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Inhibition of cortical synaptic transmission, behavioral nociceptive, and anxiodepressive-like responses by arecoline in adult mice. 异甲唑啉对成年小鼠大脑皮层突触传递、行为痛觉和焦虑抑郁样反应的抑制作用
IF 3.6 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-06-17 DOI: 10.1186/s13041-024-01106-5
Qi-Yu Chen, Yuxiang Zhang, Yujie Ma, Min Zhuo

Areca nut, the seed of Areca catechu L., is one of the most widely consumed addictive substances in the world after nicotine, ethanol, and caffeine. The major effective constituent of A. catechu, arecoline, has been reported to affect the central nervous system. Less is known if it may affect pain and its related emotional responses. In this study, we found that oral application of arecoline alleviated the inflammatory pain and its induced anxiolytic and anti-depressive-like behavior. Arecoline also increased the mechanical nociceptive threshold and alleviated depression-like behavior in naïve mice. In the anterior cingulate cortex (ACC), which acts as a hinge of nociception and its related anxiety and depression, by using the multi-electrode field potential recording and whole-cell patch-clamp recording, we found that the evoked postsynaptic transmission in the ACC of adult mice has been inhibited by the application of arecoline. The muscarinic receptor is the major receptor of the arecoline in the ACC. Our results suggest that arecoline alleviates pain, anxiety, and depression-like behavior in both physiological and pathological conditions, and this new mechanism may help to treat patients with chronic pain and its related anxiety and disorder in the future.

作为儿茶属植物Areca catechu L.的种子,Areca nut是继尼古丁、乙醇和咖啡因之后世界上消费最广泛的成瘾物质之一。据报道,儿茶中的主要有效成分 "山豆根碱 "会影响中枢神经系统。至于它是否会影响疼痛及其相关的情绪反应,目前还知之甚少。在这项研究中,我们发现口服阿可灵可减轻炎症性疼痛及其诱发的抗焦虑和抗抑郁行为。阿瑞考林还能提高小鼠的机械痛觉阈值并减轻其抑郁样行为。通过多电极场电位记录和全细胞膜片钳记录,我们发现在作为痛觉及其相关的焦虑和抑郁铰链的前扣带回皮层(ACC)中,应用阿可林可抑制成年小鼠 ACC 中诱发的突触后传递。在 ACC 中,毒蕈碱受体是阿糖胞苷的主要受体。我们的研究结果表明,无论是在生理还是病理条件下,阿可林都能缓解疼痛、焦虑和抑郁样行为,这种新的机制可能有助于未来治疗慢性疼痛患者及其相关的焦虑和失调。
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引用次数: 0
Chemogenetic activation of histamine neurons promotes retrieval of apparently lost memories. 组胺神经元的化学激活可促进明显丢失记忆的恢复。
IF 3.6 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-06-15 DOI: 10.1186/s13041-024-01111-8
Yuto Yokoi, Ayame Kubo, Kyoka Nishimura, Yuki Takamura, Yoshikazu Morishita, Masabumi Minami, Hiroshi Nomura

Memory retrieval can become difficult over time, but it is important to note that memories that appear to be forgotten might still be stored in the brain, as shown by their occasional spontaneous retrieval. Histamine in the central nervous system is a promising target for facilitating the recovery of memory retrieval. Our previous study demonstrated that histamine H3 receptor (H3R) inverse agonists/antagonists, activating histamine synthesis and release, enhance activity in the perirhinal cortex and help in retrieving forgotten long-term object recognition memories. However, it is unclear whether enhancing histaminergic activity alone is enough for the recovery of memory retrieval, considering that H3Rs are also located in other neuron types and affect the release of multiple neurotransmitters. In this study, we employed a chemogenetic method to determine whether specifically activating histamine neurons in the tuberomammillary nucleus facilitates memory retrieval. In the novel object recognition test, control mice did not show a preference for objects based on memory 1 week after training, but chemogenetic activation of histamine neurons before testing improved memory retrieval. This selective activation did not affect the locomotor activity or anxiety-related behavior. Administering an H2R antagonist directly into the perirhinal cortex inhibited the recovery of memory retrieval induced by the activation of histamine neurons. Furthermore, we utilized the Barnes maze test to investigate whether chemogenetic activation of histamine neurons influences the retrieval of forgotten spatial memories. Control mice explored all the holes in the maze equally 1 week after training, whereas mice with chemogenetically activated histamine neurons spent more time around the target hole. These findings indicate that chemogenetic activation of histamine neurons in the tuberomammillary nucleus can promote retrieval of seemingly forgotten object recognition and spatial memories.

