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Changes in Structural Covariance among Olfactory-related Brain Regions in Anosmia Patients. 嗅觉障碍患者嗅觉相关脑区结构协方差的变化
IF 2.4 4区 医学 Q1 Medicine Pub Date : 2024-04-30 DOI: 10.5607/en24007
Suji Lee, Yumi Song, Haejin Hong, Yoonji Joo, Eunji Ha, Youngeun Shim, Seung-No Hong, Jungyoon Kim, In Kyoon Lyoo, Sujung Yoon, Dae Woo Kim

Anosmia, characterized by the loss of smell, is associated not only with dysfunction in the peripheral olfactory system but also with changes in several brain regions involved in olfactory processing. Specifically, the orbitofrontal cortex is recognized for its pivotal role in integrating olfactory information, engaging in bidirectional communication with the primary olfactory regions, including the olfactory cortex, amygdala, and entorhinal cortex. However, little is known about alterations in structural connections among these brain regions in patients with anosmia. In this study, high-resolution T1-weighted images were obtained from participants. Utilizing the volumes of key brain regions implicated in olfactory function, we employed a structural covariance approach to investigate brain reorganization patterns in patients with anosmia (n=22) compared to healthy individuals (n=30). Our structural covariance analysis demonstrated diminished connectivity between the amygdala and entorhinal cortex, components of the primary olfactory network, in patients with anosmia compared to healthy individuals (z=-2.22, FDR-corrected p=0.039). Conversely, connectivity between the orbitofrontal cortex-a major region in the extended olfactory network-and amygdala was found to be enhanced in the anosmia group compared to healthy individuals (z=2.32, FDR-corrected p=0.039). However, the structural connections between the orbitofrontal cortex and entorhinal cortex did not differ significantly between the groups (z=0.04, FDR-corrected p=0.968). These findings suggest a potential structural reorganization, particularly of higher-order cortical regions, possibly as a compensatory effort to interpret the limited olfactory information available in individuals with olfactory loss.

以嗅觉丧失为特征的嗅觉缺失症不仅与外周嗅觉系统的功能障碍有关,还与参与嗅觉处理的多个脑区的变化有关。具体来说,眶额皮层被认为在整合嗅觉信息方面起着关键作用,它与嗅觉皮层、杏仁核和内侧皮层等主要嗅觉区域进行双向交流。然而,人们对嗅觉失调症患者这些脑区之间结构连接的改变知之甚少。在这项研究中,研究人员获得了参与者的高分辨率 T1 加权图像。利用与嗅觉功能有关联的关键脑区的体积,我们采用结构协方差方法研究了与健康人(人数=30)相比,嗜嗅症患者(人数=22)的大脑重组模式。我们的结构协方差分析表明,与健康人相比,主要嗅觉网络的组成部分杏仁核和内嗅皮层之间的连通性减弱(z=-2.22,FDR 校正 p=0.039)。相反,与健康人相比,嗜嗅症组患者的眶额皮层--扩展嗅觉网络的主要区域--与杏仁核之间的连接性增强(z=2.32,FDR校正后p=0.039)。然而,眶额皮层和内侧皮层之间的结构连接在组间没有显著差异(z=0.04,FDR校正后p=0.968)。这些研究结果表明,在嗅觉缺失的个体中,可能存在结构重组,尤其是高阶皮层区域的结构重组,这可能是为了解释有限的嗅觉信息而做出的补偿性努力。
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引用次数: 0
Alterations in Brain Morphometric Networks and Their Relationship with Memory Dysfunction in Patients with Type 2 Diabetes Mellitus. 2 型糖尿病患者大脑形态计量网络的变化及其与记忆功能障碍的关系
IF 2.4 4区 医学 Q1 Medicine Pub Date : 2024-04-30 DOI: 10.5607/en24005
Rye Young Kim, Yoonji Joo, Eunji Ha, Haejin Hong, Chaewon Suh, Youngeun Shim, Hyeonji Lee, Yejin Kim, Jae-Hyoung Cho, Sujung Yoon, In Kyoon Lyoo

