PVALB

引言 食物摄入与机体生存紧密相关，它的失调不仅可能影响生存，也可能引起肥胖等健康问题。下丘脑是能量稳态的调节中心，通过整合中枢和外周信号调节食物摄入和能量消耗，从而维持体重稳定。 下丘脑室旁核（PVH）是下丘脑内一个异质性高的脑区，通过不同类型的神经元调节能量稳态。现有研究表明大多数PVH神经元主要通过投射臂旁核（PB）或下丘脑腹内侧核 (VMH) 来抑制食欲。然而，关于PVH调节食欲的其它神经环路仍有待于阐明，这对于深入理解PVH在调节食欲和维持体重稳定中的作用至关重要。 2024年10月16日，天津医科大学朱宪彝纪念医院内分泌研究所谢向阳教授和中国科学院生物物理所张树利研究员合作在Nature Communications在线发表题为Paraventricular hypothalamic RUVBL2 neurons suppress appetite by enhancing excitatory synaptic transmission in distinct neurocircuits的研究论文。该研究揭示PVH调节食欲的两条新型神经环路，并阐明PVH RUVBL2通过增强这两条环路的兴奋性突触传递而抑制食欲。 首先，研究者发现能量缺乏导致RUVBL2在PVH的表达显著降低，提示RUVBL2在食欲调节中的作用。研究者构建了Ruvbl2fl/fl小鼠模型，通过脑立体定向注射技术向PVH脑区注射AAV-Cre病毒，发现PVH RUVBL2的敲除会导致过度摄食引起的肥胖。为了探究PVHRUVBL2神经元在控制饱腹感中的作用，研究者使用化学遗传学和光遗传学操纵PVHRUVBL2神经元的活性，发现激活PVHRUVBL2神经元抑制食欲，而抑制PVHRUVBL2神经元则促进食欲。 为了确定接受PVHRUVBL2神经元轴突投射的脑区，研究者进行了顺行跨单突触示踪实验。发现LSv、POA、DMH、ARC、MeA、PB和NTS脑区会接受PVHRUVBL2神经元的直接投射。逆行示踪实验也证明PVHRUVBL2神经元与上述七个大脑区域存在突触联系。然后，研究者利用环路特异性的化学遗传学技术证明PVHRUVBL2神经元通过PVHRUVBL2→ARC，PVHRUVBL2→DMH和PVHRUVBL2→PB发挥食欲抑制作用。 接下来，研究者想要探究PVH RUVBL2和PVHRUVBL2神经元抑制食欲的突触机制。考虑到进食行为异常可能是由于兴奋性或抑制性突触传递障碍引起的，研究者通过电生理实验检测PVH RUVBL2敲除对突触传递的影响。结果表明PVH RUVBL2敲除损害了PVHRUVBL2→ARC和PVHRUVBL2→DMH神经环路的兴奋性突触传递，但不影响抑制性突触传递。突触传递障碍可能是由于突触前输入或突触囊泡分布异常影响突触可塑性而引起。因此，研究者猜测RUVBL2敲除可能损害突触前输入或突触前囊泡分布，从而导致突触传递异常。通过免疫组化，研究者发现 RUVBL2敲除后， ARC或DMH中VGluT2标记点显著降低。电镜分析表明，RUVBL2敲除显著减少ARC和DMH中PVHRUVBL2神经元轴突末端距离活跃区（AZ）200nm以内的突触囊泡数量。ChIP-Seq联合RNA-Seq分析也证实RUVBL2调控与神经元轴突形成和突触囊泡相关基因的表达。这些数据综合表明PVH RUVBL2敲除导致突触前boutons和突触囊泡分布的改变，从而损害兴奋性突触传递。 最后，研究者探索了增加RUVBL2在PVH中的表达是否增强兴奋性突触传递并且抑制食欲。利用Ruvbl2KI/KI;Sim1-Cre小鼠模型实现RUVBL2在PVH中的过表达，研究者发现RUVBL2过表达导致突触囊泡分布发生变化，增强PVHRUVBL2→ARC和PVHRUVBL2→DMH神经环路的兴奋性突触传递，从而抑制食物摄入，显著缓解高脂肪饮食（HFD）诱导的肥胖。 总之，该研究揭示了PVH调节食欲的新神经环路：PVHRUVBL2→ARC和PVHRUVBL2→DMH，并阐明RUVBL2通过调节突触可塑性影响食欲。因此，调节突触可塑性有望是调节食欲和体重的有效方法。该研究也进一步提示ARC和PVH之间可能存在正反馈回路，从而促进最大或维持持续饱腹感，这对于防止过度摄食具有重要意义。 PVH RUVBL2 通过PVHRUVBL2→ARC和PVHRUVBL2→DMH神经环路调节食欲（Credit: Nature Communications） 参考文献 https://doi-org.libproxy1.nus.edu.sg/10.1038/s41467-024-53258-6 责编|探索君 排版|探索君 来源|BioArt End 往期精选 围观 一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版） 热文 Cell | 是什么决定了细胞的大小？ 热文 Nature | 2024年值得关注的七项技术 热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望 热文 CRISPR技术进化史 | 24年Cell综述

*仅供医学专业人士阅读参考从神经病理学的角度来看，阿尔茨海默病（AD）是一种极其复杂的疾病，尽管科学家已经发现了关键病理蛋白β淀粉样蛋白（Aβ）和过度磷酸化的tau蛋白（ptau），但目前以减少病理蛋白负担为目标的治疗策略的获益并不理想，其中的障碍之一就是缺乏对大脑细胞类型的复杂性和它们在疾病中如何被影响的理解。近年来，大脑细胞统计网络倡议（BICCN）和大脑细胞图谱网络倡议（BICAN）通过单细胞基因组学和空间转录组学等方法构建了包含各类型脑细胞的知识库。以此为基础，西雅图阿尔茨海默病脑细胞图谱（SEA-AD）联盟希望能够单独构建AD及相关痴呆症的最高分辨率、多模式、全脑细胞图谱。在今天的《自然·神经科学》上，由艾伦脑科学研究所和华盛顿大学研究人员领导的团队发表了最新研究成果[1]。他们结合BICCN的知识库和来自84名具有不同AD病理供体的大脑颞中回细胞，揭示了AD的两个阶段：病理缓慢积累的早期阶段和病理指数级增加的晚期阶段，前者存在炎性小胶质细胞、反应性星形胶质细胞、生长抑素抑制性神经元丢失以及少突胶质细胞前体细胞的髓鞘再生反应，后者存在兴奋性神经元，及Pvalb+和Vip+抑制性神经元亚型的丢失。颞中回是涉及语言和语义记忆处理，以及高阶视觉（物体的识别和分类）处理的区域，研究已经证实了颞中回是AD临床前阶段相关ptau病理的关键脑区，其中新皮层的ptau会蔓延至整个大脑。研究人员从84名志愿者捐献的死后大脑尸检样本中收集了颞中回，志愿者的平均死亡年龄为88岁，其中51名为女性，平均死后间隔时间为7.0小时。