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The Effects of Acute Stress on Evoked-cortical Connectivity through Wide-field Optical Mapping of Neural and Hemodynamic Signals. 通过对神经和血液动力学信号的宽视场光学绘图研究急性应激对诱发皮层连接性的影响
IF 1.8 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-06-30 DOI: 10.5607/en23009
Hayeon Kim, Haebin Jeong, Jiyoung Lee, Jaeseung Yei, Minah Suh

A single exposure to stress can induce functional changes in neurons, potentially leading to acute stress disorder or post-traumatic stress disorder. In this study, we used in vivo wide-field optical mapping to simultaneously measure neural calcium signals and hemodynamic responses over the whole cortical area. We found that cortical mapping to whisker stimuli was altered under acute stress conditions. In particular, callosal projections in the anterior cortex (primary/secondary motor, somatosensory forelimb cortex) relative to barrel field (S1BF) of somatosensory cortex were weakened. On the contrary, the projections in posterior cortex relative to S1BF were mostly unchanged or were only occasionally strengthened. In addition, changes in intra-cortical connection were opposite to those in inter-cortical connection. Thus, the S1BF connections to the anterior cortex were strengthened while those to the posterior cortex were weakened. This suggests that the well-known barrel cortex projection route was enhanced. In summary, our in vivo wide-field optical mapping study indicates that a single acute stress can impact whole-brain networks, affecting both neural and hemodynamic responses.

单次暴露于应激可诱发神经元的功能变化,从而可能导致急性应激障碍或创伤后应激障碍。在这项研究中,我们利用体内宽视场光学映射同时测量了整个皮层区域的神经钙信号和血液动力学反应。我们发现,在急性应激条件下,大脑皮层对胡须刺激的映射发生了改变。特别是,相对于躯体感觉皮层的桶状场(S1BF),前部皮层(初级/次级运动、躯体感觉前肢皮层)的胼胝体投射减弱了。相反,后部皮层相对于 S1BF 的投射大部分保持不变或偶尔增强。此外,皮层内连接的变化与皮层间连接的变化相反。因此,S1BF 与前部皮层的连接加强了,而与后部皮层的连接却减弱了。这表明,众所周知的桶状皮层投射路线得到了加强。总之,我们的活体广域光学绘图研究表明,一次急性应激可影响整个大脑网络,同时影响神经和血液动力学反应。
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引用次数: 0
Analgesic Effect of Auricular Vagus Nerve Stimulation on Oxaliplatin-induced Peripheral Neuropathic Pain in a Rodent Model. 耳廓迷走神经刺激对啮齿动物模型中奥沙利铂诱发的外周神经病理性疼痛的镇痛效果
IF 1.8 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-06-30 DOI: 10.5607/en24012
In Seon Baek, Seunghwan Choi, Heera Yoon, Geehoon Chung, Sun Kwang Kim

Cancer chemotherapy often triggers peripheral neuropathy in patients, leading to neuropathic pain in the extremities. While previous research has explored various nerve stimulation to alleviate chemotherapy-induced peripheral neuropathy (CIPN), evidence on the effectiveness of noninvasive auricular vagus nerve stimulation (aVNS) remains uncertain. This study aimed to investigate the efficacy of non-invasive aVNS in relieving CIPN pain. To induce CIPN in experimental animals, oxaliplatin was intraperitoneally administered to rats (6 mg/kg). Mechanical and cold allodynia, the representative symptoms of neuropathic pain, were evaluated using the von Frey test and acetone test, respectively. The CIPN animals were randomly assigned to groups and treated with aVNS (5 V, square wave) at different frequencies (2, 20, or 100 Hz) for 20 minutes. Results revealed that 20 Hz aVNS exhibited the most pronounced analgesic effect, while 2 or 100 Hz aVNS exhibited weak effects. Immunohistochemistry analysis demonstrated increased c-Fos expression in the locus coeruleus (LC) in the brain of CIPN rats treated with aVNS compared to sham treatment. To elucidate the analgesic mechanisms involving the adrenergic descending pathway, α1-, α2-, or β-adrenergic receptor antagonists were administered to the spinal cord before 20 Hz aVNS. Only the β-adrenergic receptor antagonist, propranolol, blocked the analgesic effect of aVNS. These findings suggest that 20 Hz aVNS may effectively alleviate CIPN pain through β-adrenergic receptor activation.