Cognitive dysfunction, a significant complication of type 2 diabetes mellitus (T2DM), can potentially manifest even from the early stages of the disease. Despite evidence of global brain atrophy and related cognitive dysfunction in early-stage T2DM patients, specific regions vulnerable to these changes have not yet been identified. The study enrolled patients with T2DM of less than five years' duration and without chronic complications (T2DM group, n=100) and demographically similar healthy controls (control group, n=50). High-resolution T1-weighted magnetic resonance imaging data were subjected to independent component analysis to identify structurally significant components indicative of morphometric networks. Within these networks, the groups' gray matter volumes were compared, and distinctions in memory performance were assessed. In the T2DM group, the relationship between changes in gray matter volume within these networks and declines in memory performance was examined. Among the identified morphometric networks, the T2DM group exhibited reduced gray matter volumes in both the precuneus (Bonferroni-corrected p=0.003) and insular-opercular (Bonferroni-corrected p=0.024) networks relative to the control group. Patients with T2DM demonstrated significantly lower memory performance than the control group (p=0.001). In the T2DM group, reductions in gray matter volume in both the precuneus (r=0.316, p=0.001) and insular-opercular (r=0.199, p=0.047) networks were correlated with diminished memory performance. Our findings indicate that structural alterations in the precuneus and insular-opercular networks, along with memory dysfunction, can manifest within the first 5 years following a diagnosis of T2DM.

认知功能障碍是 2 型糖尿病(T2DM)的一个重要并发症,甚至在疾病的早期阶段就可能表现出来。尽管有证据表明早期的T2DM患者会出现整体脑萎缩和相关的认知功能障碍,但目前尚未发现易受这些变化影响的特定区域。该研究招募了病程不到五年且无慢性并发症的 T2DM 患者(T2DM 组,100 人)和人口统计学相似的健康对照组(对照组,50 人)。对高分辨率 T1 加权磁共振成像数据进行了独立成分分析,以确定指示形态网络的重要结构成分。在这些网络中,比较了各组的灰质体积,并评估了记忆表现的差异。在 T2DM 组中,研究了这些网络中灰质体积的变化与记忆能力下降之间的关系。在已确定的形态计量网络中,T2DM 组与对照组相比,楔前叶(经 Bonferroni 校正后 p=0.003)和岛叶-小脑(经 Bonferroni 校正后 p=0.024)网络的灰质体积均有所减少。T2DM患者的记忆力明显低于对照组(P=0.001)。在 T2DM 组中,楔前叶(r=0.316,p=0.001)和岛叶-小脑(r=0.199,p=0.047)网络灰质体积的减少与记忆能力的下降相关。我们的研究结果表明,楔前叶和岛叶-小丘网络结构的改变以及记忆功能障碍可在确诊T2DM后的头5年内表现出来。
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引用次数: 0
Possible Roles of Extracellular Vesicles in the Pathogenesis and Interventions of Immune-Mediated Central Demyelinating Diseases. 细胞外小泡在免疫介导的中枢脱髓鞘疾病的发病机制和干预中可能发挥的作用。
IF 2.4 4区 医学 Q1 Medicine Pub Date : 2024-04-30 DOI: 10.5607/en24002
Chutithep Teekaput, Kitti Thiankhaw, Nipon Chattipakorn, Siriporn C Chattipakorn

