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Chronic corticosterone exposure causes anxiety- and depression-related behaviors with altered gut microbial and brain metabolomic profiles in adult male C57BL/6J mice. 慢性皮质酮暴露会导致成年雄性 C57BL/6J 小鼠出现焦虑和抑郁相关行为,并改变肠道微生物和大脑代谢组图谱。
IF 3.3 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-11-07 DOI: 10.1186/s13041-024-01146-x
Hirotaka Shoji, Yasuhiro Maeda, Tsuyoshi Miyakawa

Chronic exposure to glucocorticoids in response to long-term stress is thought to be a risk factor for major depression. Depression is associated with disturbances in the gut microbiota composition and peripheral and central energy metabolism. However, the relationship between chronic glucocorticoid exposure, the gut microbiota, and brain metabolism remains largely unknown. In this study, we first investigated the effects of chronic corticosterone exposure on various domains of behavior in adult male C57BL/6J mice treated with the glucocorticoid corticosterone to evaluate them as an animal model of depression. We then examined the gut microbial composition and brain and plasma metabolome in corticosterone-treated mice. Chronic corticosterone treatment resulted in reduced locomotor activity, increased anxiety-like and depression-related behaviors, decreased rotarod latency, reduced acoustic startle response, decreased social behavior, working memory deficits, impaired contextual fear memory, and enhanced cued fear memory. Chronic corticosterone treatment also altered the composition of gut microbiota, which has been reported to be associated with depression, such as increased abundance of Bifidobacterium, Turicibacter, and Corynebacterium and decreased abundance of Barnesiella. Metabolomic data revealed that long-term exposure to corticosterone led to a decrease in brain neurotransmitter metabolites, such as serotonin, 5-hydroxyindoleacetic acid, acetylcholine, and gamma-aminobutyric acid, as well as changes in betaine and methionine metabolism, as indicated by decreased levels of adenosine, dimethylglycine, choline, and methionine in the brain. These results indicate that mice treated with corticosterone have good face and construct validity as an animal model for studying anxiety and depression with altered gut microbial composition and brain metabolism, offering new insights into the neurobiological basis of depression arising from gut-brain axis dysfunction caused by prolonged exposure to excessive glucocorticoids.

长期暴露于糖皮质激素以应对长期压力被认为是重度抑郁症的一个风险因素。抑郁症与肠道微生物群组成以及外周和中枢能量代谢紊乱有关。然而,慢性糖皮质激素暴露、肠道微生物群和脑代谢之间的关系在很大程度上仍然未知。在本研究中,我们首先研究了长期暴露于皮质酮对成年雄性 C57BL/6J 小鼠各种行为领域的影响,并将其作为抑郁症的动物模型进行评估。然后,我们研究了皮质酮处理小鼠的肠道微生物组成以及大脑和血浆代谢组。慢性皮质酮治疗会导致小鼠运动活动减少、焦虑样和抑郁相关行为增加、旋转潜伏期缩短、声学惊吓反应减弱、社交行为减少、工作记忆缺陷、情境恐惧记忆受损以及诱导恐惧记忆增强。慢性皮质酮治疗还改变了肠道微生物群的组成,而据报道,肠道微生物群的组成与抑郁症有关,如双歧杆菌、Toricibacter和Corynebacterium的丰度增加和Barnesiella的丰度降低。代谢组学数据显示,长期暴露于皮质酮会导致大脑神经递质代谢物的减少,如血清素、5-羟基吲哚乙酸、乙酰胆碱和γ-氨基丁酸,以及甜菜碱和蛋氨酸代谢的变化,表现为大脑中腺苷、二甲基甘氨酸、胆碱和蛋氨酸水平的降低。这些结果表明,用皮质酮治疗的小鼠作为研究焦虑症和抑郁症的动物模型,在肠道微生物组成和脑代谢改变方面具有良好的面貌和构造有效性,为研究长期暴露于过量糖皮质激素导致的肠脑轴功能紊乱所引起的抑郁症的神经生物学基础提供了新的见解。
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引用次数: 0
NDRG1 upregulation by ubiquitin proteasome system dysfunction aggravates neurodegeneration. 泛素蛋白酶体系统功能障碍导致的 NDRG1 上调加重了神经退行性变。
IF 3.3 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-10-23 DOI: 10.1186/s13041-024-01150-1
Tomonori Hoshino, Atsushi Mukai, Hirofumi Yamashita, Hidemi Misawa, Makoto Urushitani, Yoshitaka Tashiro, Shu-Ichi Matsuzawa, Ryosuke Takahashi