随着时间的推移,记忆检索可能会变得困难,但重要的是要注意,看似已被遗忘的记忆可能仍然储存在大脑中,这一点从它们偶尔会自发检索到就可以看出。中枢神经系统中的组胺是促进记忆恢复的一个很有希望的靶点。我们之前的研究表明,组胺 H3 受体(H3R)反向激动剂/拮抗剂能激活组胺的合成和释放,增强边缘皮层的活动,有助于找回遗忘的长期物体识别记忆。然而,考虑到 H3Rs 还分布在其他神经元类型中,并影响多种神经递质的释放,目前还不清楚仅增强组胺能活性是否足以恢复记忆检索。在这项研究中,我们采用了一种化学遗传学方法来确定特异性激活结节乳突核中的组胺神经元是否能促进记忆恢复。在新物体识别测试中,对照组小鼠在训练一周后并没有表现出基于记忆的物体偏好,但在测试前通过化学方法激活组胺神经元可改善记忆检索。这种选择性激活不会影响小鼠的运动活动或与焦虑相关的行为。在脐周皮层直接注射 H2R 拮抗剂可抑制组胺神经元激活引起的记忆恢复。此外,我们还利用巴恩斯迷宫试验来研究组胺神经元的化学激活是否会影响遗忘空间记忆的检索。对照组小鼠在训练1周后同样探索了迷宫中的所有洞口,而化学激活组胺神经元的小鼠则在目标洞口周围花费了更多时间。这些研究结果表明,用化学方法激活小结节乳突核中的组胺神经元可促进看似被遗忘的物体识别和空间记忆的恢复。
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引用次数: 0
Visualization of the existence of growth hormone secretagogue receptor in the rat nucleus accumbens. 大鼠脑核中生长激素分泌受体的可视化。
IF 3.3 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-06-13 DOI: 10.1186/s13041-024-01109-2
Seohyeon Lee, Wen Ting Cai, Hyung Shin Yoon, Jeong-Hoon Kim

The potential role of the ghrelin receptor, also known as the growth hormone secretagogue receptor (GHSR), within the nucleus accumbens (NAcc) in regulating drug addiction and feeding has been documented; however, the pattern of its expression in this site remains elusive. In this study, we characterized the expression patterns of GHSR1a and 1b, two subtypes of GHSRs, within the NAcc of the rat brain by immunohistochemistry. We visually detected GHSR signals, for the first time, at the protein level in the NAcc in which they were mostly expressed in neurons including both medium spiny neurons (MSNs) and non-MSNs. Furthermore, GHSR1a was found expressed as localized near the cellular membrane or some in the cytoplasm, whereas GHSR1b expressed solely throughout the large cytoplasmic area. The existence and subcellular expression pattern of GHSRs in the NAcc identified in this study will contribute to improving our understanding about the role of GHSR-mediated neurosignaling in feeding and drug addiction.

