Current Opinion in Neurobiology最新文献

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The genetics of autosomal recessive early-onset Parkinson's disease 常染色体隐性早发性帕金森病的遗传学研究。

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-11-17 DOI: 10.1016/j.conb.2025.103141

Guillaume Cogan, Suzanne Lesage, Alexis Brice

Early-onset Parkinson's disease (EOPD) is usually defined as Parkinson's disease (PD) occurring before the age of 40–50 years. Unlike late-onset PD, EOPD is often due to pathogenic mutations in autosomal recessive genes. Two phenotypes can be distinguished: typical EOPD, which progresses slowly (PRKN, PINK1 and DJ-1), and atypical PD, often associated with additional symptoms (ATP13A2, FBXO7, DNAJC6, VPS13C, SYNJ1, PLA2G6). In this review, we will highlight recent advances and remaining challenges. The frequency of causal genetic mutations and the genotype-phenotype landscape of PRKN-associated PD has been refined. Long-read sequencing has solved several undiagnosed cases with a single PRKN mutation. Five new genes have been reported to contribute to EOPD associated with various neurological signs (PTPA, DAGLB, PSMF1, EPG5, SGIP1). Small molecules targeting PRKN dysfunctions are expected to enter clinical trials in the coming years, paving the way for targeted therapies in EOPD.

早发性帕金森病（EOPD）通常被定义为40-50岁之前发生的帕金森病（PD）。与迟发性帕金森病不同，EOPD通常是由常染色体隐性基因的致病突变引起的。可以区分两种表型：典型的EOPD，其进展缓慢（PRKN、PINK1和DJ-1），以及非典型PD，通常伴有其他症状（ATP13A2、FBXO7、DNAJC6、VPS13C、SYNJ1、PLA2G6）。在这篇综述中，我们将强调最近的进展和仍然存在的挑战。因果基因突变的频率和prkn相关PD的基因型-表型景观已被完善。长读测序已经解决了几个未确诊的单一PRKN突变病例。据报道，有5个新基因与EOPD相关，并伴有各种神经症状（PTPA、DAGLB、PSMF1、EPG5、SGIP1）。靶向PRKN功能障碍的小分子有望在未来几年进入临床试验，为EOPD的靶向治疗铺平道路。

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Corrigendum to “Single vesicle tracking for studying synaptic vesicle dynamics in small central synapses” [Curr Opin Neurobiol (76) (2022) 102596] “单个囊泡跟踪用于研究小中枢突触的突触囊泡动力学”的勘误表[当代神经生物学杂志（76）（2022）102596]。

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-11-17 DOI: 10.1016/j.conb.2025.103142

Chungwon Park , Sangyong Jung , Hyokeun Park

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Protein mechanism and therapeutic design in Parkinson's disease: A structural biology perspective 帕金森病的蛋白质机制和治疗设计：结构生物学视角。

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-11-16 DOI: 10.1016/j.conb.2025.103140

Danielle M. Simons , Jean-François Trempe

Parkinson's disease (PD) remains one of the most elusive, progressive neurological diseases to treat due to an incomplete understanding of its pathology. Current symptomatic therapies revolve around alleviating symptoms with dopamine replacement therapy; however, this mode of treatment does not always provide long-term relief or address the underlying cause. Thus, there is still a need to better understand the mechanisms of proteins implicated in neurodegeneration as the key to developing disease-modifying treatments. Here we discuss recent advances in our understanding of six protein targets for PD therapy: α-synuclein, LRRK2, GBA1, PARKIN, PINK1, and USP30. For each, we highlight novel structures that shine light both on pathogenic mechanisms as well as novel therapies. We discuss drugs targeting these proteins that are in clinical trials, and how structures are used to improve them.