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are two of the most devastating immune-mediated central demyelinating disorders. NMOSD was once considered as a variant of MS until the discovery of an antibody specific to the condition. Despite both MS and NMOSD being considered central demyelinating disorders, their pathogenesis and clinical manifestations are distinct, however the exact mechanisms associated with each disease remain unclear. Extracellular vesicles (EVs) are nano-sized vesicles originating in various cells which serve as intercellular communicators. There is a large body of evidence to show the possible roles of EVs in the pathogenesis of several diseases, including the immune-mediated central demyelinating disorders. Various types of EVs are found across disease stages and could potentially be used as a surrogate marker, as well as acting by carrying a cargo of biochemical molecules. The possibility for EVs to be used as a next-generation targeted treatment for the immune-mediated central demyelinating disorders has been investigated. The aim of this review was to comprehensively identify, compile and discuss key findings from in vitro, in vivo and clinical studies. A summary of all findings shows that: 1) the EV profiles of MS and NMOSD differ from those of healthy individuals, 2) the use of EV markers as liquid biopsy diagnostic tools appears to be promising biomarkers for both MS and NMOSD, and 3) EVs are being studied as a potential targeted therapy for MS and NMOSD. Any controversial findings are also discussed in this review.

多发性硬化症(MS)和神经脊髓炎视神经谱系障碍(NMOSD)是两种最具破坏性的免疫介导的中枢性脱髓鞘疾病。NMOSD 曾一度被认为是多发性硬化症的一种变异,直到发现了一种针对这种疾病的特异性抗体。尽管多发性硬化症和 NMOSD 都被认为是中枢性脱髓鞘疾病,但它们的发病机制和临床表现却截然不同,然而与每种疾病相关的确切机制仍不清楚。细胞外囊泡(EVs)是源自各种细胞的纳米级囊泡,是细胞间的交流媒介。大量证据表明,EVs 在多种疾病的发病机制中可能发挥作用,包括免疫介导的中枢性脱髓鞘疾病。在疾病的各个阶段都能发现各种类型的 EVs,它们有可能被用作替代标记物,并通过携带生化分子货物发挥作用。EVs被用作免疫介导的中枢脱髓鞘疾病的下一代靶向治疗的可能性已被研究。本综述旨在全面确定、汇编和讨论体外、体内和临床研究的主要发现。所有研究结果的总结显示1)多发性硬化症和 NMOSD 的 EV 特征与健康人不同;2)使用 EV 标记作为液体活检诊断工具似乎是治疗多发性硬化症和 NMOSD 的有前途的生物标记物;3)EV 正在被研究作为治疗多发性硬化症和 NMOSD 的潜在靶向疗法。本综述还讨论了任何有争议的发现。
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引用次数: 0
Pharmacological Inhibition of LRRK2 Exhibits Neuroprotective Activity in Mouse Photothrombotic Stroke Model. 药理抑制 LRRK2 在小鼠光血栓中风模型中显示出神经保护活性
IF 2.4 4区 医学 Q1 Medicine Pub Date : 2024-02-29 DOI: 10.5607/en23023
Jeong-Ah Hwang, Seung Kyu Choi, Seong Hwan Kim, Dong Woon Kim

Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of Parkinson's disease (PD). Interestingly, recent studies have reported an increased risk of stroke in patients with PD harboring LRRK2 mutations, but there is no evidence showing the functional involvement of LRRK2 in stroke. Here, we found that LRRK2 kinase activity was significantly induced in the Rose-Bengal (RB) photothrombosis-induced stroke mouse model. Interestingly, stroke infarct volumes were significantly reduced, and neurological deficits were diminished by pharmacological inhibition of LRRK2 kinase activity using MLi-2, a brain-penetrant LRRK2 kinase inhibitor. Immunohistochemical analysis showed p-LRRK2 level in stroke lesions, co-localizing with mitophagy-related proteins (PINK, Parkin, LC3B, cytochrome c), suggesting their involvement in stroke progression. Overlapping p-LRRK2 with cytochrome c/TUNEL/JC-1 (an indicator of mitochondrial membrane potential) puncta in RB photothrombosis indicated LRRK2-induced mitochondrial apoptosis, which was blocked by MLi-2. These results suggest that pharmacological inhibition of LRRK2 kinase activity could attenuate mitochondrial apoptosis, ultimately leading to neuroprotective potential in stroke progression. In conclusion, LRRK2 kinase activity might be neuro-pathogenic due to impaired mitophagy in stroke progression, and pharmacological inhibition of LRRK2 kinase activity could be beneficial in reducing the risk of stroke in patients with LRRK2 mutations.