胃泌素受体又称生长激素分泌受体(GHSR),它在大鼠脑核(NAcc)中调节药物成瘾和进食的潜在作用已被证实;然而,它在该部位的表达模式却仍然难以捉摸。在这项研究中,我们通过免疫组化鉴定了 GHSR1a 和 1b 这两种亚型 GHSR 在大鼠大脑 NAcc 中的表达模式。我们首次在蛋白水平上直观地检测到 GHSR 信号在 NAcc 中的表达,它们主要在神经元(包括中刺神经元(MSN)和非中刺神经元)中表达。此外,还发现 GHSR1a 在细胞膜附近或部分细胞质中表达,而 GHSR1b 仅在整个大细胞质区域表达。本研究发现的GHSR在NAcc中的存在和亚细胞表达模式将有助于加深我们对GHSR介导的神经信号转导在进食和药物成瘾中的作用的理解。
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引用次数: 0
Adolescent chemogenetic activation of dopaminergic neurons leads to reversible decreases in amphetamine-induced stereotypic behavior. 青春期化学基因激活多巴胺能神经元会导致苯丙胺诱导的刻板行为可逆性减少。
IF 3.6 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-06-11 DOI: 10.1186/s13041-024-01110-9
Muhammad O Chohan, Amy B Lewandowski, Rebecca N Siegel, Kally C O'Reilly, Jeremy Veenstra-VanderWeele

Chronic perturbations of neuronal activity can evoke homeostatic and new setpoints for neurotransmission. Using chemogenetics to probe the relationship between neuronal cell types and behavior, we recently found reversible decreases in dopamine (DA) transmission, basal behavior, and amphetamine (AMPH) response following repeated stimulation of DA neurons in adult mice. It is unclear, however, whether altering DA neuronal activity via chemogenetics early in development leads to behavioral phenotypes that are reversible, as alterations of neuronal activity during developmentally sensitive periods might be expected to induce persistent effects on behavior. To examine the impact of developmental perturbation of DA neuron activity on basal and AMPH behavior, we expressed excitatory hM3D(Gq) in postnatal DA neurons in TH-Cre and WT mice. Basal and CNO- or AMPH-induced locomotion and stereotypy was evaluated in a longitudinal design, with clozapine N-oxide (CNO, 1.0 mg/kg) administered across adolescence (postnatal days 15-47). Repeated CNO administration did not impact basal behavior and only minimally reduced AMPH-induced hyperlocomotor response in adolescent TH-CrehM3Dq mice relative to WThM3Dq littermate controls. Following repeated CNO administration, however, AMPH-induced stereotypic behavior robustly decreased in adolescent TH-CrehM3Dq mice relative to controls. A two-month CNO washout period rescued the diminished AMPH-induced stereotypic behavior. Our findings indicate that the homeostatic compensations that take place in response to chronic hM3D(Gq) stimulation during adolescence are temporary and are dependent on ongoing chemogenetic stimulation.

神经元活动的慢性扰动可唤起神经传递的平衡和新的设定点。最近,我们利用化学遗传学探究了神经元细胞类型与行为之间的关系,发现在反复刺激成年小鼠的多巴胺(DA)神经元后,多巴胺(DA)传递、基础行为和苯丙胺(AMPH)反应会出现可逆性下降。然而,目前还不清楚在发育早期通过化学遗传学改变DA神经元活性是否会导致可逆的行为表型,因为在发育敏感期改变神经元活性可能会对行为产生持续影响。为了研究 DA 神经元活性的发育扰动对基础行为和 AMPH 行为的影响,我们在 TH-Cre 和 WT 小鼠的出生后 DA 神经元中表达了兴奋性 hM3D(Gq)。我们在整个青春期(出生后第 15-47 天)对氯氮平 N-氧化物(CNO,1.0 mg/kg)进行了纵向设计,评估了基础行为以及 CNO 或 AMPH 诱导的运动和刻板行为。与 WThM3Dq 同卵对照组相比,重复给药 CNO 不会影响 TH-CrehM3Dq 小鼠的基础行为,也只会轻微降低 AMPH 诱导的过度运动反应。然而,在重复给予 CNO 后,相对于对照组,AMPH 诱导的青少年 TH-CrehM3Dq 小鼠的刻板行为显著减少。两个月的 CNO 冲洗期可挽救 AMPH 诱导的刻板行为的减少。我们的研究结果表明,在青春期对 hM3D(Gq) 的慢性刺激所产生的平衡补偿是暂时的,并且依赖于持续的化学刺激。
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引用次数: 0
Exploration of new space elicits phosphorylation of GluA1(Ser831) and S6K and expression of Arc in the hippocampus in vivo as in long-term potentiation. 探索新空间会引起 GluA1(Ser831)和 S6K 的磷酸化,以及体内海马中 Arc 的表达,这与长期电位一样。
IF 3.3 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-06-10 DOI: 10.1186/s13041-024-01100-x
Roberta Cagnetta, Jean-Claude Lacaille, Nahum Sonenberg