Protein turnover is crucial for cell survival, and the impairment of proteostasis leads to cell death. Aging is associated with a decline in proteostasis, as the progressive accumulation of damaged proteins is a hallmark of age-related disorders such as neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We previously discovered that the declining function of the ubiquitin-proteasome system (UPS) in motor neurons contributes to sporadic ALS pathologies, such as progressive motor neuron loss, protein accumulation, and glial activation. However, the mechanisms of UPS dysfunction-induced cell damage, such as cell death and aggregation, are not fully understood. This study used transcriptome analysis of motor neurons with UPS dysfunction and found that the expression of N-myc downstream regulated 1 (NDRG1) gets upregulated by UPS dysfunction. Additionally, the upregulation of NDRG1 induces cell death in the Neuro2a mouse neuroblastoma cell line. These results suggest that NDRG1 is a potential marker for UPS dysfunction and may play a role in neurodegeneration, such as that seen in ALS.

蛋白质的更替对细胞的存活至关重要,而蛋白稳态受损则会导致细胞死亡。衰老与蛋白稳态的下降有关,因为受损蛋白质的逐渐积累是神经退行性疾病(包括肌萎缩性脊髓侧索硬化症(ALS))等与年龄有关的疾病的标志。我们之前发现,运动神经元中泛素-蛋白酶体系统(UPS)功能的衰退是导致渐冻人症(ALS)病变的原因之一,如渐进性运动神经元缺失、蛋白质积累和神经胶质激活。然而,UPS 功能障碍诱发细胞损伤(如细胞死亡和聚集)的机制尚未完全明了。本研究利用转录组分析了 UPS 功能障碍的运动神经元,发现 UPS 功能障碍会上调 N-myc 下游调节 1(NDRG1)的表达。此外,NDRG1 的上调会诱导 Neuro2a 小鼠神经母细胞瘤细胞系的细胞死亡。这些结果表明,NDRG1 是 UPS 功能障碍的潜在标志物,可能在神经退行性变(如渐冻人症)中发挥作用。
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引用次数: 0
Ultrastructural characterization of hippocampal inhibitory synapses under resting and stimulated conditions. 静息和受刺激状态下海马抑制性突触的超微结构特征。
IF 3.3 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-10-22 DOI: 10.1186/s13041-024-01151-0
Jung-Hwa Tao-Cheng, Sandra Lara Moreira, Christine A Winters

The present study uses electron microscopy to document ultrastructural characteristics of hippocampal GABAergic inhibitory synapses under resting and stimulated conditions in three experimental systems. Synaptic profiles were sampled from stratum pyramidale and radiatum of the CA1 region from (1) perfusion fixed mouse brains, (2) immersion fixed rat organotypic slice cultures, and from (3) rat dissociated hippocampal cultures of mixed cell types. Synapses were stimulated in the brain by a 5 min delay in perfusion fixation to trigger an ischemia-like excitatory condition, and by treating the two culture systems with 90 mM high K+ for 2-3 min to depolarize the neurons. Upon such stimulation conditions, the presynaptic terminals of the inhibitory synapses exhibited similar structural changes to those seen in glutamatergic excitatory synapses, with depletion of synaptic vesicles, increase of clathrin-coated vesicles and appearance of synaptic spinules. However, in contrast to excitatory synapses, no structural differences were detected in the postsynaptic compartment of the inhibitory synapses upon stimulation. There were no changes in the appearance of material associated with the postsynaptic membrane or the length and curvature of the membrane. Also no change was detected in the labeling density of gephyrin, a GABAergic synaptic marker, lining the postsynaptic membrane. Furthermore, virtually all inhibitory synaptic clefts remained rigidly apposed, unlike in the case of excitatory synapses where ~ 20-30% of cleft edges were open upon stimulation, presumably to facilitate the clearance of neurotransmitters from the cleft. The fact that no open clefts were induced in inhibitory synapses upon stimulation suggests that inhibitory input may not need to be toned down under these conditions. On the other hand, similar to excitatory synapse, EGTA (a calcium chelator) induced open clefts in ~ 18% of inhibitory synaptic cleft edges, presumably disrupting similar calcium-dependent trans-synaptic bridges in both types of synapses.

