT-qPCR showed that IGF2BP2 directly interacts with ZIKV vRNA 3' nontranslated region. Using ZIKV sub-genomic replicons and a replication-independent vRO induction system, we demonstrated that IGF2BP2 knockdown impairs <i>de novo</i> vRO biogenesis and, consistently, vRNA synthesis. Finally, the analysis of immunopurified IGF2BP2 complex using quantitative mass spectrometry and RT-qPCR revealed that ZIKV infection alters the protein and RNA interactomes of IGF2BP2. Altogether, our data support that ZIKV hijacks and remodels the IGF2BP2 ribonucleoprotein complex to regulate vRO biogenesis and vRNA neosynthesis.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A reciprocal interaction between gut bacteria and gut cells affects protein absorption in the host.
肠道细菌和肠道细胞之间的相互影响会影响宿主对蛋白质的吸收。
{"title":"Balancing microbial composition through diet.","authors":"L Catalina Acuff, Karen Guillemin","doi":"10.7554/eLife.104560","DOIUrl":"https://doi.org/10.7554/eLife.104560","url":null,"abstract":"<p><p>A reciprocal interaction between gut bacteria and gut cells affects protein absorption in the host.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The sustained success of Mycobacterium tuberculosis as a pathogen arises from its ability to persist within macrophages for extended periods and its limited responsiveness to antibiotics. Furthermore, the high incidence of resistance to the few available antituberculosis drugs is a significant concern, especially since the driving forces of the emergence of drug resistance are not clear. Drug-resistant strains of Mycobacterium tuberculosis can emerge through de novo mutations, however, mycobacterial mutation rates are low. To unravel the effects of antibiotic pressure on genome stability, we determined the genetic variability, phenotypic tolerance, DNA repair system activation, and dNTP pool upon treatment with current antibiotics using Mycobacterium smegmatis. Whole-genome sequencing revealed no significant increase in mutation rates after prolonged exposure to first-line antibiotics. However, the phenotypic fluctuation assay indicated rapid adaptation to antibiotics mediated by non-genetic factors. The upregulation of DNA repair genes, measured using qPCR, suggests that genomic integrity may be maintained through the activation of specific DNA repair pathways. Our results, indicating that antibiotic exposure does not result in de novo adaptive mutagenesis under laboratory conditions, do not lend support to the model suggesting antibiotic resistance development through drug pressure-induced microevolution.
结核分枝杆菌作为病原体之所以能够持续存在,是因为它能够在巨噬细胞内长期存活,而且对抗生素的反应能力有限。此外,对现有的几种抗结核药物产生抗药性的发生率很高,这也是一个令人严重关切的问题,尤其是抗药性出现的驱动力尚不明确。结核分枝杆菌的耐药菌株可通过新突变产生,但分枝杆菌的突变率很低。为了揭示抗生素压力对基因组稳定性的影响,我们使用烟草分枝杆菌测定了使用当前抗生素处理时的遗传变异性、表型耐受性、DNA 修复系统激活情况和 dNTP 池。全基因组测序显示,长期接触一线抗生素后,突变率没有明显增加。然而,表型波动分析表明,非遗传因素介导了对抗生素的快速适应。利用 qPCR 测定的 DNA 修复基因上调表明,基因组的完整性可能是通过激活特定的 DNA 修复途径来维持的。我们的研究结果表明,在实验室条件下,抗生素暴露不会导致新的适应性突变,因此不支持通过药物压力诱导的微进化产生抗生素耐药性的模型。
{"title":"Genetic stability of <i>Mycobacterium smegmatis</i> under the stress of first-line antitubercular agents.","authors":"Dániel Molnár, Éva Viola Surányi, Tamás Trombitás, Dóra Füzesi, Rita Hirmondó, Judit Toth","doi":"10.7554/eLife.96695","DOIUrl":"https://doi.org/10.7554/eLife.96695","url":null,"abstract":"<p><p>The sustained success of <i>Mycobacterium tuberculosis</i> as a pathogen arises from its ability to persist within macrophages for extended periods and its limited responsiveness to antibiotics. Furthermore, the high incidence of resistance to the few available antituberculosis drugs is a significant concern, especially since the driving forces of the emergence of drug resistance are not clear. Drug-resistant strains of <i>Mycobacterium tuberculosis</i> can emerge through de novo mutations, however, mycobacterial mutation rates are low. To unravel the effects of antibiotic pressure on genome stability, we determined the