癌症化疗通常会引发患者的周围神经病变,导致四肢神经性疼痛。以往的研究探索了各种神经刺激方法来缓解化疗引起的周围神经病变(CIPN),但无创耳部迷走神经刺激(aVNS)的有效性仍不确定。本研究旨在探讨无创迷走神经刺激对缓解 CIPN 疼痛的疗效。为诱导实验动物出现 CIPN,给大鼠腹腔注射奥沙利铂(6 毫克/千克)。分别使用 von Frey 试验和丙酮试验评估神经病理性疼痛的代表性症状--机械异感和冷异感。CIPN 动物被随机分配到各组,并接受不同频率(2、20 或 100 Hz)的 aVNS(5 V,方波)治疗 20 分钟。结果显示,20 Hz aVNS 的镇痛效果最明显,而 2 Hz 或 100 Hz aVNS 的镇痛效果较弱。免疫组化分析表明,与假治疗相比,接受 aVNS 治疗的 CIPN 大鼠脑部神经节(LC)中的 c-Fos 表达增加。为了阐明涉及肾上腺素能递减通路的镇痛机制,在 20 Hz aVNS 之前给脊髓注射了 α1-、α2- 或 β-肾上腺素能受体拮抗剂。只有β肾上腺素能受体拮抗剂普萘洛尔能阻断aVNS的镇痛作用。这些研究结果表明,20 Hz aVNS 可通过激活 β 肾上腺素能受体有效缓解 CIPN 疼痛。
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引用次数: 0
NKCC1 in Neonatal Cochlear Support Cells Reloads Ions Necessary for Cochlear Spontaneous Activity. 新生儿耳蜗支持细胞中的 NKCC1 重载耳蜗自发活动所需的离子
IF 2.4 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-04-30 DOI: 10.5607/en24003
Kwon-Woo Kang, Kushal Sharma, Shi-Hyun Park, Jae Kwang Lee, Justin C Lee, Eunyoung Yi

In the auditory system, the spontaneous activity of cochlear inner hair cells (IHCs) is initiated by the release of ATP from inner supporting cells (ISCs). This ATP release sets off a cascade, activating purinergic autoreceptors, opening of Ca2+-activated Cl- channel TMEM16A, Cl- efflux and osmotic cell shrinkage. Then, the shrunken ISCs efficiently regain their original volume, suggesting the existence of mechanisms for refilling Cland K+, priming them for subsequent activity. This study explores the potential involvement of NKCCs (Na+-K+-Cl- cotransporters) and KCCs (K+-Cl- cotransporters) in ISC spontaneous activity, considering their capability to transport both Cl- and K+ ions across the cell membrane. Employing a combination of immunohistochemistry, pharmacological interventions, and shRNA experiment, we unveiled the pivotal role of NKCC1 in cochlear spontaneous activity. Immunohistochemistry revealed robust NKCC1 expression in ISCs, persisting until the 2nd postnatal week. Intriguingly, we observed a developmental shift in NKCC1 expression from ISCs to synaptophysin-positive efferent terminals at postnatal day 18, hinting at its potential involvement in modulating synaptic transmission during the post-hearing period. Experiments using bumetanide, a well-known NKCC inhibitor, supported the functional significance of NKCC1 in ISC spontaneous activity. Bumetanide significantly reduced the frequency of spontaneous extracellular potentials (sEP) and spontaneous optical changes (sOCs) in ISCs. NKCC1-shRNA experiments conducted in cultured cochlear tissues further supported these findings, demonstrating a substantial decrease in event frequency and area. Taken together, we revealed the role of NKCC1 in shaping the ISC spontaneous activity that govern auditory pathway development.