帕金森氏病（PD）仍然是一个最难以捉摸的，进行性神经系统疾病治疗由于不完全了解其病理。目前的对症治疗围绕着用多巴胺替代疗法缓解症状；然而，这种治疗方式并不总是提供长期的缓解或解决根本原因。因此，仍有必要更好地了解与神经退行性变有关的蛋白质的机制，这是开发改善疾病治疗的关键。在这里，我们讨论了最近我们对PD治疗的六个蛋白靶点的理解进展：α-突触核蛋白，LRRK2, GBA1， PARKIN， PINK1和USP30。对于每一种，我们都强调了新的结构，这些结构既照亮了致病机制，也照亮了新的治疗方法。我们将讨论临床试验中针对这些蛋白质的药物，以及如何使用结构来改善它们。

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Setting the stage for statistical learning? Sensitivity to environmental statistics in early sensory processing 为统计学学习搭建舞台？早期感觉加工中对环境统计的敏感性。

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-11-15 DOI: 10.1016/j.conb.2025.103139

Miguel Maravall , Livia de Hoz

Our brains make sense of the world on a moment-by-moment basis despite its enormous complexity, largely because its overall statistical structure can be detected, learned, and generalized across experiences. Exposure to specific regularities (e.g., in speech) results in an unsupervised, incidental, form of learning, commonly known as statistical learning (SL). SL is well-established from a cognitive perspective and often assumed to require high-level cortical or hippocampal processing. However, accumulating evidence suggests that SL emerges much earlier in ascending sensory pathways. Despite this, our understanding of the forms it might take in subcortical sensory centres is relatively limited. Here, we review neuronal sensitivity to statistics in early sensory regions and ask how this sensitivity relates to SL. We feature examples of adaptive responses elicited by stimulus repetitions, omissions, changes in stimulus distribution, and more complex patterning, highlighting the interplay between adaptive coding and SL as manifestations of sensitivity to environmental statistics.

我们的大脑在每时每刻的基础上理解世界，尽管它非常复杂，很大程度上是因为它的整体统计结构可以通过经验被检测、学习和概括。暴露于特定的规律（例如，在讲话中）会导致一种无监督的、偶然的学习形式，通常被称为统计学习（SL）。从认知的角度来看，SL是公认的，通常认为它需要高水平的皮层或海马处理。然而，越来越多的证据表明，SL在上升感觉通路中出现得更早。尽管如此，我们对它在皮层下感觉中心可能采取的形式的理解相对有限。在这里，我们回顾了早期感觉区域的神经元对统计数据的敏感性，并询问这种敏感性与SL之间的关系。我们以刺激重复、省略、刺激分布变化和更复杂的模式引起的适应性反应为例，强调了适应性编码和SL之间的相互作用，作为对环境统计敏感性的表现。

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From neurons to novelty: Circuit mechanisms shaping courtship evolution 从神经元到新奇：形成求爱进化的电路机制

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-11-15 DOI: 10.1016/j.conb.2025.103137

Philipp Brand , Rory T. Coleman

The vast diversity of animal behaviors has long inspired ethologists and neuroscientists, but circuit mechanisms driving this variation remain elusive. Recent advances in genetic tools and comparative approaches have enabled unprecedented insights into how neural circuits evolve to produce behavioral novelty. Here we focus on the discoveries emerging from the study of courtship behaviors, which are particularly well poised to capitalize on these advances. Comparative studies of sensory and motor circuits have begun to demonstrate that evolution can act through diverse mechanisms. The modular organization of courtship-controlling circuits emerges as a key feature facilitating rapid evolutionary innovation while maintaining essential functions. Changes in the neuronal composition of circuits, by both cellular and subcellular mechanisms, represent common mechanisms. Organisms may even carry vestigial circuits with the latent potential to be repurposed for new behavioral paradigms. We highlight how understanding the ‘extended nervous system’ of a species has begun to provide these critical insights into courtship evolution and offers fertile ground for future discoveries. As comparative approaches expand beyond model organisms, evolutionary neuroscience is on the cusp of revealing the principles governing behavioral diversity in nature.