genetic variability, phenotypic tolerance, DNA repair system activation, and dNTP pool upon treatment with current antibiotics using <i>Mycobacterium smegmatis</i>. Whole-genome sequencing revealed no significant increase in mutation rates after prolonged exposure to first-line antibiotics. However, the phenotypic fluctuation assay indicated rapid adaptation to antibiotics mediated by non-genetic factors. The upregulation of DNA repair genes, measured using qPCR, suggests that genomic integrity may be maintained through the activation of specific DNA repair pathways. Our results, indicating that antibiotic exposure does not result in de novo adaptive mutagenesis under laboratory conditions, do not lend support to the model suggesting antibiotic resistance development through drug pressure-induced microevolution.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hong Yu, Hiroshi Nishio, Joseph Barbi, Marisa Mitchell-Flack, Paolo D A Vignali, Ying Zheng, Andriana Lebid, Kwang-Yu Chang, Juan Fu, Makenzie Higgins, Ching-Tai Huang, Xuehong Zhang, Zhiguang Li, Lee Blosser, Ada Tam, Charles Drake, Drew Pardoll
The adaptive T cell response is accompanied by continuous rewiring of the T cell's electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report in mice that neuritin (Nrn1) contributes to tolerance development by modulating regulatory and effector T cell function. Nrn1 expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. Nrn1 deficiency in mice causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor Nrn1 in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response.
适应性 T 细胞反应伴随着 T 细胞电力和新陈代谢状态的不断重新布线。离子通道和营养物质转运体整合来自环境的生物电和生化信号,设定细胞的电和代谢状态。不同的电和代谢状态有助于 T 细胞免疫或耐受。在这里,我们以小鼠为研究对象,报告了神经营养素(Nrn1)通过调节调节性和效应性 T 细胞的功能来促进耐受性的发展。Nrn1 在调节性 T 细胞中的表达促进其扩增和抑制功能,而在 T 效应细胞中的表达则抑制其炎症反应。小鼠缺乏 Nrn1 会导致调节性 T 细胞和效应 T 细胞中的离子通道和营养物质转运体表达失调,导致不同的代谢结果,并影响自身免疫疾病的进展和恢复。这些发现确定了神经营养因子 Nrn1 的一种新的免疫功能,即以细胞环境依赖的方式调节 T 细胞代谢状态,并调节免疫反应的结果。
{"title":"Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity.","authors":"Hong Yu, Hiroshi Nishio, Joseph Barbi, Marisa Mitchell-Flack, Paolo D A Vignali, Ying Zheng, Andriana Lebid, Kwang-Yu Chang, Juan Fu, Makenzie Higgins, Ching-Tai Huang, Xuehong Zhang, Zhiguang Li, Lee Blosser, Ada Tam, Charles Drake, Drew Pardoll","doi":"10.7554/eLife.96812","DOIUrl":"https://doi.org/10.7554/eLife.96812","url":null,"abstract":"<p><p>The adaptive T cell response is accompanied by continuous rewiring of the T cell's electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report in mice that neuritin (<i>Nrn1</i>) contributes to tolerance development by modulating regulatory and effector T cell function. <i>Nrn1</i> expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. <i>Nrn1</i> deficiency in mice causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor <i>Nrn1</i> in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The advent of midazolam holds profound implications for modern clinical practice. The hypnotic and sedative effects of midazolam afford it broad clinical applicability. However, the specific mechanisms underlying the modulation of altered consciousness by midazolam remain elusive. Herein, using pharmacology, optogenetics, chemogenetics, fiber photometry, and gene knockdown, this in vivo research revealed the role of locus coeruleus (LC)-ventrolateral preoptic nucleus noradrenergic neural circuit in regulating midazolam-induced altered consciousness. This effect was mediated by α1 adrenergic receptors. Moreover, gamma-aminobutyric acid receptor type A (GABAA-R) represents a mechanistically crucial binding site in the LC for midazolam. These findings will provide novel insights into the neural circuit mechanisms underlying the recovery of consciousness after midazolam administration and will help guide the timing of clinical dosing and propose effective intervention targets for timely recovery from midazolam-induced loss of consciousness.