The brain responds to experience through modulation of synaptic transmission, that is synaptic plasticity. An increase in the strength of synaptic transmission is manifested as long-term potentiation (LTP), while a decrease in the strength of synaptic transmission is expressed as long-term depression (LTD). Most of the studies of synaptic plasticity have been carried out by induction via electrophysiological stimulation. It is largely unknown in which behavioural tasks such synaptic plasticity occurs. Moreover, some stimuli can induce both LTP and LTD, thus making it difficult to separately study the different forms of synaptic plasticity. Two studies have shown that an aversive memory task - inhibitory avoidance learning and contextual fear conditioning - physiologically and selectively induce LTP and an LTP-like molecular change, respectively, in the hippocampus in vivo. Here, we show that a non-aversive behavioural task - exploration of new space - physiologically and selectively elicits a biochemical change in the hippocampus that is a hallmark of LTP. Specifically, we found that exploration of new space induces an increase in the phosphorylation of GluA1(Ser831), without affecting the phosphorylation of GluA1(Ser845), which are biomarkers of early-LTP and not NMDAR-mediated LTD. We also show that exploration of new space engenders the phosphorylation of the translational regulator S6K and the expression of Arc, which are features of electrophysiologically-induced late-LTP in the hippocampus. Therefore, our results show that exploration of new space is a novel non-aversive behavioural paradigm that elicits molecular changes in vivo that are analogous to those occurring during early- and late-LTP, but not during NMDAR-mediated LTD.

大脑通过调节突触传递对经验做出反应,这就是突触可塑性。突触传递强度的增加表现为长期延时(LTP),而突触传递强度的降低则表现为长期抑制(LTD)。大多数突触可塑性研究都是通过电生理刺激诱导进行的。目前还不清楚这种突触可塑性发生在哪些行为任务中。此外,有些刺激可同时诱导 LTP 和 LTD,因此很难分别研究不同形式的突触可塑性。有两项研究表明,厌恶性记忆任务--抑制性回避学习和情境性恐惧条件反射--分别在体内海马中生理上和选择性地诱导 LTP 和类似 LTP 的分子变化。在这里,我们展示了一种非逆转性的行为任务--探索新空间--在生理上和选择性地引起海马的生化变化,这种变化是 LTP 的标志。具体来说,我们发现探索新空间会诱导 GluA1(Ser831)的磷酸化增加,而不影响 GluA1(Ser845)的磷酸化,后者是早期 LTP 而非 NMDAR 介导的 LTD 的生物标志物。我们还发现,对新空间的探索会引起翻译调节因子 S6K 的磷酸化和 Arc 的表达,而这正是电生理诱导的海马晚期 LTP 的特征。因此,我们的研究结果表明,探索新空间是一种新型的非厌恶行为范式,它在体内引起的分子变化类似于早期和晚期LTP期间发生的变化,但不类似于NMDAR介导的LTD期间发生的变化。
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引用次数: 0
Globus pallidus is not independent from striatal direct pathway neurons: an up-to-date review. 苍白球并非独立于纹状体直接通路神经元:最新综述。
IF 3.6 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-06-07 DOI: 10.1186/s13041-024-01107-4
Fumino Fujiyama, Fuyuki Karube, Yasuharu Hirai

