Current Opinion in Neurobiology最新文献

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Release your inhibitions: The cell biology of GABAergic postsynaptic plasticity 释放你的抑制：gaba能突触后可塑性的细胞生物学。

IF 4.8 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-02-01 DOI: 10.1016/j.conb.2024.102952

Theresa M. Welle, Katharine R. Smith

GABAergic synaptic inhibition controls circuit function by regulating neuronal plasticity, excitability, and firing. To achieve these goals, inhibitory synapses themselves undergo several forms of plasticity via diverse mechanisms, strengthening and weakening phasic inhibition in response to numerous activity-induced stimuli. These mechanisms include changing the number and arrangement of functional GABA_ARs within the inhibitory postsynaptic domain (iPSD), which can profoundly regulate inhibitory synapse strength. Here, we explore recent advances in our molecular understanding of inhibitory postsynaptic plasticity, with a focus on modulation of the trafficking, protein–protein interactions, nanoscale-organization, and posttranscriptional regulation of GABA_ARs and iPSD proteins. What has emerged is a complex mechanistic picture of how synaptic inhibition is controlled, with critical ramifications for cognition under typical and pathogenic conditions.

gaba能突触抑制通过调节神经元可塑性、兴奋性和放电来控制回路功能。为了实现这些目标，抑制性突触本身通过不同的机制经历了几种形式的可塑性，在响应众多活动诱导的刺激时加强和减弱相抑制。这些机制包括改变抑制性突触后结构域（iPSD）内功能性GABAARs的数量和排列，从而深刻调节抑制性突触的强度。在这里，我们探讨了抑制性突触后可塑性的分子理解的最新进展，重点关注GABAARs和iPSD蛋白的运输调节、蛋白-蛋白相互作用、纳米级组织和转录后调控。已经出现的是突触抑制如何被控制的复杂机制图景，在典型和致病条件下对认知具有关键影响。

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Excitatory/Inhibitory imbalance as a mechanism linking autism and sleep problems 兴奋性/抑制性失衡是自闭症和睡眠问题之间的联系机制。

IF 4.8 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-02-01 DOI: 10.1016/j.conb.2024.102968

Michelle C.D. Bridi , Lucia Peixoto

Sleep problems occur more frequently in individuals with autism spectrum disorder (ASD) than in typically developing individuals, and recent studies support a genetic link between ASD and sleep disturbances. However, it remains unclear how sleep problems may be mechanistically connected to ASD phenotypes. A longstanding hypothesis posits that an imbalance between excitatory and inhibitory (E/I) signaling in the brain underlies the behavioral characteristics of ASD. In recent years, emerging evidence has shown that regulation of the E/I ratio is coupled to sleep/wake states in wild-type animal models. In this review, we will explore the idea of altered E/I regulation over the sleep/wake cycle as a mechanism bridging sleep disruption and behavioral phenotypes in ASD.

与正常发育的个体相比，自闭症谱系障碍（ASD）患者出现睡眠问题的频率更高，最近的研究支持自闭症谱系障碍和睡眠障碍之间存在遗传联系。然而，睡眠问题与ASD表型之间的机制联系尚不清楚。一个长期存在的假设认为，大脑中兴奋性和抑制性（E/I）信号之间的不平衡是ASD行为特征的基础。近年来，新出现的证据表明，在野生型动物模型中，E/I比率的调节与睡眠/清醒状态有关。在这篇综述中，我们将探讨在睡眠/觉醒周期中改变的E/I调节作为ASD中连接睡眠中断和行为表型的机制。

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The promise of cyclic AMP modulation to restore cognitive function in neurodevelopmental disorders 循环AMP调节恢复神经发育障碍患者认知功能的前景。

IF 4.8 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-02-01 DOI: 10.1016/j.conb.2024.102966