{"title":"NE contribution to rebooting unconsciousness caused by midazolam.","authors":"LeYuan Gu, WeiHui Shao, Lu Liu, Qing Xu, YuLing Wang, JiaXuan Gu, Yue Yang, ZhuoYue Zhang, YaXuan Wu, Yue Shen, Qian Yu, XiTing Lian, HaiXiang Ma, YuanLi Zhang, HongHai Zhang","doi":"10.7554/eLife.97954","DOIUrl":"https://doi.org/10.7554/eLife.97954","url":null,"abstract":"<p><p>The advent of midazolam holds profound implications for modern clinical practice. The hypnotic and sedative effects of midazolam afford it broad clinical applicability. However, the specific mechanisms underlying the modulation of altered consciousness by midazolam remain elusive. Herein, using pharmacology, optogenetics, chemogenetics, fiber photometry, and gene knockdown, this in vivo research revealed the role of locus coeruleus (LC)-ventrolateral preoptic nucleus noradrenergic neural circuit in regulating midazolam-induced altered consciousness. This effect was mediated by α1 adrenergic receptors. Moreover, gamma-aminobutyric acid receptor type A (GABAA-R) represents a mechanistically crucial binding site in the LC for midazolam. These findings will provide novel insights into the neural circuit mechanisms underlying the recovery of consciousness after midazolam administration and will help guide the timing of clinical dosing and propose effective intervention targets for timely recovery from midazolam-induced loss of consciousness.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dena Goldblatt, Basak Rosti, Kyla Rose Hamling, Paige Leary, Harsh Panchal, Marlyn Li, Hannah Gelnaw, Stephanie Huang, Cheryl Quainoo, David Schoppik
Sensorimotor reflex circuits engage distinct neuronal subtypes, defined by precise connectivity, to transform sensation into compensatory behavior. Whether and how motor neuron populations specify the subtype fate and/or sensory connectivity of their pre-motor partners remains controversial. Here, we discovered that motor neurons are dispensable for proper connectivity in the vestibular reflex circuit that stabilizes gaze. We first measured activity following vestibular sensation in pre-motor projection neurons after constitutive loss of their extraocular motor neuron partners. We observed normal responses and topography indicative of unchanged functional connectivity between sensory neurons and projection neurons. Next, we show that projection neurons remain anatomically and molecularly poised to connect appropriately with their downstream partners. Lastly, we show that the transcriptional signatures that typify projection neurons develop independently of motor partners. Our findings comprehensively overturn a long-standing model: that connectivity in the circuit for gaze stabilization is retrogradely determined by motor partner-derived signals. By defining the contribution of motor neurons to specification of an archetypal sensorimotor circuit, our work speaks to comparable processes in the spinal cord and advances our understanding of principles of neural development.
{"title":"Motor neurons are dispensable for the assembly of a sensorimotor circuit for gaze stabilization.","authors":"Dena Goldblatt, Basak Rosti, Kyla Rose Hamling, Paige Leary, Harsh Panchal, Marlyn Li, Hannah Gelnaw, Stephanie Huang, Cheryl Quainoo, David Schoppik","doi":"10.7554/eLife.96893","DOIUrl":"https://doi.org/10.7554/eLife.96893","url":null,"abstract":"<p><p>Sensorimotor reflex circuits engage distinct neuronal subtypes, defined by precise connectivity, to transform sensation into compensatory behavior. Whether and how motor neuron populations specify the subtype fate and/or sensory connectivity of their pre-motor partners remains controversial. Here, we discovered that motor neurons are dispensable for proper connectivity in the vestibular reflex circuit that stabilizes gaze. We first measured activity following vestibular sensation in pre-motor projection neurons after constitutive loss of their extraocular motor neuron partners. We observed normal responses and topography indicative of unchanged functional connectivity between sensory neurons and projection neurons. Next, we show that projection neurons remain anatomically and molecularly poised to connect appropriately with their downstream partners. Lastly, we show that the transcriptional signatures that typify projection neurons develop independently of motor partners. Our findings comprehensively overturn a long-standing model: that connectivity in the circuit for gaze stabilization is retrogradely determined by motor partner-derived signals. By defining the contribution of motor neurons to specification of an archetypal sensorimotor circuit, our work speaks to comparable processes in the spinal cord and advances our understanding of principles of neural development.