Striatal projection neurons, which are classified into two groups-direct and indirect pathway neurons, play a pivotal role in our understanding of the brain's functionality. Conventional models propose that these two pathways operate independently and have contrasting functions, akin to an "accelerator" and "brake" in a vehicle. This analogy further elucidates how the depletion of dopamine neurons in Parkinson's disease can result in bradykinesia. However, the question arises: are these direct and indirect pathways truly autonomous? Despite being distinct types of neurons, their interdependence cannot be overlooked. Single-neuron tracing studies employing membrane-targeting signals have shown that the majority of direct pathway neurons terminate not only in the output nuclei, but also in the external segment of the globus pallidus (GP in rodents), a relay nucleus of the indirect pathway. Recent studies have unveiled the existence of arkypallidal neurons, which project solely to the striatum, in addition to prototypic neurons. This raises the question of which type of GP neurons receive these striatal axon collaterals. Our morphological and electrophysiological experiments showed that the striatal direct pathway neurons may affect prototypic neurons via the action of substance P on neurokinin-1 receptors. Conversely, another research group has reported that direct pathway neurons inhibit arkypallidal neurons via GABA. Regardless of the neurotransmitter involved, it can be concluded that the GP is not entirely independent of direct pathway neurons. This review article underscores the intricate interplay between different neuronal pathways and challenges the traditional understanding of their independence.