本研究利用电子显微镜记录了三个实验系统中海马 GABA 能抑制性突触在静息和刺激条件下的超微结构特征。研究人员从(1)灌注固定的小鼠大脑、(2)浸泡固定的大鼠有机切片培养物和(3)混合细胞类型的大鼠离体海马培养物的CA1区金字塔层和放射层采集了突触轮廓样本。大脑灌注固定延迟 5 分钟以触发类似缺血的兴奋状态,并用 90 mM 高 K+处理两种培养系统 2-3 分钟以去极化神经元,从而刺激大脑突触。在这种刺激条件下,抑制性突触的突触前末端表现出与谷氨酸能兴奋性突触类似的结构变化,突触小泡耗竭,凝集素包裹的小泡增加,突触小刺出现。然而,与兴奋性突触不同,抑制性突触的突触后区在受到刺激时没有发现结构上的差异。突触后膜相关物质的外观、膜的长度和弧度均无变化。此外,突触后膜上的 GABA 能突触标记物 gephyrin 的标记密度也没有变化。此外,几乎所有抑制性突触裂隙都保持着刚性贴合,这与兴奋性突触的情况不同,在兴奋性突触中,约有 20-30% 的裂隙边缘在受到刺激时是开放的,这可能是为了促进神经递质从裂隙中清除。抑制性突触在受到刺激时没有开放的裂隙,这一事实表明抑制性输入在这些条件下可能不需要减弱。另一方面,与兴奋性突触类似,EGTA(一种钙螯合剂)在约 18% 的抑制性突触裂隙边缘诱导出开放裂隙,这可能破坏了这两种突触中类似的钙依赖性跨突触桥。
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引用次数: 0
Mechanisms of glutamate receptors hypofunction dependent synaptic transmission impairment in the hippocampus of schizophrenia susceptibility gene Opcml-deficient mouse model. 精神分裂症易感基因 Opcml 缺失小鼠模型海马中谷氨酸受体功能低下依赖性突触传递损伤的机制。
IF 3.3 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-10-17 DOI: 10.1186/s13041-024-01148-9
Xiaoxuan Sun, Hu Meng, Tianlan Lu, Weihua Yue, Dai Zhang, Lifang Wang, Jun Li

Schizophrenia is a severe psychiatric disorder with high heritability, characterized by positive and negative symptoms as well as cognitive abnormalities. Dysfunction in glutamate synapse is strongly implicated in the pathophysiology of schizophrenia. However, the precise role of the perturbed glutamatergic system in contributing to the cognitive abnormalities of schizophrenia at the synaptic level remains largely unknown. Although our previous work found that Opcml promotes spine maturation and Opcml-deficient mice exhibit schizophrenia-related cognitive impairments, the synaptic mechanism remains unclear. By using whole-cell patch clamp recording, we found that decreased neuronal excitability and alterations in intrinsic membrane properties of CA1 PNs in Opcml-deficient mice. Furthermore, Opcml deficiency leads to impaired glutamatergic transmission in hippocampus, which is closely related to postsynaptic AMPA/NMDA receptors dysfunction, resulting in the disturbances of E/I balance. Additionally, we found that the aripiprazole which we used to ameliorate abnormal cognitive behaviors also rescued the impaired glutamatergic transmission in Opcml-deficient mice. These findings will help to understand the synaptic mechanism in schizophrenia pathogenesis, providing insights into schizophrenia therapeutics with glutamatergic disruption.