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Many cell fate decisions are determined transcriptionally. Accordingly, some fate specification is prevented by Inhibitor of DNA-binding (Id) proteins that interfere with DNA binding by master regulatory transcription factors. We show that the Drosophila Id protein Extra macrochaetae (Emc) also affects developmental decisions by regulating caspase activity. Emc, which prevents proneural bHLH transcription factors from specifying neural cell fate, also prevents homodimerization of another bHLH protein, Daughterless (Da), and thereby maintains expression of the Death-Associated Inhibitor of Apoptosis (diap1) gene. Accordingly, we found that multiple effects of emc mutations on cell growth and on eye development were all caused by activation of caspases. These effects included acceleration of the morphogenetic furrow, failure of R7 photoreceptor cell specification, and delayed differentiation of non-neuronal cone cells. Within emc mutant clones, Notch signaling was elevated in the morphogenetic furrow, increasing morphogenetic furrow speed. This was associated with caspase-dependent increase in levels of Delta protein, the transmembrane ligand for Notch. Posterior to the morphogenetic furrow, elevated Delta cis-inhibited Notch signaling that was required for R7 specification and cone cell differentiation. Growth inhibition of emc mutant clones in wing imaginal discs also depended on caspases. Thus, emc mutations reveal the importance of restraining caspase activity even in non-apoptotic cells to prevent abnormal development, in the Drosophila eye through effects on Notch signaling.
{"title":"Extramacrochaetae regulates Notch signaling in the <i>Drosophila</i> eye through non-apoptotic caspase activity.","authors":"Sudershana Nair, Nicholas E Baker","doi":"10.7554/eLife.91988","DOIUrl":"https://doi.org/10.7554/eLife.91988","url":null,"abstract":"<p><p>Many cell fate decisions are determined transcriptionally. Accordingly, some fate specification is prevented by Inhibitor of DNA-binding (Id) proteins that interfere with DNA binding by master regulatory transcription factors. We show that the <i>Drosophila</i> Id protein Extra macrochaetae (Emc) also affects developmental decisions by regulating caspase activity. Emc, which prevents proneural bHLH transcription factors from specifying neural cell fate, also prevents homodimerization of another bHLH protein, Daughterless (Da), and thereby maintains expression of the <i>Death-Associated Inhibitor of Apoptosis</i> (<i>diap1</i>) gene. Accordingly, we found that multiple effects of <i>emc</i> mutations on cell growth and on eye development were all caused by activation of caspases. These effects included acceleration of the morphogenetic furrow, failure of R7 photoreceptor cell specification, and delayed differentiation of non-neuronal cone cells. Within <i>emc</i> mutant clones, Notch signaling was elevated in the morphogenetic furrow, increasing morphogenetic furrow speed. This was associated with caspase-dependent increase in levels of Delta protein, the transmembrane ligand for Notch. Posterior to the morphogenetic furrow, elevated Delta cis-inhibited Notch signaling that was required for R7 specification and cone cell differentiation. Growth inhibition of <i>emc</i> mutant clones in wing imaginal discs also depended on caspases. Thus, <i>emc</i> mutations reveal the importance of restraining caspase activity even in non-apoptotic cells to prevent abnormal development, in the <i>Drosophila</i> eye through effects on Notch signaling.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"12 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bacillus velezensis is a species of Bacillus that has been widely investigated because of its broad-spectrum antimicrobial activity. However, most studies on B. velezensis have focused on the biocontrol of plant diseases, with few reports on antagonizing Salmonella Typhimurium infections. In this investigation, it was discovered that B. velezensis HBXN2020, which was isolated from healthy black pigs, possessed strong anti-stress and broad-spectrum antibacterial activity. Importantly, B. velezensis HBXN2020 did not cause any adverse side effects in mice when administered at various doses (1×107, 1×108, and 1×109 CFU) for 14 days. Supplementing B. velezensis HBXN2020 spores, either as a curative or preventive measure, dramatically reduced the levels of S. Typhimurium ATCC14028 in the mice's feces, ileum, cecum, and colon, as well as the disease activity index (DAI), in a model of infection caused by this pathogen in mice. Additionally, supplementing B. velezensis HBXN2020 spores significantly regulated cytokine levels (Tnfa, Il1b, Il6, and Il10) and maintained the expression of tight junction proteins and mucin protein. Most importantly, adding B. velezensis HBXN2020 spores to the colonic microbiota improved its stability and increased the amount of beneficial bacteria (Lactobacillus and Akkermansia). All together, B. velezensis HBXN2020 can improve intestinal microbiota stability and barrier integrity and reduce inflammation to help treat infection by S. Typhimurium.
