{"title":"An RNA editing strategy rescues gene duplication in a mouse model of MECP2 duplication syndrome and nonhuman primates","authors":"Dong Yang, Xiaoqing Wu, Yinan Yao, Mengsi Duan, Xing Wang, Guoling Li, Aiguo Guo, Meixian Wu, Yuanhua Liu, Jin Zheng, Renxia Zhang, Tong Li, Alvin Luk, Xuan Yao, Linyu Shi, Chunlong Xu, Hui Yang","doi":"10.1038/s41593-024-01838-6","DOIUrl":"10.1038/s41593-024-01838-6","url":null,"abstract":"Duplication of methyl-CpG-binding protein 2 (MECP2) gene causes MECP2 duplication syndrome (MDS). To normalize the duplicated MECP2 in MDS, we developed a high-fidelity Cas13Y (hfCas13Y) system capable of targeting the MECP2 (hfCas13Y-gMECP2) messenger RNA for degradation and reducing protein levels in the brain of humanized MECP2 transgenic mice. Moreover, the intracerebroventricular adeno-associated virus (AAV) delivery of hfCas13Y-gMECP2 in newborn or adult MDS mice restored dysregulated gene expression and improved behavior deficits. Notably, treatment with AAV9-hfCas13Y-gMECP2 extended the median survival of MECP2 transgenic mice from 156.5 to 226 d. Furthermore, studies with monkeys showed a single injection of AAV9-hfCas13Y-gMECP2 was sufficient to drive robust expression of hfCas13Y in widespread brain regions, with MECP2 knockdown efficiency reaching 52.19 ± 0.03% and significantly decreased expression of biomarker gene GDF11. Our results demonstrate that the RNA-targeting hfCas13Y-gMECP2 system is an effective intervention for MDS, providing a potential strategy for treating other dosage-sensitive diseases. Duplication of the MECP2 gene (encoding methyl-CpG-binding protein 2) causes MECP2 duplication syndrome. Here the authors develop a Cas13Y system capable of targeting the MECP2 mRNA for degradation and reducing protein levels in the brain of humanized MECP2-transgenic mice and nonhuman primates.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 1","pages":"72-83"},"PeriodicalIF":21.2,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marta Pereira-Iglesias, Joel Maldonado-Teixido, Alejandro Melero, Joaquin Piriz, Elena Galea, Richard M. Ransohoff, Amanda Sierra
{"title":"Microglia as hunters or gatherers of brain synapses","authors":"Marta Pereira-Iglesias, Joel Maldonado-Teixido, Alejandro Melero, Joaquin Piriz, Elena Galea, Richard M. Ransohoff, Amanda Sierra","doi":"10.1038/s41593-024-01818-w","DOIUrl":"10.1038/s41593-024-01818-w","url":null,"abstract":"Over a decade ago, it was discovered that microglia, the brain’s immune cells, engulf synaptic material in a process named microglial pruning. This term suggests that microglia actively sculpt brain circuits by tagging and phagocytosing unwanted synapses. However, live imaging studies have yet to demonstrate how microglial synapse elimination occurs. To address this issue, we propose a new conceptual framework distinguishing between two potential mechanisms of synapse elimination, culling and scavenging. During culling, microglia may use a contractile ring to sever the neuronal plasma membrane, removing the unwanted synapse. During scavenging, synapse elimination is neuronal-driven, and the neuronal plasma membrane fission machinery sheds off synapses that are later phagocytosed by microglia. We will discuss the current limitations of studying microglial synapse elimination and evaluate evidence supporting either culling or scavenging. Discerning between these mechanisms is essential for determining the therapeutic value of phagocytosis modulators in diseases with altered brain connectivity. How microglia sculpt brain circuits is not clear. Here, the authors propose that their contribution to synapse removal may occur by severing synapses (culling) or collecting synapses shed off by neurons (scavenging).","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 1","pages":"15-23"},"PeriodicalIF":21.2,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maëla A. Paul, Séverine M. Sigoillot, Léa Marti, Francisco J. Urra Quiroz, Marine Delagrange, Hiu W. Cheung, David C. Martinelli, Elie Oriol, Vincent Hakim, Philippe Mailly, Fekrije Selimi