Aniket Bhattacharya , Luka Turkalj , M. Chiara Manzini

Cyclic AMP (cAMP) is a key regulator of synaptic function and is dysregulated in both neurodevelopmental (NDD) and neurodegenerative disorders. Due to the ease of diffusion and promiscuity of downstream effectors, cAMP signaling is restricted within spatiotemporal domains to localize activation. Among the best-studied mechanisms is the feedback inhibition of cAMP-dependent protein kinase (PKA) activity by phosphodiesterases 4 (PDE4s) at synapses controlling neuronal plasticity, which is largely regulated by PDE4D. In fact, genetic variants in genes for multiple PKA subunits and PDE4D lead to NDDs. Here, we discuss the rationale for choosing PDE4D as a candidate for the design of selective allosteric inhibitors and the recent advances in clinical trials. These new compounds improve cognitive function in preclinical animal models due to improved selectivity and more physiological inhibition of the active enzyme. We also discuss opportunities for better understanding of PDE4D function in general, and for the development of next-generation inhibitors.

环AMP （cAMP）是突触功能的关键调节因子，在神经发育（NDD）和神经退行性疾病中都存在失调。由于下游效应物易于扩散和混杂，cAMP信号被限制在时空域中以局部激活。其中研究最多的机制是磷酸二酯酶4 （PDE4s）在控制神经元可塑性的突触上对camp依赖性蛋白激酶（PKA）活性的反馈抑制，这在很大程度上是由PDE4D调节的。事实上，多个PKA亚基和PDE4D基因的遗传变异会导致ndd。在这里，我们讨论了选择PDE4D作为设计选择性变构抑制剂的基本原理以及临床试验的最新进展。这些新化合物在临床前动物模型中由于提高了选择性和更多的生理抑制活性酶而改善了认知功能。我们还讨论了更好地了解PDE4D功能的机会，以及开发下一代抑制剂的机会。

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Revisiting the genetic architecture of autism spectrum disorders in the genomic era: Insights from East Asian studies 在基因组时代重新审视自闭症谱系障碍的遗传结构：来自东亚研究的见解

IF 4.8 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2024-11-30 DOI: 10.1016/j.conb.2024.102936

Zilong Qiu, Ailian Du

This review delves into the genetic landscape of Autism Spectrum Disorder (ASD) in the genomic era, with a special focus on insights from East Asian populations. We analyze a spectrum of genetic research, including whole-exome and whole-genome sequencing, to elucidate both the challenges and advancements in comprehending the genetic foundations of ASD. Critical findings from this review highlight the identification of de novo variants, particularly noting the significant role of rare variants that differ from the common variants identified in earlier research. The review emphasizes the importance of large, diverse, and meticulously maintained ASD cohorts, which are essential for advancing genetic studies and developing potential therapeutic interventions. Through collaborative international efforts, we argue for a global perspective necessary to grasp the intricate genetic factors underlying ASD.

这篇综述深入研究了基因组时代自闭症谱系障碍（ASD）的遗传景观，特别关注东亚人群的见解。我们分析了一系列遗传学研究，包括全外显子组和全基因组测序，以阐明理解ASD遗传基础的挑战和进展。这篇综述的关键发现强调了新生变异的识别，特别指出了与早期研究中发现的常见变异不同的罕见变异的重要作用。该综述强调了大规模、多样化和精心维护的ASD队列的重要性，这对于推进遗传研究和开发潜在的治疗干预措施至关重要。通过国际合作，我们认为有必要从全球的角度来把握ASD背后复杂的遗传因素。

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Editorial overview: Addiction 编辑概述：成瘾

IF 4.8 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2024-11-28 DOI: 10.1016/j.conb.2024.102933

Mariella De Biasi, Gavan McNally

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Construction destruction: Contribution of dyregulated proteostasis to neurodevelopmental disorders 结构破坏：蛋白质平衡失调对神经发育障碍的贡献

IF 4.8 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2024-11-28 DOI: 10.1016/j.conb.2024.102934

Kellen D. Winden, Juan F. Ruiz, Mustafa Sahin

Genetic causes of neurodevelopmental disorders (NDDs) such as epilepsy and autism spectrum disorder are rapidly being uncovered. The genetic risk factors that are responsible for various NDDs fall into many categories, and while some genes such as those involved in synaptic transmission are expected, there are several other classes of genes whose involvement in these disorders is not intuitive. One such group of genes is involved in protein synthesis and degradation, and the balance between these opposing pathways is termed proteostasis. Here, we review these pathways, the genetics of the related neurological disorders, and some potential disease mechanisms. Improved understanding of this collection of genetic disorders will be informative for the pathogenesis of these disorders and imply novel therapeutic strategies.