动物行为的巨大多样性长期以来一直激励着行为学家和神经科学家，但驱动这种变化的电路机制仍然难以捉摸。遗传工具和比较方法的最新进展使我们能够前所未有地深入了解神经回路是如何进化产生新奇行为的。在这里，我们将重点关注从求偶行为研究中出现的发现，这些发现特别适合利用这些进步。对感觉回路和运动回路的比较研究已经开始表明，进化可以通过多种机制起作用。求爱控制电路的模块化组织成为促进快速进化创新的关键特征，同时保持基本功能。通过细胞和亚细胞机制，神经元回路组成的变化代表了共同的机制。生物体甚至可能携带有潜在潜力的退化回路，以重新利用新的行为范式。我们强调如何理解一个物种的“扩展神经系统”已经开始为求爱进化提供这些关键的见解，并为未来的发现提供肥沃的土壤。随着比较方法扩展到模式生物之外，进化神经科学正处于揭示自然界行为多样性支配原则的尖端。

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Recent advances in model systems for interrogating diseases of brain aging and associated dementia: Toward human-relevant endophenotypes 脑老化疾病和相关痴呆模型系统的最新进展：向人类相关的内表型发展

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-11-13 DOI: 10.1016/j.conb.2025.103138

Stacey J. Sukoff Rizzo

Neurodegenerative diseases are characterized by key pathological hallmarks, progressive loss of neuronal structure and function, and synaptic loss. Often, mild behavioral changes including subjective cognitive decline and neuropsychiatric symptoms precede the diagnosis and may be a harbinger of disease inception and progression. Despite the success of new treatments that attenuate pathological burden, the ability to translate clinical benefit for cognitive impairment and dementia-related behavioral syndromes remains challenging. While model systems are essential, the appropriate model must be carefully chosen for the specific research question, with complementary model systems necessary to capture multiple aspects of disease. This review will cover the emergence of model systems that provide more translationally relevant trajectories of the progression of pathological changes throughout brain aging, and the advancement of model systems that are able to better capture the spectrum of behavioral and cognitive changes that signal the early prodromal period prior to diagnosis.

神经退行性疾病的特点是关键的病理标志，神经元结构和功能的进行性丧失，以及突触的丧失。通常，轻微的行为改变，包括主观认知能力下降和神经精神症状在诊断之前，可能是疾病开始和进展的先兆。尽管减轻病理负担的新疗法取得了成功，但将临床效益转化为认知障碍和痴呆相关行为综合征的能力仍然具有挑战性。虽然模型系统是必不可少的，但必须为具体的研究问题仔细选择适当的模型，并需要补充模型系统来捕捉疾病的多个方面。本综述将涵盖模型系统的出现，这些模型系统提供了整个大脑衰老过程中病理变化进展的更多翻译相关轨迹，以及能够更好地捕捉诊断前早期前驱期信号的行为和认知变化谱的模型系统的进展。

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Corrigendum to “Mathematical models of learning and what can be learned from them” [Curr Opin Neurobiol 80 (2023)] “学习的数学模型以及从中可以学到什么”的更正[Curr Opin Neurobiol 80 (2023)]

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-11-07 DOI: 10.1016/j.conb.2025.103135

Omri Barak , Misha Tsodyks

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Unique and divergent features of human brain development 人类大脑发育的独特和不同特征。

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-11-03 DOI: 10.1016/j.conb.2025.103133

Iva Salamon , Daniel Z. Doyle , Rachel C. Bandler , Kartik Pattabiraman , Nenad Sestan

The human experience is shaped by evolutionary adjustments that have endowed the human brain with advanced cognitive, physiological, and morphological adaptations, surpassing those of other anthropoid primates. Although comparative mammalian studies have provided valuable insights into our evolutionary history, identifying genomic variations underpinning uniquely human phenotypic traits remains challenging. Integration of multiomic modalities with noninvasive brain imaging allows evolutionary hypotheses to be tested in previously intractable ways. This convergence marks a new era, integral to deepening our understanding of what novel and conserved features steer human brain development. In this review, we highlight multimodal efforts to study human brain evolution. We argue that efforts to connect primate and human genotype-to-phenotype relationships will accelerate over the coming years but require careful interpretation when evaluating claims of human uniqueness. Finally, we underscore the importance of continued identification of conserved aspects of brain development and the use of rigorous study designs when evaluating proposed ‘human-specific’ features.