富亮氨酸重复激酶 2(LRRK2)突变是帕金森病(PD)最常见的病因。有趣的是,最近有研究报告称,携带 LRRK2 突变的帕金森病患者中风风险增加,但没有证据显示 LRRK2 在中风中的功能性参与。在这里,我们发现在玫瑰红(RB)光血栓诱导的中风小鼠模型中,LRRK2激酶活性被显著诱导。有趣的是,使用一种脑渗透性 LRRK2 激酶抑制剂 MLi-2 对 LRRK2 激酶活性进行药物抑制后,脑卒中梗死体积明显缩小,神经功能缺损也有所减轻。免疫组化分析显示,中风病灶中的 p-LRRK2 水平与有丝分裂相关蛋白(PINK、Parkin、LC3B、细胞色素 c)共定位,表明它们参与了中风的进展。在 RB 光栓中,p-LRRK2 与细胞色素 c/TUNEL/JC-1(线粒体膜电位指标)点状重叠,表明 LRRK2 诱导了线粒体凋亡,而 MLi-2 阻断了线粒体凋亡。这些结果表明,药物抑制 LRRK2 激酶活性可减轻线粒体凋亡,最终在脑卒中进展过程中起到神经保护作用。总之,LRRK2 激酶活性可能是中风进展过程中有丝分裂受阻导致的神经致病因素,而药物抑制 LRRK2 激酶活性可能有利于降低 LRRK2 突变患者的中风风险。
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引用次数: 0
Intranasal Administration of BDNF Improves Recovery and Promotes Neural Plasticity in a Neonatal Mouse Model of Hypoxic Ischemia. 鼻内注射 BDNF 可改善缺氧缺血新生小鼠模型的恢复并促进神经可塑性。
IF 2.4 4区 医学 Q1 Medicine Pub Date : 2024-02-29 DOI: 10.5607/en23030
Serena-Kaye Sims, Madelynne Saddow, Lilly McGonegal, Catrina Sims-Robinson

The benefit of intranasal brain derived neurotrophic factor (BDNF) treatment on cognitive function in a neonatal postnatal day 7 (P7) mouse model of hypoxic ischemia (HI) was explored. Intranasal delivery is attractive in that it can promote widespread distribution of BDNF within both the brain and spinal cord. In this study we evaluated the effectiveness of intranasal BDNF to improve cognitive recovery following HI. HI is induced via ligation of the right carotid artery followed by a 45-minute exposure to an 8% oxygen/ 92% nitrogen mixture in an enclosed chamber. Male and female pups were subjected to a 2-hour hypothermia in a temperature-controlled chamber as a standard of care. A solution of saline (control) or recombinant human BDNF (Harlan Laboratories) was administered with a Gilson pipette at the same time each day for 7 days into each nasal cavity in awake mice beginning 24 hours after HI. We evaluated cognitive recovery using the novel object recognition (NOR) and western analysis to analyze neuro-markers and brain health such as synaptophysin and microtubule associated protein -2 (MAP2). The objective of this study was to evaluate the role and therapeutic potential of BDNF in neonatal HI recovery. Our results indicate that intranasal BDNF delivered within 24 hours after HI improved object discrimination at both 28 and 42 days after HI. Our results also demonstrate increased synaptophysin and MAP2 at day 42 in HI animals that received intranasal BDNF treatment compared to HI animals that were administered saline.