{"title":"Stepwise molecular specification of excitatory synapse diversity onto cerebellar Purkinje cells","authors":"Maëla A. Paul, Séverine M. Sigoillot, Léa Marti, Francisco J. Urra Quiroz, Marine Delagrange, Hiu W. Cheung, David C. Martinelli, Elie Oriol, Vincent Hakim, Philippe Mailly, Fekrije Selimi","doi":"10.1038/s41593-024-01826-w","DOIUrl":"https://doi.org/10.1038/s41593-024-01826-w","url":null,"abstract":"<p>Brain function relies on the generation of a large variety of morphologically and functionally diverse, but specific, neuronal synapses. Here we show that, in mice, the initial formation of synapses on cerebellar Purkinje cells involves a presynaptic protein—CBLN1, a member of the C1q protein family—that is secreted by all types of excitatory inputs. The molecular program then evolves only in one of the Purkinje cell inputs, the inferior olivary neurons, with the additional expression of the presynaptic secreted proteins C1QL1, CRTAC1 and LGI2. These molecules work in concert to specify the mature connectivity pattern on the Purkinje cell target. These results show that some inputs actively and gradually specify their synaptic molecular identity, while others rely on the ‘original molecular code’. Thus, the molecular specification of excitatory synapses, crucial for proper circuit function, is acquired in a stepwise manner during mouse postnatal development and obeys input-specific rules.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wojciech Ambroziak, Sara Nencini, Jörg Pohle, Kristina Zuza, Gabriela Pino, Sofia Lundh, Carolina Araujo-Sousa, Larissa I. L. Goetz, Katrin Schrenk-Siemens, Gokul Manoj, Mildred A. Herrera, Claudio Acuna, Jan Siemens
{"title":"Thermally induced neuronal plasticity in the hypothalamus mediates heat tolerance","authors":"Wojciech Ambroziak, Sara Nencini, Jörg Pohle, Kristina Zuza, Gabriela Pino, Sofia Lundh, Carolina Araujo-Sousa, Larissa I. L. Goetz, Katrin Schrenk-Siemens, Gokul Manoj, Mildred A. Herrera, Claudio Acuna, Jan Siemens","doi":"10.1038/s41593-024-01830-0","DOIUrl":"https://doi.org/10.1038/s41593-024-01830-0","url":null,"abstract":"<p>Heat acclimation is an adaptive process that improves physiological performance and supports survival in the face of increasing environmental temperatures, but the underlying mechanisms are not well understood. Here we identified a discrete group of neurons in the mouse hypothalamic preoptic area (POA) that rheostatically increase their activity over the course of heat acclimation, a property required for mice to become heat tolerant. In non-acclimated mice, peripheral thermoafferent pathways via the parabrachial nucleus activate POA neurons and mediate acute heat-defense mechanisms. However, long-term heat exposure promotes the POA neurons to gain intrinsically warm-sensitive activity, independent of thermoafferent parabrachial input. This newly gained cell-autonomous warm sensitivity is required to recruit peripheral heat tolerance mechanisms in acclimated animals. This pacemaker-like, warm-sensitive activity is driven by a combination of increased sodium leak current and enhanced utilization of the Na<sub>V</sub>1.3 ion channel. We propose that this salient neuronal plasticity mechanism adaptively drives acclimation to promote heat tolerance.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"17 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Juan Enriquez-Traba, Miguel Arenivar, Hector E. Yarur-Castillo, Chloe Noh, Rodolfo J. Flores, Tenley Weil, Snehashis Roy, Ted B. Usdin, Christina T. LaGamma, Huikun Wang, Valerie S. Tsai, Damien Kerspern, Amy E. Moritz, David R. Sibley, Andrew Lutas, Rosario Moratalla, Zachary Freyberg, Hugo A. Tejeda