人类的经历是由进化调整塑造的，这种调整赋予了人类大脑先进的认知、生理和形态适应能力，超过了其他类人猿灵长类动物。虽然比较哺乳动物研究为我们的进化史提供了有价值的见解，但确定支撑人类独特表型特征的基因组变异仍然具有挑战性。将多组学模式与非侵入性脑成像相结合，可以用以前难以处理的方法来检验进化假说。这种融合标志着一个新时代的到来，对于加深我们对哪些新颖和保守的特征引导人类大脑发育的理解是不可或缺的。在这篇综述中，我们重点介绍了研究人类大脑进化的多模式努力。我们认为，将灵长类动物和人类基因型-表型关系联系起来的努力将在未来几年加速，但在评估人类独特性的主张时需要仔细解释。最后，我们强调了在评估提出的“人类特异性”特征时，继续识别大脑发育的保守方面和使用严格的研究设计的重要性。

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Sexually dimorphic processing of pheromonal information in mice 小鼠信息素信息的两性二态处理。

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-11-01 DOI: 10.1016/j.conb.2025.103134

Takumi Itakura , Ken Murata , Kazushige Touhara

Animals exhibit appropriate social behaviors and physiological responses based on the opponent's sex. Mammals secrete sex-specific chemical cues, some of which act as pheromones and play crucial roles. Sex-specific pheromones are received by a largely sexually monomorphic detection system in the vomeronasal organ. Small populations of sensory neurons encode conspecific sex via sex-selective receptors, while complex traits are encoded by combinatorial neuronal activity. These signals are processed by sexually dimorphic dedicated neural circuits in the brain. Neural activity recording in these brain regions has revealed distributed neural encoding of sex and internal brain states associated with aggression and mating. Sex hormones play critical roles in establishing, remodeling, and modulating these systems across multiple levels, enabling adaptive responses. Emerging evidence in mice sheds light on how pheromonal information is transformed into the neural representation of sex and internal state through adaptive modulatory mechanisms, ultimately triggering appropriate sex-specific responses.

动物根据对手的性别表现出适当的社会行为和生理反应。哺乳动物分泌性别特异性的化学线索，其中一些作为信息素起着至关重要的作用。性别性别的信息素是由犁鼻器官中一个很大程度上的性单态检测系统接收的。小群体的感觉神经元通过性别选择受体编码同种性，而复杂的特征是通过组合神经元活动编码的。这些信号由大脑中两性二态的专用神经回路处理。这些大脑区域的神经活动记录揭示了与攻击和交配有关的性别和大脑内部状态的分布式神经编码。性激素在多个层面上建立、重塑和调节这些系统，实现适应性反应中起着至关重要的作用。在小鼠身上出现的新证据揭示了信息素信息如何通过适应性调节机制转化为性别和内部状态的神经表征，最终引发适当的性别特异性反应。

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Towards the establishment of treatments for neurodegenerative diseases using human iPSCs 利用人类多能干细胞建立神经退行性疾病的治疗方法

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-10-30 DOI: 10.1016/j.conb.2025.103132

Haruhisa Inoue

Since their discovery and development, human induced pluripotent stem cells (iPSCs) have brought about notable advances in biomedical science and have become an essential infrastructure for medical research and applications. This review discusses the current status of iPSC-based cell therapies, drug discovery, and therapeutic developments for neurodegenerative diseases with unmet medical needs. It also highlights research approaches employing cohorts of iPSCs derived from sporadic neurodegenerative diseases to advance prevention and diagnostic support. It further considers future directions for the use of iPSCs in the treatment of neurodegenerative disorders.

人类诱导多能干细胞（iPSCs）自发现和发展以来，在生物医学科学方面取得了显著进展，并已成为医学研究和应用的重要基础设施。本文综述了基于ipsc的细胞疗法的现状，药物发现，以及未满足医疗需求的神经退行性疾病的治疗进展。它还强调了利用来自散发性神经退行性疾病的iPSCs队列来推进预防和诊断支持的研究方法。它进一步考虑了在神经退行性疾病治疗中使用iPSCs的未来方向。

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