精神分裂症是一种具有高度遗传性的严重精神疾病,以阳性和阴性症状以及认知异常为特征。谷氨酸突触功能障碍与精神分裂症的病理生理学密切相关。然而,谷氨酸能系统紊乱在突触水平上导致精神分裂症认知异常的确切作用在很大程度上仍然未知。尽管我们之前的研究发现Opcml能促进脊柱成熟,且Opcml缺失的小鼠表现出精神分裂症相关的认知障碍,但突触机制仍不清楚。通过全细胞膜片钳记录,我们发现Opcml缺陷小鼠CA1 PN的神经元兴奋性降低,固有膜特性发生改变。此外,Opcml缺陷导致海马的谷氨酸能传导受损,这与突触后AMPA/NMDA受体功能障碍密切相关,从而导致E/I平衡紊乱。此外,我们还发现,用于改善异常认知行为的阿立哌唑也能挽救Opcml缺陷小鼠受损的谷氨酸能传导。这些发现将有助于理解精神分裂症发病机制中的突触机制,为利用谷氨酸能干扰治疗精神分裂症提供启示。
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引用次数: 0
Theta-gamma-coupling as predictor of working memory performance in young and elderly healthy people. θ-伽马耦合是预测年轻人和老年人工作记忆能力的指标。
IF 3.3 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-10-16 DOI: 10.1186/s13041-024-01149-8
Mohammed Abubaker, Wiam Al Qasem, Kateřina Pilátová, Petr Ježdík, Eugen Kvašňák

The relationship between working memory (WM) and neuronal oscillations can be studied in detail using brain stimulation techniques, which provide a method for modulating these oscillations and thus influencing WM. The endogenous coupling between the amplitude of gamma oscillations and the phase of theta oscillations is crucial for cognitive control. Theta/gamma peak-coupled transcranial alternating current stimulation (TGCp-tACS) can modulate this coupling and thus influence WM performance. This study investigated the effects of TGCp-tACS on WM in older adults and compared their responses with those of younger participants from our previous work who underwent the same experimental design. Twenty-eight older subjects underwent both TGCp-tACS and sham stimulation sessions at least 72 h apart. Resting-state electroencephalography (EEG) was recorded before and after the interventions, and a WM task battery with five different WM tasks was performed during the interventions to assess various WM components. Outcomes measured included WM task performance (e.g., accuracy, reaction time (RT)) and changes in power spectral density (PSD) in different frequency bands. TGCp-tACS significantly decreased accuracy and RT on the 10- and 14-point Sternberg tasks and increased RT on the Digit Symbol Substitution Test in older adults. In contrast, younger participants showed a significant increase in accuracy only on the 14-item Sternberg task. Electrophysiological analysis revealed a decrease in delta and theta PSD and an increase in high gamma PSD in both younger and older participants after verum stimulation. In conclusion, theta-gamma coupling is essential for WM and modulation of this coupling affects WM performance. The effects of TGCp-tACS on WM vary with age due to natural brain changes. To better support older adults, the study suggests several strategies to improve cognitive function, including: Adjusting stimulation parameters, applying stimulation to two sites, conducting multiple sessions, and using brain imaging techniques for precise targeting.