在听觉系统中,耳蜗内毛细胞(IHC)的自发活动是由内支持细胞(ISC)释放的 ATP 启动的。ATP 的释放会引发一系列连锁反应,包括激活嘌呤能自受体、打开 Ca2+ 激活的 Cl- 通道 TMEM16A、Cl- 外流和渗透性细胞收缩。然后,萎缩的 ISC 会有效地恢复其原有体积,这表明存在重新填充 Cland K+ 的机制,从而为其后续活动做好准备。考虑到NKCCs(Na+-K+-Cl-共转运体)和KCCs(K+-Cl-共转运体)具有跨细胞膜转运Cl-和K+离子的能力,本研究探讨了它们参与ISC自发活动的可能性。通过免疫组化、药物干预和 shRNA 实验,我们揭示了 NKCC1 在耳蜗自发活动中的关键作用。免疫组化显示,NKCC1在ISC中的表达很强,一直持续到出生后第2周。耐人寻味的是,我们观察到 NKCC1 的表达在发育过程中发生了转变,即在出生后第 18 天从 ISC 转移到突触素阳性的传出末梢,这表明它可能参与了听觉后时期突触传递的调节。使用著名的 NKCC 抑制剂布美他尼进行的实验证实了 NKCC1 在 ISC 自发活动中的重要功能。布美他尼显著降低了 ISC 的自发胞外电位(sEP)和自发光学变化(sOC)的频率。在培养的耳蜗组织中进行的 NKCC1-shRNA 实验进一步证实了这些发现,证明了事件频率和面积的大幅减少。综上所述,我们揭示了 NKCC1 在影响听觉通路发育的 ISC 自发活动中的作用。
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引用次数: 0
Sensory Stimulation-dependent Npas4 Expression in the Olfactory Bulb during Early Postnatal Development. 出生后早期发育过程中嗅球中依赖于感觉刺激的 Npas4 表达
IF 2.4 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-04-30 DOI: 10.5607/en23037
Oh-Hoon Kwon, Jiyun Choe, Dokyeong Kim, Sunghwan Kim, Cheil Moon

The development of the olfactory system is influenced by sensory inputs, and it maintains neuronal generation and plasticity throughout the lifespan. The olfactory bulb contains a higher proportion of interneurons than other brain regions, particularly during the early postnatal period of neurogenesis. Although the relationship between sensory stimulation and olfactory bulb development during the postnatal period has been well studied, the molecular mechanisms have yet to be identified. In this study, we used western blotting and immunohistochemistry to analyze the expression of the transcription factor Npas4, a neuron-specific immediate-early gene that acts as a developmental regulator in many brain regions. We found that Npas4 is highly expressed in olfactory bulb interneurons during the early postnatal stages and gradually decreases toward the late postnatal stages. Npas4 expression was observed in all olfactory bulb layers, including the rostral migratory stream, where newborn neurons are generated and migrate to the olfactory bulb. Under sensory deprivation, the olfactory bulb size and the number of olfactory bulb interneurons were reduced. Furthermore, Npas4 expression and the expression of putative Npas4 downstream molecules were decreased. Collectively, these findings indicate that Npas4 expression induced by sensory input plays a role in the formation of neural circuits with excitatory mitral/tufted cells by regulating the survival of olfactory bulb interneurons during the early stages of postnatal development.

嗅觉系统的发育受到感官输入的影响,并在整个生命周期中保持神经元的生成和可塑性。与其他脑区相比,嗅球含有较高比例的中间神经元,尤其是在出生后早期的神经发生期。尽管对出生后时期感觉刺激与嗅球发育之间的关系已有深入研究,但其分子机制仍有待确定。在这项研究中,我们利用 Western 印迹和免疫组化技术分析了转录因子 Npas4 的表达,Npas4 是一种神经元特异性的即刻早期基因,在许多脑区起着发育调控作用。我们发现,Npas4在出生后早期的嗅球中间神经元中高度表达,并在出生后晚期逐渐减少。Npas4在嗅球各层均有表达,包括喙迁徙流,新生神经元在此产生并迁徙至嗅球。在感觉剥夺的情况下,嗅球的大小和嗅球中间神经元的数量都会减少。此外,Npas4 的表达和推定的 Npas4 下游分子的表达也减少了。总之,这些研究结果表明,在出生后发育的早期阶段,由感觉输入诱导的Npas4表达通过调节嗅球中间神经元的存活,在具有兴奋性丝裂细胞/簇细胞的神经环路的形成过程中发挥作用。
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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 Q3 MEDICINE, RESEARCH & EXPERIMENTAL 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
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 1.8 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL 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
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 1.8 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL 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 Q3 MEDICINE, RESEARCH & EXPERIMENTAL 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 Q3 MEDICINE, RESEARCH & EXPERIMENTAL 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 Q3 MEDICINE, RESEARCH & EXPERIMENTAL 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
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Experimental Neurobiology
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