42人具有高AD神经病理学变化，21人为中等，12人为低，9人无AD。研究人员分析了340万个不同形态的高质量细胞核，将它们与BICCN中的MTG细胞分类相匹配。SEA-AD的分析计划他们使用机器学习方法量化了一系列神经病理学变量，包括常规的AD神经病理分期标志物ptau的神经原纤维缠结和Aβ斑块，AD相关共病的病理标志物pTDP-43和α-突触核蛋白，以及细胞变化标志物，包括小胶质细胞的IBA1、星形胶质细胞的GFAP、神经元的NeuN等。量化后再对变量的变化轨迹进行建模，研究人员根据AD严重程度定义了早期和晚期两个阶段，早期时，病理水平较低，认知不受影响，但表现出神经元丢失和早期淀粉样蛋白病理，晚期时，AD病理、神经元丢失和认知障碍显著增加。此前的BICCN研究从典型神经发育的成年人中确定了颞中回内151个转录不同的细胞类型和状态，可分为3个主要类别（兴奋性神经元、抑制性神经元和非神经元细胞）的24个亚类。研究人员以此为参照，根据前面的分析结果构建了颞中回的多模态AD细胞图谱。随着疾病严重程度的增加，不同细胞有着不同的变化，研究人员定义了随疾病严重程度增加而减少的细胞为脆弱型，增加的为关联型，二者合称为受影响型，不变化的为不受影响型。脆弱型包括一部分兴奋性端脑内侧束（IT）神经元，一部分来自内侧神经节隆起（生长抑素抑制性和Pvalb+）和尾部神经节隆起（Vip、Lamp5和Sncg+）的GABA能中间神经元。在受影响型非神经元细胞中，研究人员观察到了一类小胶质细胞和星形胶质细胞的增加，以及一类少突胶质细胞和少突胶质细胞祖细胞的减少。脆弱型神经元和受影响型非神经元细胞脆弱型生长抑素抑制性神经元表现出AD特异性分子变化，一些特异性激酶，包括酪氨酸激酶和钙离子/钙调蛋白依赖激酶家族，以及E3泛素连接酶减少。对小胶质细胞和星形胶质细胞的分析与此前一致，活化的两类细胞与炎症、干扰素反应和MHC-II相关基因表达变化共同发生，小胶质细胞中的四种转录因子RUNX1、IKZF1、NFATC2、MAF在AD早期阶段增加，它们预计能够调节201个基因的表达，包括上述基因。小胶质细胞中四种转录因子增加及靶基因星形胶质细胞的情况较为复杂，在AD早期，细胞粘附分子和神经元导向因子，信号受体和GFAP表达增加，在AD晚期，部分细胞粘附分子、轴突导向和信号受体表达持续增加，另外，hedgehog信号受体及其下游靶向转录因子GLI1，以及表皮生长因子及其受体也增加。少突胶质细胞中，与Aβ合成有关的基因平均表达显著增加，最高的为APP和PSEN1，少突胶质细胞的早期丢失可能归因于细胞毒性较高的Aβ分子，此外，一种γ分泌酶成分、调节髓鞘形成的转录因子和一种髓鞘结构成分也在早期时增加，晚期时，胆固醇生物合成基因家族显著增加，这是已知的AD病因学关键过程。这些初步的发现和完整的研究数据可以通过研究人员搭建的SEA-AD网站进行查询。这项研究为全面了解在AD病程中受影响的特定细胞类型，这些细胞位于组织微结构中的位置，以及它们何时随着疾病的进展而受到影响做出了重要参考，研究人员认为，通过公开分享这些结果，能够为AD研究提供统一的框架。参考文献：[1] Gabitto, M.I., Travaglini, K.J., Rachleff, V.M. et al. Integrated multimodal cell atlas of Alzheimer’s disease. Nat Neurosci (2024). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41593-024-01774-5.本文作者丨应雨妍

MyRisk®, FirstGene®, Prequel®, and Foresight® studies among 10 datasets to be shared by MyriadSALT LAKE CITY, Sept. 18, 2024 (GLOBE NEWSWIRE) -- Myriad Genetics, Inc. (NASDAQ: MYGN), a leader in genetic testing and precision medicine, today announced it will showcase 10 studies highlighting its advancements in oncology and reproductive genetic testing at the National Society of Genetic Counselors (NSGC) 43rd Annual Conference, which will take place from Sept. 17-21, 2024, in New Orleans, LA. The research will highlight the value of genetic and genomic testing in patient care and will cover the company’s MyRisk Hereditary Cancer Test, FirstGene Multiple Prenatal Screen, Prequel Prenatal Screen and Foresight Carrier Screen. “At Myriad, we’re committed to partnering with genetic counselors in an effort to make genetic testing more accessible, affordable and easier to use for all patient populations,” said Susan Manley, Senior Vice President of Medical Services, Myriad Genetics. “We’re excited to share our new research with the genetic counselor community at this year’s NSGC Conference and to showcase how our latest advancements may help better inform personalized care and improve outcomes for patients.” Myriad’s latest innovations and support services will be on display at booth #119 and through a series of poster presentations at the conference. Myriad’s Presentation Schedule Wednesday, Sept. 18, 2024, from 12:15-2:00pm and 5:45-7:00pm CDT Poster CAN91: Age at Diagnosis of Breast Cancer for Women with Pathogenic Variants in BARD1, RAD51C, and RAD51DSummary: This study shows that the median age of breast cancer diagnosis with pathogenic variants (PVs) in BARD1, RAD51C, and RAD51D is similar to that of other breast cancer genes. Additionally, it shows that a significant number of PV carriers are diagnosed prior to the recommended screening age of 40 years. Poster PRE323: Outcomes in pregnancies that screened positive for rare autosomal aneuploidies (RAAs) Summary: By linking prenatal cell-free DNA results to insurance claims data, this study provides evidence that RAA-screen positive patients have higher rates of miscarriage and preterm birth as compared to RAA-screen negative patients. Poster PRE333: Complications and outcomes of pregnancies screening positive for microdeletions 22q11.2, 15q11.2, 1p36, 4p, or 5pSummary: This study shows that microdeletion screen-positive pregnancies may experience higher rates of ultrasound abnormalities and pregnancy complications. Poster PRE347: Validation of fetal and maternal recessive disease genotyping with FirstGene: a combined, non-invasive prenatal cfDNA assay for fetal aneuploidy, recessive diseases, and serological screeningSummary: This study indicates that the FirstGene screen accurately identifies fetal SNV and INDELs for recessive conditions. Poster PRE349: Validation of fetal and maternal spinal muscular atrophy (SMA) and hemoglobin (Hb) Bart’s screening with FirstGene, a combined, non-invasive prenatal cfDNA assay for fetal aneuploidy, recessive diseases, and serological screening Summary: This study indicates that the FirstGene screen accurately identifies maternal and fetal SMA and Hb Bart’s disease status. Poster PRE351: Validation of fetal RHD copy number calling in FirstGene, a combined, non-invasive prenatal cfDNA assay for fetal aneuploidy, recessive diseases, and serological screeningSummary: This study indicates that the FirstGene assay accurately determines fetal RHD copy number in RhD-negative pregnant patients. Thursday, Sept. 19, 2024, from 12:00-3:00pm and 4:30-6:30pm CDT Poster PRE324: A comparison of carrier rates derived from different data sourcesSummary: This study shows high concordance in carrier rates between Myriad’s database and gnomAD data. Poster PRE344: Investigating cancer diagnosis codes after atypical findings on noninvasive prenatal cell-free DNA (pcfDNA) screeningSummary: This study indicates that patients with an autosomal monosomy or multiple aneuploidies on pcfDNA have a higher risk of a cancer diagnosis than those without. Poster PRE348: Validation of fetal aneuploidy detection