利用脑刺激技术可以详细研究工作记忆(WM)与神经元振荡之间的关系,这种技术提供了一种调节这些振荡从而影响 WM 的方法。伽马振荡的振幅和θ振荡的相位之间的内源性耦合对认知控制至关重要。θ/γ峰值耦合经颅交变电流刺激(TGCp-tACS)可以调节这种耦合,从而影响 WM 的表现。本研究调查了 TGCp-tACS 对老年人 WM 的影响,并将他们的反应与我们之前工作中接受相同实验设计的年轻受试者的反应进行了比较。28 名老年受试者同时接受了 TGCp-tACS 和假刺激,两次刺激至少间隔 72 小时。在干预前后记录了静息状态脑电图(EEG),并在干预期间执行了包含五种不同 WM 任务的 WM 任务电池,以评估各种 WM 成分。测量结果包括 WM 任务表现(如准确性、反应时间 (RT))和不同频段的功率谱密度 (PSD) 变化。TGCp-tACS 明显降低了老年人在 10 点和 14 点 Sternberg 任务中的准确性和反应时间,并提高了数字符号替换测试的反应时间。相比之下,年轻参与者仅在 14 点 Sternberg 任务中的准确率有明显提高。电生理分析表明,在verum刺激后,年轻和老年参与者的delta和theta PSD都有所下降,而高γ PSD则有所上升。总之,θ-γ耦合对 WM 至关重要,而调节这种耦合会影响 WM 的表现。由于大脑的自然变化,TGCp-tACS 对 WM 的影响随年龄而变化。为了更好地支持老年人,研究提出了几种改善认知功能的策略,包括调整刺激参数、对两个部位进行刺激、进行多次治疗以及使用脑成像技术进行精确定位。
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引用次数: 0
Proteasome inhibition suppresses the induction of lipocalin-2 upon systemic lipopolysaccharide challenge in mice. 蛋白酶体抑制剂可抑制小鼠全身性脂多糖挑战时脂钙蛋白-2的诱导。
IF 3.3 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-10-03 DOI: 10.1186/s13041-024-01147-w
Jin-Sil Bae, Ji-Eun Heo, Kwon-Yul Ryu

Lipocalin-2 (Lcn2), a protein secreted by immune-activated cells, including reactive astrocytes, is detrimental to the brain and induces neurodegeneration. We previously showed that Lcn2 levels are reduced in primary mouse astrocytes after treatment with the proteasome inhibitor bortezomib (BTZ). However, it remains unknown whether a decrease in Lcn2 levels after BTZ treatment can also be observed in vivo and whether it reduces neurotoxicity during lipopolysaccharide (LPS)-induced systemic inflammation in vivo. To answer these questions, we performed LPS challenge experiments by intraperitoneal injection in mice and found that Lcn2 levels were significantly increased in the brain, recapitulating in vitro experiments using astrocytes. Co-administration of LPS and BTZ reduced the Lcn2 levels compared to the levels in LPS-treated controls. Upon LPS challenge, the expression levels of glial marker genes were upregulated in the mouse brain. Of note, this upregulation was hampered by the co-administration of BTZ. Taken together, our results suggested that BTZ can reduce LPS-induced Lcn2 levels and may alleviate LPS-induced neuroinflammation and neurotoxicity in mice.

脂联素-2(Lcn2)是一种由免疫激活细胞(包括反应性星形胶质细胞)分泌的蛋白质,对大脑有害并诱发神经退行性变。我们以前曾发现,蛋白酶体抑制剂硼替佐米(BTZ)治疗后,原代小鼠星形胶质细胞中的 Lcn2 水平会降低。然而,在体内是否也能观察到硼替佐米(BTZ)治疗后 Lcn2 水平的降低,以及在脂多糖(LPS)诱导的体内全身性炎症过程中,Lcn2 是否会降低神经毒性,这些仍是未知数。为了回答这些问题,我们对小鼠进行了腹腔注射 LPS 挑战实验,发现 Lcn2 在大脑中的水平显著升高,再现了使用星形胶质细胞进行的体外实验。与 LPS 处理的对照组相比,联合给药 LPS 和 BTZ 可降低 Lcn2 的水平。在 LPS 挑战下,小鼠大脑中胶质标记基因的表达水平上调。值得注意的是,联合使用 BTZ 会阻碍这种上调。综上所述,我们的研究结果表明,BTZ 可降低 LPS 诱导的 Lcn2 水平,并可减轻 LPS 诱导的小鼠神经炎症和神经毒性。
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引用次数: 0
Improving working memory by electrical stimulation and cross-frequency coupling. 通过电刺激和跨频耦合改善工作记忆
IF 3.3 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-10-01 DOI: 10.1186/s13041-024-01142-1
Wiam Al Qasem, Mohammed Abubaker, Kateřina Pilátová, Petr Ježdík, Eugen Kvašňák