韦氏芽孢杆菌(Bacillus velezensis)是芽孢杆菌中的一种,因其具有广谱抗菌活性而被广泛研究。然而,关于 B. velezensis 的研究大多集中在植物病害的生物防治方面,很少有关于拮抗伤寒沙门氏菌感染的报道。本次研究发现,从健康黑猪体内分离出的 B. velezensis HBXN2020 具有很强的抗应激和广谱抗菌活性。重要的是,以不同剂量(1×107、1×108 和 1×109 CFU)连续给药 14 天,B. velezensis HBXN2020 不会对小鼠造成任何不良副作用。在由该病原体引起的小鼠感染模型中,作为治疗或预防措施补充 B. velezensis HBXN2020 孢子可显著降低小鼠粪便、回肠、盲肠和结肠中的鼠伤寒杆菌 ATCC14028 的含量以及疾病活动指数(DAI)。此外,补充 B. velezensis HBXN2020 孢子可显著调节细胞因子水平(Tnfa、Il1b、Il6 和 Il10),并维持紧密连接蛋白和粘蛋白的表达。最重要的是,在结肠微生物群中添加 B. velezensis HBXN2020 孢子能提高其稳定性,并增加有益菌(乳酸杆菌和 Akkermansia)的数量。总之,B. velezensis HBXN2020 可以提高肠道微生物区系的稳定性和屏障完整性,减少炎症,从而帮助治疗伤寒杆菌感染。
{"title":"<i>Bacillus velezensis</i> HBXN2020 alleviates <i>Salmonella</i> Typhimurium infection in mice by improving intestinal barrier integrity and reducing inflammation.","authors":"Linkang Wang, Haiyan Wang, Xinxin Li, Mengyuan Zhu, Dongyang Gao, Dayue Hu, Zhixuan Xiong, Xiangmin Li, Ping Qian","doi":"10.7554/eLife.93423","DOIUrl":"10.7554/eLife.93423","url":null,"abstract":"<p><p><i>Bacillus velezensis</i> is a species of <i>Bacillus</i> that has been widely investigated because of its broad-spectrum antimicrobial activity. However, most studies on <i>B. velezensis</i> have focused on the biocontrol of plant diseases, with few reports on antagonizing <i>Salmonella</i> Typhimurium infections. In this investigation, it was discovered that <i>B. velezensis</i> HBXN2020, which was isolated from healthy black pigs, possessed strong anti-stress and broad-spectrum antibacterial activity. Importantly, <i>B. velezensis</i> HBXN2020 did not cause any adverse side effects in mice when administered at various doses (1×10<sup>7</sup>, 1×10<sup>8</sup>, and 1×10<sup>9</sup> CFU) for 14 days. Supplementing <i>B. velezensis</i> HBXN2020 spores, either as a curative or preventive measure, dramatically reduced the levels of <i>S.</i> Typhimurium ATCC14028 in the mice's feces, ileum, cecum, and colon, as well as the disease activity index (DAI), in a model of infection caused by this pathogen in mice. Additionally, supplementing <i>B. velezensis</i> HBXN2020 spores significantly regulated cytokine levels (<i>Tnfa</i>, <i>Il1b</i>, <i>Il6</i>, and <i>Il10</i>) and maintained the expression of tight junction proteins and mucin protein. Most importantly, adding <i>B. velezensis</i> HBXN2020 spores to the colonic microbiota improved its stability and increased the amount of beneficial bacteria (<i>Lactobacillus</i> and <i>Akkermansia</i>). All together, <i>B. velezensis</i> HBXN2020 can improve intestinal microbiota stability and barrier integrity and reduce inflammation to help treat infection by <i>S.</i> Typhimurium.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}