纹状体投射神经元分为两类--直接通路神经元和间接通路神经元,它们在我们了解大脑功能方面发挥着关键作用。传统模型认为,这两种途径独立运行,功能截然不同,类似于汽车的 "油门 "和 "刹车"。这一比喻进一步阐明了帕金森病中多巴胺神经元的耗竭是如何导致运动迟缓的。然而,问题来了:这些直接和间接通路真的是自主的吗?尽管神经元的类型不同,但它们之间的相互依存关系不容忽视。利用膜靶向信号进行的单神经元追踪研究表明,大多数直接通路神经元不仅终止于输出核,而且终止于间接通路的中继核--苍白球外节(啮齿类动物为 GP)。最近的研究发现,除了原型神经元外,还存在只投射到纹状体的杏仁核神经元。这就提出了一个问题,即哪种类型的 GP 神经元会接收这些纹状体轴突副束。我们的形态学和电生理实验表明,纹状体直接通路神经元可能通过物质 P 对神经激肽-1 受体的作用来影响原型神经元。相反,另一个研究小组报告称,直接通路神经元通过 GABA 抑制杏仁核神经元。无论涉及哪种神经递质,都可以得出结论:GP 并非完全独立于直接通路神经元。这篇综述文章强调了不同神经元通路之间错综复杂的相互作用,并对传统的独立理解提出了挑战。
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引用次数: 0
TDP43 interacts with MLH1 and MSH6 proteins in a DNA damage-inducible manner TDP43 以 DNA 损伤诱导的方式与 MLH1 和 MSH6 蛋白相互作用
IF 3.6 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-06-05 DOI: 10.1186/s13041-024-01108-3
Vincent E. Provasek, Manohar Kodavati, Brandon Kim, Joy Mitra, Muralidhar L. Hegde
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double-strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that the TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complementary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 h treatment of 10 μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS-affected neurons.
肌萎缩性脊髓侧索硬化症(ALS)是一种影响运动神经元的致命性神经退行性疾病。肌萎缩侧索硬化症的神经病理学特征之一是基因组损伤增加和 DNA 修复能力受损。TAR-DNA结合蛋白43(TDP43)与渐冻人症的散发性和家族性形式都有关联,通常表现为蛋白聚集的细胞膜错定位,称为TDP43蛋白病。TDP43 是一种无处不在的 RNA/DNA 结合蛋白,在多种疾病过程中具有功能性影响,包括 DNA 双链断裂(DSB)的修复。众所周知,TDP43 可调控 RNA 代谢,但我们实验室发现它还能直接在蛋白质水平上促进 DNA 修复。在这里,我们发现 TDP43 蛋白以 DNA 损伤诱导的方式与 DNA 错配修复(MMR)蛋白 MLH1 和 MSH6 相互作用。我们利用已分化的 SH-SY5Y 神经元培养物,通过近接试验(PLA)和共免疫沉淀(CoIP)试验这两种互补方法来确定这种诱导关系。我们观察到,在10 μM甲基甲磺酸甲酯(MMS)(一种用于诱导MMR修复的DNA烷化剂)处理2小时后,TDP43与MLH1和MSH6相互作用的信号显著增加。同样,我们还观察到,在使用针对 TDP43 的 siRNA 处理的细胞系中,这种效应也会消失。最后,我们证实,与年龄匹配的对照组相比,这些蛋白质相互作用在 ALS 患者的腰脊髓样本中明显增加。这些结果将有助于我们今后的研究,以了解在 ALS 受影响的神经元中 TDP43-MMR 相互作用的机制和后果。
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引用次数: 0
Dendritic spine head diameter is reduced in the prefrontal cortex of progranulin haploinsufficient mice 单倍体基因缺陷小鼠前额叶皮层树突棘头直径减小
IF 3.6 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-06-05 DOI: 10.1186/s13041-024-01095-5
Anna K. Cook, Kelsey M. Greathouse, Phaedra N. Manuel, Noelle H. Cooper, Juliana M. Eberhardt, Cameron D. Freeman, Audrey J. Weber, Jeremy H. Herskowitz, Andrew E. Arrant
Loss-of-function mutations in the progranulin (GRN) gene are an autosomal dominant cause of Frontotemporal Dementia (FTD). These mutations typically result in haploinsufficiency of the progranulin protein. Grn+/– mice provide a model for progranulin haploinsufficiency and develop FTD-like behavioral abnormalities by 9–10 months of age. In previous work, we demonstrated that Grn+/– mice develop a low dominance phenotype in the tube test that is associated with reduced dendritic arborization of layer II/III pyramidal neurons in the prelimbic region of the medial prefrontal cortex (mPFC), a region key for social dominance behavior in the tube test assay. In this study, we investigated whether progranulin haploinsufficiency induced changes in dendritic spine density and morphology. Individual layer II/III pyramidal neurons in the prelimbic mPFC of 9–10 month old wild-type or Grn+/– mice were targeted for iontophoretic microinjection of fluorescent dye, followed by high-resolution confocal microscopy and 3D reconstruction for morphometry analysis. Dendritic spine density in Grn+/– mice was comparable to wild-type littermates, but the apical dendrites in Grn+/– mice had a shift in the proportion of spine types, with fewer stubby spines and more thin spines. Additionally, apical dendrites of Grn+/– mice had longer spines and smaller thin spine head diameter in comparison to wild-type littermates. These changes in spine morphology may contribute to altered circuit-level activity and social dominance deficits in Grn+/– mice.
前花粉蛋白(GRN)基因的功能缺失突变是导致额颞叶痴呆症(FTD)的常染色体显性病因。这些突变通常会导致原花粉蛋白的单倍体缺乏。Grn+/-小鼠提供了一种原花青素单倍蛋白缺乏的模型,并在 9-10 个月大时出现类似于 FTD 的行为异常。在之前的研究中,我们证明了 Grn+/- 小鼠在试管试验中会出现低支配力表型,这与内侧前额叶皮层(mPFC)前边缘区 II/III 层锥体神经元树突轴化减少有关,而内侧前额叶皮层前边缘区是试管试验中社会支配行为的关键区域。在这项研究中,我们探讨了单倍蛋白缺乏是否会诱发树突棘密度和形态的变化。我们对 9-10 个月大的野生型小鼠或 Grn+/- 小鼠的前边缘 mPFC 中的单个 II/III 层锥体神经元进行了荧光染料离子显微注射,然后用高分辨率共聚焦显微镜和三维重建技术进行了形态学分析。Grn+/-小鼠的树突棘密度与野生型同窝小鼠相当,但Grn+/-小鼠的顶端树突棘类型比例发生了变化,粗棘减少,细棘增多。此外,与野生型小鼠相比,Grn+/-小鼠的顶端树突具有更长的棘突和更小的细棘突头直径。脊柱形态的这些变化可能是导致Grn+/-小鼠回路级活动改变和社会优势缺陷的原因。
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引用次数: 0
Chronic unpredictable stress induces autophagic death of adult hippocampal neural stem cells. 慢性不可预测压力诱导成体海马神经干细胞自噬死亡
IF 3.6 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-06-03 DOI: 10.1186/s13041-024-01105-6
Seongwon Choe, Hyeonjeong Jeong, Jieun Choi, Seong-Woon Yu