Working memory (WM) is essential for the temporary storage and processing of information required for complex cognitive tasks and relies on neuronal theta and gamma oscillations. Given the limited capacity of WM, researchers have investigated various methods to improve it, including transcranial alternating current stimulation (tACS), which modulates brain activity at specific frequencies. One particularly promising approach is theta-gamma peak-coupled-tACS (TGCp-tACS), which simulates the natural interaction between theta and gamma oscillations that occurs during cognitive control in the brain. The aim of this study was to improve WM in healthy young adults with TGCp-tACS, focusing on both behavioral and neurophysiological outcomes. Thirty-one participants completed five WM tasks under both sham and verum stimulation conditions. Electroencephalography (EEG) recordings before and after stimulation showed that TGCp-tACS increased power spectral density (PSD) in the high-gamma region at the stimulation site, while PSD decreased in the theta and delta regions throughout the cortex. From a behavioral perspective, although no significant changes were observed in most tasks, there was a significant improvement in accuracy in the 14-item Sternberg task, indicating an improvement in phonological WM. In conclusion, TGCp-tACS has the potential to promote and improve the phonological component of WM. To fully realize the cognitive benefits, further research is needed to refine the stimulation parameters and account for individual differences, such as baseline cognitive status and hormonal factors.

工作记忆(WM)对于临时存储和处理复杂认知任务所需的信息至关重要,它依赖于神经元的θ和γ振荡。鉴于工作记忆的容量有限,研究人员已经研究了各种方法来改善工作记忆,其中包括经颅交变电流刺激(tACS),它可以调节特定频率的大脑活动。θ-γ峰值耦合经颅交流电刺激(TGCp-tACS)是一种特别有前途的方法,它模拟了大脑在认知控制过程中θ和γ振荡之间的自然交互作用。本研究旨在通过 TGCp-tACS 改善健康年轻人的 WM,重点关注行为和神经生理学结果。31 名参与者在假刺激和真刺激条件下完成了五项 WM 任务。刺激前后的脑电图(EEG)记录显示,TGCp-tACS 增加了刺激部位高伽马区的功率谱密度(PSD),同时降低了整个皮层的θ和δ区的功率谱密度。从行为角度来看,虽然在大多数任务中没有观察到明显的变化,但在 14 项 Sternberg 任务中准确率有了显著提高,这表明语音 WM 有了改善。总之,TGCp-tACS 具有促进和改善 WM 中语音部分的潜力。要充分实现认知方面的益处,还需要进一步的研究来完善刺激参数并考虑个体差异,如基线认知状态和荷尔蒙因素。
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引用次数: 0
Electroacupuncture inhibited carrageenan-induced pain aversion by activating GABAergic neurons in the ACC. 电针通过激活ACC中的GABA能神经元抑制卡拉胶诱导的疼痛厌恶。
IF 3.3 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-09-27 DOI: 10.1186/s13041-024-01144-z
Yichen Zhu, Haiju Sun, Siqi Xiao, Zui Shen, Xixiao Zhu, Yifang Wang, Xiaofen He, Boyi Liu, Yongliang Jiang, Yi Liang, Janqiao Fang, Xiaomei Shao

Pain aversion is an avoidance response to painful stimuli. Previous research has indicated that the anterior cingulate cortex (ACC) is involved in pain aversion processing. However, as interneurons, the role of GABAergic neurons in the ACC (GABAACC neurons) in pain aversion is still unclear. Electroacupuncture (EA) has been shown to ameliorate pain aversion, but the mechanism is not clarified. The present study provided evidence that inhibition of GABAACC neurons contributed to pain aversion. EA alleviated pain aversion by activating GABAACC neurons in an intensity-dependent manner. Specifically, 0.3 mA EA stimulation showed better effects on pain aversion than 0.1 mA stimulation, which could be reversed by chemical genetic inhibition of GABAACC neurons. These results provide a novel mechanism by which EA alleviates pain aversion by reversing GABAACC neurons.