with FirstGene: a combined, non-invasive prenatal cfDNA assay for fetal aneuploidy, recessive diseases, and serological screeningSummary: This study indicates that fetal aneuploidy screening on the FirstGene assay is comparable to that of standalone WGS-based pcfDNA screening with fetal fraction amplification. Lunch Symposium: At 12:45pm CDT, Myriad will host a lunch symposium titled ‘How genetic counselors can integrate breast cancer risk assessment programs into surgical, primary care, OB/GYN, and imaging clinics’, moderated by Myriad’s Susan Manley. Myriad will also have a virtual presentation, Characteristics and Cancer Incidence in MITF p.E318K Carriers, available for viewing on the NSGC online experience platform. This study shows that MITF carriers have an increased risk of melanoma, but not renal cancer, as several other studies have suggested. For more information about Myriad’s presence at NSGC, please visit: https://myriad.com/nsgc2024/. Updates will also be shared across Myriad’s LinkedIn and X channels throughout the conference. About Myriad GeneticsMyriad Genetics is a leading genetic testing and precision medicine company dedicated to advancing health and well-being for all. Myriad develops and offers genetic tests that help assess the risk of developing disease or disease progression and guide treatment decisions across medical specialties where genetic insights can significantly improve patient care and lower healthcare costs. For more information, visit www.myriad.com. Safe Harbor StatementThis press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the company's commitment to partnering with genetic counselors in an effort to make genetic testing more accessible, affordable and easier to use for all patient populations and how the company’s latest advancement may help better inform personalized care and improve outcomes for patients. These “forward-looking statements” are management’s expectations of future events as of the date hereof and are subject to known and unknown risks and uncertainties that could cause actual results, conditions, and events to differ materially and adversely from those anticipated. Such factors include those risks described in the company’s filings with the U.S. Securities and Exchange Commission, including the company’s Annual Report on Form 10-K filed on February 28, 2024, as well as any updates to those risk factors filed from time to time in the company’s Quarterly Reports on Form 10-Q or Current Reports on Form 8-K. Myriad is not under any obligation, and it expressly disclaims any obligation, to update or alter any forward-looking statements, whether as a result of new information, future events or otherwise except as required by law. Investor ContactMatt Scalo(801) 584-3532IR@myriad.com Media ContactGlenn Farrell(385) 318-3718PR@myriad.com