Chronic psychological stress is a critical factor for neurological complications like anxiety disorders, dementia, and depression. Our previous results show that chronic restraint stress causes cognitive deficits and mood dysregulation by inducing autophagic death of adult hippocampal neural stem cells (NSCs). However, it is unknown whether other models of psychological stress also induce autophagic death of adult hippocampal NSCs. Here, we show that chronic unpredictable stress (CUS) for 10 days impaired memory function and increased anxiety in mice. Immunohistochemical staining with SOX2 and KI67 revealed a significant reduction in the number of NSCs in the hippocampus following exposure to CUS. However, these deficits were prevented by NSC-specific, inducible conditional deletion of Atg7. These findings suggest that autophagic death of adult hippocampal NSCs is a critical pathogenic mechanism underlying stress-induced brain disorders.

慢性心理压力是焦虑症、痴呆症和抑郁症等神经系统并发症的关键因素。我们之前的研究结果表明,慢性束缚应激通过诱导成体海马神经干细胞(NSCs)的自噬死亡,导致认知障碍和情绪失调。然而,其他心理应激模型是否也会诱导成年海马神经干细胞自噬性死亡尚不清楚。在这里,我们发现持续10天的慢性不可预知应激(CUS)会损害小鼠的记忆功能并增加焦虑。SOX2和KI67的免疫组化染色显示,暴露于CUS后海马中的NSCs数量显著减少。然而,NSC特异性诱导性条件性缺失Atg7可以防止这些缺陷。这些研究结果表明,成年海马NSCs的自噬死亡是应激诱导的脑部疾病的一个关键致病机制。
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引用次数: 0
Hypothalamic protein profiling from mice subjected to social defeat stress. 社会挫败应激小鼠下丘脑蛋白质图谱分析
IF 3.6 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-05-27 DOI: 10.1186/s13041-024-01096-4
Shiladitya Mitra, Ghantasala S Sameer Kumar, Anumita Samanta, Mathias V Schmidt, Suman S Thakur

The Hypothalmic-Pituitary-Adrenal axis also known as the HPA axis is central to stress response. It also acts as the relay center between the body and the brain. We analysed hypothalamic proteome from mice subjected to chronic social defeat paradigm using iTRAQ based quantitative proteomics to identify changes associated with stress response. We identified greater than 2000 proteins after processing our samples analysed through Q-Exactive (Thermo) and Orbitrap Velos (Thermo) at 5% FDR. Analysis of data procured from the runs showed that the proteins whose levels were affected belonged primarily to mitochondrial and metabolic processes, translation, complement pathway among others. We also found increased levels of fibrinogen, myelin basic protein (MBP) and neurofilaments (NEFL, NEFM, NEFH) in the hypothalamus from socially defeated mice. Interestingly, research indicates that these proteins are upregulated in blood and CSF of subjects exposed to trauma and stress. Since hypothalamus secreted proteins can be found in blood and CSF, their utility as biomarkers in depression holds an impressive probability and should be validated in clinical samples.

下丘脑-垂体-肾上腺轴(又称 HPA 轴)是压力反应的核心。它也是身体和大脑之间的中继中心。我们利用基于 iTRAQ 的定量蛋白质组学分析了长期社会挫败范式下小鼠的下丘脑蛋白质组,以确定与应激反应相关的变化。通过Q-Exactive(Thermo)和Orbitrap Velos(Thermo)在5% FDR条件下对样本进行分析处理后,我们鉴定出了2000多种蛋白质。对运行数据的分析表明,水平受到影响的蛋白质主要属于线粒体和代谢过程、翻译、补体途径等。我们还发现,在社交失败小鼠的下丘脑中,纤维蛋白原、髓鞘碱性蛋白(MBP)和神经丝(NEFL、NEFM、NEFH)的含量也有所增加。有趣的是,研究表明,这些蛋白质在遭受创伤和压力的受试者的血液和脑脊液中上调。由于下丘脑分泌蛋白可在血液和脑脊液中发现,它们作为抑郁症生物标志物的可能性很大,应在临床样本中进行验证。
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引用次数: 0
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Molecular Brain
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