疼痛厌恶是一种对疼痛刺激的回避反应。以往的研究表明,前扣带回皮层(ACC)参与了疼痛厌恶的处理过程。然而,作为中间神经元,ACC 中的 GABA 能神经元(GABAACC 神经元)在疼痛厌恶中的作用仍不清楚。电针(EA)已被证明能改善疼痛厌恶,但其机制尚未明确。本研究提供了抑制 GABAACC 神经元导致疼痛厌恶的证据。EA通过激活GABAACC神经元以强度依赖的方式缓解疼痛厌恶。具体来说,0.3毫安的EA刺激比0.1毫安的刺激对疼痛厌恶有更好的效果,而这种效果可以通过对GABAACC神经元的化学遗传抑制逆转。这些结果提供了一种新的机制,即EA通过逆转GABAACC神经元来减轻疼痛厌恶感。
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引用次数: 0
Shank3 deficiency alters midbrain GABAergic neuron morphology, GABAergic markers and synaptic activity in primary striatal neurons. Shank3 缺陷会改变中脑 GABA 能神经元的形态、GABA 能标记和初级纹状体神经元的突触活动。
IF 3.3 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-09-27 DOI: 10.1186/s13041-024-01145-y
Zuzana Bačová, Bohumila Jurkovičová-Tarabová, Tomáš Havránek, Denisa Mihalj, Veronika Borbélyová, Zdenko Pirnik, Boris Mravec, Daniela Ostatníková, Ján Bakoš

Abnormalities in gamma-aminobutyric acid (GABA)ergic neurotransmission play a role in the pathogenesis of autism, although the mechanisms responsible for alterations in specific brain regions remain unclear. Deficits in social motivation and interactions are core symptoms of autism, likely due to defects in dopaminergic neural pathways. Therefore, investigating the morphology and functional roles of GABAergic neurons within dopaminergic projection areas could elucidate the underlying etiology of autism. The aim of this study was to (1) compare the morphology and arborization of glutamate decarboxylase (GAD)-positive neurons from the midbrain tegmentum; (2) evaluate synaptic activity in primary neurons from the striatum; and (3) assess GABAergic postsynaptic puncta in the ventral striatum of wild-type (WT) and Shank3-deficient mice. We found a significant decrease in the number of short neurites in GAD positive primary neurons from the midbrain tegmentum in Shank3-deficient mice. The application of a specific blocker of GABAA receptors (GABAAR) revealed significantly increased frequency of spontaneous postsynaptic currents (sPSCs) in Shank3-deficient striatal neurons compared to their WT counterparts. The mean absolute amplitude of the events was significantly higher in striatal neurons from Shank3-deficient compared to WT mice. We also observed a significant reduction in gephyrin/GABAAR γ2 colocalization in the striatum of adult male Shank3-deficient mice. The gene expression of collybistin was significantly lower in the nucleus accumbens while gephyrin and GABAAR γ2 were lower in the ventral tegmental area (VTA) in male Shank3-deficient compared to WT mice. In conclusion, Shank3 deficiency leads to alterations in GABAergic neurons and impaired GABAergic function in dopaminergic brain areas. These changes may underlie autistic symptoms, and potential interventions modulating GABAergic activity in dopaminergic pathways may represent new treatment modality.

γ-氨基丁酸(GABA)能神经递质的异常在自闭症的发病机制中起着一定的作用,但具体脑区发生改变的机制仍不清楚。自闭症的核心症状是社交动机和互动障碍,这可能是多巴胺能神经通路缺陷所致。因此,研究多巴胺能投射区内GABA能神经元的形态和功能作用可以阐明自闭症的潜在病因。本研究的目的是:(1)比较中脑被盖区谷氨酸脱羧酶(GAD)阳性神经元的形态和轴化;(2)评估纹状体初级神经元的突触活动;以及(3)评估野生型(WT)和Shank3缺陷型小鼠腹侧纹状体的GABA能突触后点状突触。我们发现,Shank3 缺陷小鼠中脑被盖部 GAD 阳性初级神经元的短神经元数目明显减少。应用 GABAA 受体(GABAAR)的特异性阻断剂发现,与 WT 小鼠相比,Shank3 缺失型纹状体神经元中突触后自发电流(sPSC)的频率显著增加。与 WT 小鼠相比,Shank3 缺陷小鼠纹状体神经元中的事件平均绝对振幅明显更高。我们还观察到,在成年雄性 Shank3 缺陷小鼠的纹状体中,ephyrin/GABAAR γ2共定位明显减少。与 WT 小鼠相比,Shank3 缺陷雄性小鼠凹凸核中 collybistin 的基因表达明显降低,而腹侧被盖区(VTA)中 gephyrin 和 GABAAR γ2 的基因表达则更低。总之,Shank3缺陷导致GABA能神经元的改变和多巴胺能脑区GABA能功能受损。这些变化可能是自闭症症状的基础,而调节多巴胺能通路中GABA能活性的潜在干预措施可能是新的治疗模式。
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引用次数: 0
γ-Aminobutyric acid type A receptor β1 subunit gene polymorphisms are associated with the sedative and amnesic effects of midazolam. γ-氨基丁酸A型受体β1亚基基因多态性与咪达唑仑的镇静和失忆作用有关。
IF 3.3 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-09-27 DOI: 10.1186/s13041-024-01141-2
Yoshihiko Kosaki, Daisuke Nishizawa, Junko Hasegawa, Kaori Yoshida, Kazutaka Ikeda, Tatsuya Ichinohe