神经发育障碍（ndd）如癫痫和自闭症谱系障碍的遗传原因正在迅速被发现。导致各种ndd的遗传风险因素分为许多类别，虽然一些基因（如参与突触传递的基因）是可以预料的，但还有其他几类基因与这些疾病的关系并不直观。其中一组基因参与蛋白质合成和降解，这些相反途径之间的平衡被称为蛋白质平衡。在这里，我们回顾这些途径，相关神经系统疾病的遗传学，以及一些潜在的疾病机制。提高对这些遗传疾病的理解将有助于了解这些疾病的发病机制，并暗示新的治疗策略。

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Impacts of adverse childhood experiences on individuals with autism spectrum disorder 童年不良经历对自闭症谱系障碍患者的影响

IF 4.8 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2024-11-06 DOI: 10.1016/j.conb.2024.102932

Tsutomu Takeda , Manabu Makinodan , Michihiro Toritsuka , Nakao Iwata

Individuals with autism spectrum disorder (ASD) are more likely to experience adverse childhood experiences (ACEs) compared with typically developing (TD) individuals, which predisposes them to an elevated risk of mental health issues. This review elucidates the profound impact of ACEs on individuals with ASD by synthesizing findings from a plethora of epidemiologic and biological studies, encompassing genetics, epigenetics, and neuroimaging. Despite the limited number of studies explicitly focusing on this intersection, the extant literature consistently demonstrates that ASD individuals are disproportionately affected by ACEs, leading to significant deterioration in mental health and brain function. Furthermore, the nature and extent of the effects of ACEs appear to diverge between ASD and TD populations, underscoring the necessity for tailored clinical and research approaches. Understanding these complex and intertwined interactions is imperative for advancing both clinical practice and research, with the goal of mitigating the adverse outcomes associated with ACEs in ASD individuals.

自闭症谱系障碍（ASD）患者与发育正常（TD）的患者相比，更有可能经历不良童年经历（ACE），这使他们出现心理健康问题的风险增加。本综述综合了大量流行病学和生物学研究的结果，包括遗传学、表观遗传学和神经影像学研究，阐明了 ACE 对 ASD 患者的深远影响。尽管明确关注这一交叉点的研究数量有限，但现有文献一致表明，ASD 患者受到 ACE 的影响尤为严重，导致心理健康和大脑功能显著恶化。此外，ACE 影响的性质和程度在 ASD 和 TD 群体中似乎也不尽相同，这突出表明有必要采用量身定制的临床和研究方法。了解这些复杂而又相互交织的相互作用对于推进临床实践和研究都是势在必行的，其目标是减轻与 ASD 患者 ACE 相关的不良后果。

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On the targeting of voltage-gated calcium channels to neurotransmitter release sites 电压门控钙通道在神经递质释放点的定位

IF 4.8 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2024-11-04 DOI: 10.1016/j.conb.2024.102931

Morven Chin, Pascal S. Kaeser

At the presynaptic active zone, voltage-gated Ca²⁺ channels (Ca_Vs) mediate Ca²⁺ entry for neurotransmitter release. Ca_Vs are a large family of proteins, and different subtypes have distinct localizations across neuronal somata, dendrites and axons. Here, we review how neurons establish and maintain a specific Ca_V repertoire at their active zones. We focus on molecular determinants for cargo assembly, presynaptic delivery and release site tethering, and we discuss recent work that has identified key roles of the Ca_V intracellular C-terminus. Finally, we evaluate how these mechanisms may differ between different types of neurons. Work on Ca_Vs provides insight into the protein targeting pathways that help maintain neuronal polarity.