本研究探讨了鼻内注射脑源性神经营养因子(BDNF)对新生儿缺氧缺血(HI)模型中新生儿出生后第 7 天(P7)认知功能的益处。鼻内给药的吸引力在于它能促进 BDNF 在大脑和脊髓内的广泛分布。在这项研究中,我们评估了鼻内注射 BDNF 对改善 HI 后认知恢复的有效性。HI是通过结扎右颈动脉诱发的,随后在密闭室中暴露于8%的氧气/92%的氮气混合物中45分钟。作为护理标准,雌雄幼犬在温控室中接受 2 小时低体温。从HI后24小时开始,每天同一时间用Gilson移液管在清醒小鼠的每个鼻腔中注入生理盐水(对照组)或重组人BDNF(Harlan实验室)溶液,持续7天。我们使用新物体识别(NOR)和 Western 分析法评估了认知能力的恢复情况,以分析神经标记物和脑健康状况,如突触素和微管相关蛋白 -2 (MAP2)。本研究的目的是评估 BDNF 在新生儿 HI 恢复中的作用和治疗潜力。我们的研究结果表明,在脑损伤后 24 小时内给予鼻内 BDNF 可改善脑损伤后 28 天和 42 天的物体辨别能力。我们的结果还表明,与注射生理盐水的 HI 动物相比,接受 BDNF 鼻内注射治疗的 HI 动物在第 42 天时突触素和 MAP2 均有所增加。
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引用次数: 0
Exploring Brainstem Structural Abnormalities: Potential Biomarkers for Panic Disorder. 探索脑干结构异常:恐慌症的潜在生物标志物。
IF 2.4 4区 医学 Q1 Medicine Pub Date : 2024-02-29 DOI: 10.5607/en23034
Hye-Min Kim, Chanmi Kang, Boram Chae, June Christoph Kang, Ho-Kyoung Yoon

Panic disorder (PD), characterized by recurrent and intense panic attacks, presents a complex interplay between psychological and neurobiological factors. Although the amygdala and hippocampus have been studied extensively in the context of PD, the brainstem's involvement remains relatively underexplored. This study aims to address this gap by examining structural abnormalities within specific brainstem regions, including the medulla, pons, and midbrain. The study sample population comprised twenty-one adult patients diagnosed with PD and an age-gender-education-matched control group. Utilizing rigorous inclusion and exclusion criteria, confounding factors related to comorbid psychiatric conditions and brain structure abnormalities were minimized. Our findings revealed a significant reduction in medulla volume among PD patients, a finding that persisted even after correcting for individual differences in total intracranial volume. The medulla's role in cardiovascular regulation and autonomic function, coupled with its involvement in fear responses, underscores its potential significance in the pathophysiology of PD. This study elucidates the medulla's structural abnormalities as a potential biomarker for PD. Understanding the role of the brainstem in PD could pave the way for more targeted and effective interventions for this condition.

恐慌症(PD)的特点是反复出现强烈的恐慌发作,它是心理和神经生物学因素之间复杂相互作用的结果。虽然杏仁核和海马已被广泛研究,但脑干在恐慌症中的参与程度仍相对不足。本研究旨在通过检测特定脑干区域(包括延髓、脑桥和中脑)的结构异常来填补这一空白。研究样本人群包括21名确诊为帕金森病的成年患者和一个年龄-性别-教育程度相匹配的对照组。利用严格的纳入和排除标准,最大限度地减少了与合并精神疾病和脑结构异常相关的混杂因素。我们的研究结果表明,髓质体积在帕金森病患者中明显缩小,即使在校正了颅内总体积的个体差异后,这一结果依然存在。髓质在心血管调节和自主神经功能中的作用,以及它在恐惧反应中的参与,凸显了它在帕金森病病理生理学中的潜在意义。本研究阐明了延髓结构异常作为一种潜在的脑退化症生物标志物的作用。了解脑干在帕金森病中的作用可为更有针对性、更有效地干预帕金森病铺平道路。
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引用次数: 0
An Autopsy-proven Case-based Review of Autoimmune Encephalitis. 基于尸检病例的自身免疫性脑炎回顾。
IF 2.4 4区 医学 Q1 Medicine Pub Date : 2024-02-29 DOI: 10.5607/en23036
Yu-Mi Shim, Seong-Ik Kim, So Dug Lim, Kwanghoon Lee, Eric Eunshik Kim, Jae Kyung Won, Sung-Hye Park