{"title":"Dissociable control of motivation and reinforcement by distinct ventral striatal dopamine receptors","authors":"Juan Enriquez-Traba, Miguel Arenivar, Hector E. Yarur-Castillo, Chloe Noh, Rodolfo J. Flores, Tenley Weil, Snehashis Roy, Ted B. Usdin, Christina T. LaGamma, Huikun Wang, Valerie S. Tsai, Damien Kerspern, Amy E. Moritz, David R. Sibley, Andrew Lutas, Rosario Moratalla, Zachary Freyberg, Hugo A. Tejeda","doi":"10.1038/s41593-024-01819-9","DOIUrl":"10.1038/s41593-024-01819-9","url":null,"abstract":"Dopamine (DA) release in striatal circuits, including the nucleus accumbens medial shell (mNAcSh), tracks separable features of reward like motivation and reinforcement. However, the cellular and circuit mechanisms by which DA receptors transform DA release into distinct constructs of reward remain unclear. Here we show that DA D3 receptor (D3R) signaling in the mNAcSh drives motivated behavior in mice by regulating local microcircuits. Furthermore, D3Rs coexpress with DA D1 receptors, which regulate reinforcement, but not motivation. Paralleling dissociable roles in reward function, we report nonoverlapping physiological actions of D3R and DA D1 receptor signaling in mNAcSh neurons. Our results establish a fundamental framework wherein DA signaling within the same nucleus accumbens cell type is physiologically compartmentalized via actions on distinct DA receptors. This structural and functional organization provides neurons in a limbic circuit with the unique ability to orchestrate dissociable aspects of reward-related behaviors relevant to the etiology of neuropsychiatric disorders. Ventral striatal dopamine D3 and D1 receptors regulate motivation and reinforcement, respectively, through dissociable physiological actions.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 1","pages":"105-121"},"PeriodicalIF":21.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Motivating interest in D3 dopamine receptors","authors":"Nicolas X. Tritsch","doi":"10.1038/s41593-024-01820-2","DOIUrl":"10.1038/s41593-024-01820-2","url":null,"abstract":"Reward signaling via dopamine is most commonly thought of as acting through neurons expressing either D1 or D2 dopamine receptors. Enriquez-Traba et al. show that neurons in the ventral striatum co-express D1 and D3 receptors, which they use to signal dissociable aspects of reward.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 1","pages":"6-7"},"PeriodicalIF":21.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Richard Karlsson Linnér, Travis T. Mallard, Peter B. Barr, Sandra Sanchez-Roige, James W. Madole, Morgan N. Driver, Holly E. Poore, Ronald de Vlaming, Andrew D. Grotzinger, Jorim J. Tielbeek, Emma C. Johnson, Mengzhen Liu, Sara Brin Rosenthal, Trey Ideker, Hang Zhou, Rachel L. Kember, Joëlle A. Pasman, Karin J. H. Verweij, Dajiang J. Liu, Scott Vrieze, COGA Collaborators, Henry R. Kranzler, Joel Gelernter, Kathleen Mullan Harris, Elliot M. Tucker-Drob, Irwin D. Waldman, Abraham A. Palmer, K. Paige Harden, Philipp D. Koellinger, Danielle M. Dick
{"title":"Author Correction: Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction","authors":"Richard Karlsson Linnér, Travis T. Mallard, Peter B. Barr, Sandra Sanchez-Roige, James W. Madole, Morgan N. Driver, Holly E. Poore, Ronald de Vlaming, Andrew D. Grotzinger, Jorim J. Tielbeek, Emma C. Johnson, Mengzhen Liu, Sara Brin Rosenthal, Trey Ideker, Hang Zhou, Rachel L. Kember, Joëlle A. Pasman, Karin J. H. Verweij, Dajiang J. Liu, Scott Vrieze, COGA Collaborators, Henry R. Kranzler, Joel Gelernter, Kathleen Mullan Harris, Elliot M. Tucker-Drob, Irwin D. Waldman, Abraham A. Palmer, K. Paige Harden, Philipp D. Koellinger, Danielle M. Dick","doi":"10.1038/s41593-024-01853-7","DOIUrl":"10.1038/s41593-024-01853-7","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 1","pages":"213-213"},"PeriodicalIF":21.2,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01853-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Meizhen Qian, Jianbao Wang, Yang Gao, Ming Chen, Yin Liu, Dengfeng Zhou, Haidong D. Lu, Xiaotong Zhang, Jia Ming Hu, Anna Wang Roe