在突触前活动区，电压门控 Ca2+ 通道（CaVs）介导 Ca2+ 进入神经递质释放。CaVs 是一个庞大的蛋白质家族，不同的亚型在神经元体细胞、树突和轴突上有不同的定位。在此，我们回顾了神经元如何在其活动区建立并维持特定的 CaV 复合物。我们将重点放在货物组装、突触前递送和释放位点系留的分子决定因素上，并讨论了最近确定 CaV 细胞内 C 端关键作用的工作。最后，我们评估了这些机制在不同类型的神经元之间可能存在的差异。有关 CaVs 的研究有助于深入了解有助于维持神经元极性的蛋白质靶向途径。

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Ferret contributions to the business of sensory neurobiology 雪貂对感觉神经生物学事业的贡献。

IF 4.8 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2024-11-01 DOI: 10.1016/j.conb.2024.102929

Rebecca H.C. Norris, Jennifer K. Bizley

In this brief review, we will highlight the ferret Mustela putorius furo as an increasingly utilized animal model for sensory systems and cognitive neuroscience research. In particular, the human like hearing range of the ferret, coupled with their amenability to training, make them an especially useful model for auditory and multisensory neuroscience. These factors, combined with the increasing availability of virally mediated circuit dissection methods, mean they occupy a unique niche as a versatile and valuable research model.

在这篇简短的综述中，我们将重点介绍白鼬（Mustela putorius furo）这一在感觉系统和认知神经科学研究中越来越常用的动物模型。特别是，雪貂的听力范围与人类相近，而且易于训练，这使它们成为听觉和多感官神经科学的一个特别有用的模型。这些因素，再加上病毒介导的电路解剖方法的日益普及，意味着雪貂作为一种多用途、有价值的研究模型占据了独特的地位。

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When the society dictates food search – Neural signalling underlying appetitive motivation in honey bees 当社会决定食物搜寻--蜜蜂食欲动机的神经信号基础

IF 4.8 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2024-10-28 DOI: 10.1016/j.conb.2024.102930

Rafael Carvalho da Silva , Louise Bestea , Gabriela de Brito Sanchez , Martin Giurfa

In honey bees, appetitive motivation is primarily driven by the needs of the colony rather than individual needs. The regulation of appetitive behavior is achieved through the coordinated action of neuropeptides, hormones and biogenic amines, which integrate multiple signals to ensure appropriate appetitive responses. Dopamine signalling underpins a food-related wanting system that is sensitive to aversive experiences. The short neuropeptide F (sNPF) enhances appetitive responsiveness, food intake and behavioral and neural responsiveness to food-related odorants. Additionally, it facilitates appetitive learning and memory. On the contrary, tachykinin-related peptides (TRPs) inhibit appetitive responses. Physiological changes during the transition to the foraging state lead to distinct patterns of insulin and adipokinetic hormone (AKH) signaling, different from those seen in solitary insects, indicating that social life had significant consequences on the systems controlling appetitive motivation. Overall, studying the neural bases of appetitive behavior in bees reveals unique aspects that arise from their social lifestyle.

蜜蜂的食欲动机主要受蜂群需求而非个体需求的驱动。食欲行为的调节是通过神经肽、激素和生物胺的协调作用来实现的，它们整合了多种信号，以确保适当的食欲反应。多巴胺信号是与食物有关的欲望系统的基础，该系统对厌恶体验很敏感。短神经肽 F（sNPF）能增强食欲反应、食物摄入量以及对食物相关气味的行为和神经反应。此外，它还能促进食欲学习和记忆。相反，速激肽（TRPs）会抑制食欲反应。在过渡到觅食状态期间，生理变化导致了胰岛素和促脂肪激素（AKH）信号的独特模式，这与在独居昆虫中看到的模式不同，表明社会生活对控制食欲动机的系统有重大影响。总之，对蜜蜂食欲行为神经基础的研究揭示了其社会生活方式所产生的独特方面。

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