Autoimmune encephalitis (AIE) is a type of immunoreactive encephalitic disorder and is recognized as the most prevalent noninfectious encephalitis. Nevertheless, the rarity of definitive AIE diagnosis through biopsy or autopsy represents a significant hurdle to understanding and managing the disease. In this article, we present the pathological findings of AIE and review the literature based on a distinct case of AIE presenting as CD8+ T-lymphocyte predominant encephalitis. We describe the clinical progression, diagnostic imaging, laboratory data, and autopsy findings of an 80-year-old deceased male patient. The patient was diagnosed with pulmonary tuberculosis 6 months before death and received appropriate medications. A week before admission to the hospital, the patient manifested symptoms such as a tendency to sleep, decreased appetite, and confusion. Although the patient temporally improved with medication including correction of hyponatremia, the patient progressed rapidly and died in 6 weeks. The brain tissue revealed lymphocytic infiltration in the gray and white matter, leptomeninges, and perivascular infiltration with a predominance of CD8+ T lymphocytes, suggesting a case of AIE. There was no detectable evidence of viral infection or underlying neoplasm. The autopsy revealed that this patient also had Alzheimer's disease, atherosclerosis, arteriolosclerosis, and aging-related tau astrogliopathy. This report emphasizes the pivotal role of pathological examination in the diagnosis of AIE, especially when serological autoantibody testing is not available or when a patient is suspected of having multiple diseases.

自身免疫性脑炎(AIE)是一种免疫反应性脑炎,是公认的最常见的非感染性脑炎。然而,通过活检或尸检明确诊断 AIE 的罕见性是了解和治疗该疾病的一大障碍。在本文中,我们介绍了 AIE 的病理结果,并根据一例表现为 CD8+ T 淋巴细胞占优势脑炎的 AIE 病例回顾了相关文献。我们描述了一名 80 岁男性死者的临床进展、影像诊断、实验室数据和尸检结果。患者在去世前 6 个月被诊断为肺结核,并接受了适当的药物治疗。入院前一周,患者出现了嗜睡、食欲下降和意识模糊等症状。虽然通过药物治疗(包括纠正低钠血症),患者的病情暂时有所好转,但病情发展迅速,6 周后死亡。脑组织显示灰质和白质、脑膜和血管周围有淋巴细胞浸润,其中以CD8+ T淋巴细胞为主,这表明这是一个AIE病例。没有检测到病毒感染或潜在肿瘤的证据。尸检显示,该患者还患有阿尔茨海默病、动脉粥样硬化、动脉硬化和与衰老相关的tau星形胶质细胞病变。这份报告强调了病理检查在诊断 AIE 中的关键作用,尤其是在无法进行血清学自身抗体检测或怀疑患者患有多种疾病时。
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引用次数: 0
Cerebral Cavernous Malformation (CCM)-like Vessel Lesion in the Aged ANKS1A-deficient Brain. ANKS1A缺陷者老年脑中的脑海绵畸形(CCM)样血管病变
IF 2.4 4区 医学 Q1 Medicine Pub Date : 2023-12-31 DOI: 10.5607/en23032
Jiyeon Lee, Haeryung Lee, Miram Shin, Soochul Park

In this study, we show that ANKS1A is specifically expressed in the brain endothelial cells of adult mice. ANKS1A deficiency in adult mice does not affect the differentiation, growth, or patterning of the cerebrovascular system; however, its absence significantly impacts the cerebrovascular system of the aged brain. In aged ANKS1A knock-out (KO) brains, vessel lesions exhibiting cerebral cavernous malformations (CCMs) are observed. In addition, CCM-like lesions show localized peripheral blood leakage into the brain. The CCM-like lesions reveal immune cells infiltrating the parenchyma. The CCM-like lesions also contain significantly fewer astrocyte endfeets and tight junctions, indicating that the integrity of the BBB has been partially compromised. CCM-like lesions display increased fibronectin expression in blood vessels, which is also confirmed in cultured endothelial cells deficient for ANKS1A. Therefore, we hypothesize that ANKS1A may play a role in maintaining or stabilizing healthy blood vessels in the brain during aging.