{"title":"Multiple loci for foveolar vision in macaque monkey visual cortex","authors":"Meizhen Qian, Jianbao Wang, Yang Gao, Ming Chen, Yin Liu, Dengfeng Zhou, Haidong D. Lu, Xiaotong Zhang, Jia Ming Hu, Anna Wang Roe","doi":"10.1038/s41593-024-01810-4","DOIUrl":"10.1038/s41593-024-01810-4","url":null,"abstract":"In humans and nonhuman primates, the central 1° of vision is processed by the foveola, a retinal structure that comprises a high density of photoreceptors and is crucial for primate-specific high-acuity vision, color vision and gaze-directed visual attention. Here, we developed high-spatial-resolution ultrahigh-field 7T functional magnetic resonance imaging methods for functional mapping of the foveolar visual cortex in awake monkeys. In the ventral pathway (visual areas V1–V4 and the posterior inferior temporal cortex), viewing of a small foveolar spot elicits a ring of multiple (eight) foveolar representations per hemisphere. This ring surrounds an area called the ‘foveolar core’, which is populated by millimeter-scale functional domains sensitive to fine stimuli and high spatial frequencies, consistent with foveolar visual acuity, color and achromatic information and motion. Thus, this elaborate rerepresentation of central vision coupled with a previously unknown foveolar core area signifies a cortical specialization for primate foveation behaviors. The retinal foveola in the primate eye is critical for seeing fine details, color, text and faces. Using ultrahigh-field functional magnetic resonance imaging, Qian et al discover that there is a highly specialized cortical brain region for processing foveolar information.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 1","pages":"137-149"},"PeriodicalIF":21.2,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01810-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Formation of long-term memory without short-term memory revealed by CaMKII inhibition","authors":"Myung Eun Shin, Paula Parra-Bueno, Ryohei Yasuda","doi":"10.1038/s41593-024-01831-z","DOIUrl":"10.1038/s41593-024-01831-z","url":null,"abstract":"Long-term memory (LTM) consolidation is thought to require the prior establishment of short-term memory (STM). Here we show that optogenetic or genetic CaMKII inhibition impairs STM for an inhibitory avoidance task at 1 h but not LTM at 1 day in mice. Similarly, cortico-amygdala synaptic potentiation was more sensitive to CaMKII inhibition at 1 h than at 1 day after training. Thus, LTM does not require the formation of STM, and CaMKII-dependent plasticity specifically regulates STM for avoidance memory. Inhibiting CaMKII impairs short-term memory (STM) in mice during an avoidance task but does not affect long-term memory (LTM). This suggests that STM and LTM are processed differently, with CaMKII critical for STM but not LTM.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 1","pages":"35-39"},"PeriodicalIF":21.2,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Carina Seah, Michael S. Breen, Tom Rusielewicz, Heather N. Bader, Changxin Xu, Christopher J. Hunter, Barry McCarthy, P. J. Michael Deans, Mitali Chattopadhyay, Jordan Goldberg, Saunil Dobariya, Frank Desarnaud, Iouri Makotkine, Janine D. Flory, Linda M. Bierer, Migle Staniskyte, NYSCF Global Stem Cell Array® Team, Scott A. Noggle, Laura M. Huckins, Daniel Paull, Kristen J. Brennand, Rachel Yehuda
{"title":"Author Correction: Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression","authors":"Carina Seah, Michael S. Breen, Tom Rusielewicz, Heather N. Bader, Changxin Xu, Christopher J. Hunter, Barry McCarthy, P. J. Michael Deans, Mitali Chattopadhyay, Jordan Goldberg, Saunil Dobariya, Frank Desarnaud, Iouri Makotkine, Janine D. Flory, Linda M. Bierer, Migle Staniskyte, NYSCF Global Stem Cell Array® Team, Scott A. Noggle, Laura M. Huckins, Daniel Paull, Kristen J. Brennand, Rachel Yehuda","doi":"10.1038/s41593-024-01854-6","DOIUrl":"10.1038/s41593-024-01854-6","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 1","pages":"214-214"},"PeriodicalIF":21.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01854-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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