Midazolam is widely used for intravenous sedation. However, wide interindividual variability is seen in the sensitivity to midazolam. The association between genetic factors and interindividual differences in midazolam sensitivity remains unclear. The present study explored the association between common genetic variants and sedative and amnesic effects of midazolam. This prospective study included patients who were scheduled to undergo dental procedures under intravenous sedation. The sedative effect was evaluated using the Ramsay sedation scale 5 min after midazolam (0.05 mg/kg) administration. We employed two parallel approaches in this study: genome-wide approach and candidate gene approach. The γ-aminobutyric acid type A receptor subunit genes were selected as candidate genes. Multivariate linear regression analyses were performed to investigate the association between the Ramsay sedation scale and genetic variants. We also analyzed the association between the presence of anterograde amnesia and genetic variants using multivariate binominal logistic regression analyses. The analyses were adjusted for potential confounding factors. A total of 191 patients were included in the analyses. In the genome-wide association analyses, no significant association was found between the genetic variants and Ramsay scores. In the candidate gene analyses, the rs73247636 (dominant model: β = 0.72 [95% confidence interval, 0.34 to 1.10], P < 0.001) and rs56278524 (dominant model: β = 0.73 [0.37 to 1.10], P < 0.001) polymorphisms of the GABRB1 gene were significantly associated with Ramsay scores. Additionally, the rs73247636 (dominant model: odds ratio [OR] = 8.39 [2.36 to 29.85], P = 0.001) and rs56278524 (dominant model: OR = 15.26 [3.42 to 68.07], P < 0.001) polymorphisms were also significantly associated with the presence of anterograde amnesia. The rs73247636 and rs56278524 single-nucleotide polymorphisms of GABRB1 were associated with the sedative and amnesic effects of midazolam.

咪达唑仑被广泛用于静脉镇静。然而,个体间对咪达唑仑的敏感性存在很大差异。遗传因素与咪达唑仑敏感性个体间差异之间的关系仍不清楚。本研究探讨了常见遗传变异与咪达唑仑镇静和失忆作用之间的关系。这项前瞻性研究纳入了计划在静脉镇静下接受牙科手术的患者。在服用咪达唑仑(0.05 毫克/千克)5 分钟后,使用拉姆塞镇静量表评估镇静效果。本研究采用了两种平行方法:全基因组方法和候选基因方法。我们选择了γ-氨基丁酸 A 型受体亚基基因作为候选基因。我们进行了多变量线性回归分析,以研究拉姆塞镇静量表与基因变异之间的关联。我们还使用多变量二项式逻辑回归分析法分析了逆行性遗忘的存在与遗传变异之间的关联。这些分析对潜在的混杂因素进行了调整。共有 191 名患者被纳入分析。在全基因组关联分析中,没有发现基因变异与拉姆塞评分之间存在显著关联。在候选基因分析中,rs73247636(显性模型:β = 0.72 [95% 置信区间,0.34 至 1.10],P
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引用次数: 0
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Molecular Brain
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