在这项研究中,我们发现 ANKS1A 在成年小鼠的脑内皮细胞中特异性表达。成年小鼠缺乏 ANKS1A 不会影响脑血管系统的分化、生长或模式化;但是,ANKS1A 的缺失会显著影响老年脑的脑血管系统。在 ANKS1A 基因敲除(KO)的老年脑中,可以观察到表现为脑洞畸形(CCMs)的血管病变。此外,CCM 样病变显示局部外周血渗入大脑。CCM 样病变显示免疫细胞浸润实质细胞。CCM 样病变中的星形胶质细胞内膜和紧密连接也明显减少,这表明 BBB 的完整性已部分受损。CCM 样病变的血管中纤维粘连蛋白表达增加,这在培养的缺失 ANKS1A 的内皮细胞中也得到了证实。因此,我们推测 ANKS1A 可能在衰老过程中起到维持或稳定大脑中健康血管的作用。
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引用次数: 0
Distinct Role of Parvalbumin Expressing Neurons in the Reticular Thalamic Nucleus in Nociception. 丘脑网状核中表达 Parvalbumin 的神经元在痛觉中的独特作用
IF 2.4 4区 医学 Q1 Medicine Pub Date : 2023-12-31 DOI: 10.5607/en23018
Sanggeon Park, Jeiwon Cho, Yeowool Huh

Loss of inhibition is suggested to cause pathological pain symptoms. Indeed, some human case reports suggest that lesions including the thalamic reticular nucleus (TRN) which provides major inhibitory inputs to other thalamic nuclei, may induce thalamic pain, a type of neuropathic pain. In support, recent studies demonstrated that activation of GABAergic neurons in the TRN reduces nociceptive responses in mice, reiterating the importance of the TRN in gating nociception. However, whether biochemically distinct neuronal types in the TRN differentially contribute to gating nociception has not been investigated. We, therefore, investigated whether the activity of parvalbumin (PV) and somatostatin (SOM) expressing neurons in the somatosensory TRN differentially modulate nociceptive behaviors using optogenetics and immunostaining techniques. We found that activation of PV neurons in the somatosensory TRN significantly reduced nociceptive behaviors, while activation of SOM neurons in the TRN had no such effect. Also, selective activation of PV neurons, but not SOM neurons, in the TRN activated relatively more PV neurons in the primary somatosensory cortex, which delivers inhibitory effect in the cortex, when measured with cFos and PV double staining. Results of our study suggest that PV neurons in the somatosensory TRN have a stronger influence in regulating nociception and that their activations may provide further inhibition in the somatosensory cortex by activating cortical PV neurons.

抑制作用的丧失被认为会导致病理性疼痛症状。事实上,一些人类病例报告表明,丘脑网状核(TRN)为其他丘脑核提供主要的抑制性输入,丘脑网状核的病变可能诱发丘脑痛(一种神经病理性疼痛)。最近的研究表明,激活丘脑网状核中的 GABA 能神经元可减轻小鼠的痛觉反应,从而重申了丘脑网状核在调控痛觉中的重要性。然而,TRN中不同类型的生化神经元是否对痛觉门控起着不同的作用尚未得到研究。因此,我们利用光遗传学和免疫染色技术研究了躯体感觉 TRN 中表达副视蛋白(PV)和体生长抑素(SOM)的神经元的活性是否会对痛觉行为产生不同的调节作用。我们发现,激活躯体感觉 TRN 中的 PV 神经元可显著减少痛觉行为,而激活 TRN 中的 SOM 神经元则没有这种效果。此外,用 cFos 和 PV 双染色法测量,选择性激活 TRN 中的 PV 神经元(而非 SOM 神经元)会激活初级躯体感觉皮层中相对较多的 PV 神经元,从而在皮层中产生抑制作用。我们的研究结果表明,躯体感觉 TRN 中的 PV 神经元在调节痛觉方面具有更强的影响力,它们的激活可能会通过激活皮层 PV 神经元进一步抑制躯体感觉皮层。
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引用次数: 0
Peripheral Neuropathy and Decreased Locomotion of a RAB40B Mutation in Human and Model Animals. 人类和模式动物的 RAB40B 突变引起的周围神经病和运动能力下降
IF 2.4 4区 医学 Q1 Medicine Pub Date : 2023-12-31 DOI: 10.5607/en23027
Wonseok Son, Hui Su Jeong, Da Eun Nam, Ah Jin Lee, Soo Hyun Nam, Ji Eun Lee, Byung-Ok Choi, Ki Wha Chung

Rab40 proteins are an atypical subgroup of Rab GTPases containing a unique suppressor of the cytokine signaling (SOCS) domain that is recruited to assemble the CRL5 E3 ligase complex for proteolytic regulation in various biological processes. A nonsense mutation deleting the C-terminal SOCS box in the RAB40B gene was identified in a family with axonal peripheral neuropathy (Charcot-Marie-Tooth disease type 2), and pathogenicity of the mutation was assessed in model organisms of zebrafish and Drosophila. Compared to control fish, zebrafish larvae transformed by the human mutant hRAB40B-Y83X showed a defective swimming pattern of stalling with restricted localization and slower motility. We were consistently able to observe reduced labeling of synaptic markers along neuromuscular junctions of the transformed larvae. In addition to the neurodevelopmental phenotypes, compared to normal hRAB40B expression, we further examined ectopic expression of hRAB40B-Y83X in Drosophila to show a progressive decline of locomotion ability. Decreased ability of locomotion by ubiquitous expression of the human mutation was reproduced not with GAL4 drivers for neuron-specific expression but only when a pan-glial GAL4 driver was applied. Using the ectopic expression model of Drosophila, we identified a genetic interaction in which Cul5 down regulation exacerbated the defective motor performance, showing a consistent loss of SOCS box of the pathogenic RAB40B. Taken together, we could assess the possible gain-of-function of the human RAB40B mutation by comparing behavioral phenotypes in animal models; our results suggest that the mutant phenotypes may be associated with CRL5-mediated proteolytic regulation.

Rab40 蛋白是 Rab GTP 酶的一个非典型亚群,含有一个独特的细胞因子信号转导抑制因子(SOCS)结构域,在各种生物过程中,该结构域被招募来组装 CRL5 E3 连接酶复合物,以进行蛋白水解调控。在一个轴突性周围神经病(Charcot-Marie-Tooth 病 2 型)家族中发现了 RAB40B 基因中删除 C 端 SOCS 框的无义突变,并在斑马鱼和果蝇等模式生物中评估了该突变的致病性。与对照组鱼类相比,由人类突变体 hRAB40B-Y83X 转化的斑马鱼幼体表现出一种有缺陷的游动模式,即定位受限的停滞和较慢的运动速度。我们一直能观察到转化后的斑马鱼幼体神经肌肉接头处的突触标记物标记减少。除了神经发育表型外,与正常的 hRAB40B 表达相比,我们进一步研究了果蝇中 hRAB40B-Y83X 的异位表达,结果显示其运动能力逐渐下降。在神经元特异性表达的GAL4驱动下,人类突变无处不在的表达导致的运动能力下降并没有重现,只有在应用泛神经胶质细胞GAL4驱动时才会重现。利用果蝇的异位表达模型,我们发现了一种遗传相互作用,在这种相互作用中,Cul5 的下调加剧了运动表现的缺陷,显示了致病的 RAB40B 的 SOCS 框的一致缺失。综上所述,我们可以通过比较动物模型的行为表型来评估人类RAB40B突变可能产生的功能增益;我们的结果表明,突变表型可能与CRL5介导的蛋白水解调节有关。
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Experimental Neurobiology
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