{"title":"Expanding ligand-receptor interaction networks for axon guidance: Structural insights into signal crosstalk and specificity","authors":"Shaotong Zhu , Alexander Jaworski , Rob Meijers","doi":"10.1016/j.conb.2025.102999","DOIUrl":"10.1016/j.conb.2025.102999","url":null,"abstract":"<div><div>Guidance of nascent axons to their targets is mediated by attractive and repulsive cues that activate receptors on the axonal growth cone. The number of ligand-receptor interactions implicated in axon pathfinding is still expanding, and large-scale cell-surface and extracellular protein interactome studies have revealed extensive crosstalk between signaling axes once thought to act independently. This raises the question how the apparent promiscuity of molecular interactions is compatible with specific signaling outcomes and effects on growth cone steering. Structural studies have provided insights into the modularity of binding interactions and shown the capacity of receptors to engage multiple ligands. Here, we review recent findings about the complexity of ligand-receptor interaction networks for axon guidance, and how structures of ligand-receptor complexes reveal mechanisms that may specify signaling output.</div></div>","PeriodicalId":10999,"journal":{"name":"Current Opinion in Neurobiology","volume":"92 ","pages":"Article 102999"},"PeriodicalIF":4.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Vagal sensory circuits of the lower airway in respiratory physiology: Insights from neuronal diversity","authors":"Jie Li, Yin Liu","doi":"10.1016/j.conb.2025.103000","DOIUrl":"10.1016/j.conb.2025.103000","url":null,"abstract":"<div><div>Sensory neurons innervating the lower airway provide essential feedback information that regulates respiratory physiology. These neurons synapse with second-order neurons in the central nervous system, which project directly or indirectly to the respiratory and autonomic centers. Both primary sensory neurons and second-order neurons within these circuits exhibit significant heterogeneity, and the precise roles of individual neuronal subtypes in coding the airway's internal states and modulating respiratory and autonomic outputs remain incompletely understood. In this review, we summarize recent advances in understanding the neuronal diversity along sensory circuits of the lower airway and their physiological functions. We also highlight the challenges in elucidating the roles of specific neuronal subtypes due to the extensive molecular and anatomical diversity among these neurons. Improving targeting specificity for neuronal manipulation, combined with the development of a comprehensive connectivity map, will be critical for revealing the coding and wiring logics that underlie the precise control of respiratory physiology.</div></div>","PeriodicalId":10999,"journal":{"name":"Current Opinion in Neurobiology","volume":"92 ","pages":"Article 103000"},"PeriodicalIF":4.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143636626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Common marmoset: An emerging non-human primate model for translational applications in brain disorders","authors":"Yefei Chen , William Menegas , Qiangge Zhang , Guoping Feng","doi":"10.1016/j.conb.2025.102998","DOIUrl":"10.1016/j.conb.2025.102998","url":null,"abstract":"<div><div>One of the fundamental challenges for modern neuroscience has been to translate discoveries from model organisms into effective therapeutics for human brain disorders. This challenge partly arises from the structural and functional differences between rodent and human brains [1]. To bridge this gap, non-human primates (NHPs) can be used as an intermediate step because of their genetic, physiological, and behavioral similarities to humans. Among NHPs, the common marmoset has become a valuable animal model in neuroscience research due to its fast generation time and unique biological and behavioral characteristics [2]. In this review, we first summarize the progress toward developing models for brain disorders. We then discuss emerging technologies and resources that will help advance our understanding of the neurobiological mechanisms underlying different brain disorders using marmoset genetic models. Finally, we describe using marmoset models to test novel therapeutic approaches such as gene therapy and neural circuit manipulation.</div></div>","PeriodicalId":10999,"journal":{"name":"Current Opinion in Neurobiology","volume":"92 ","pages":"Article 102998"},"PeriodicalIF":4.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Neurodevelopmental impact of CNV models in ASD: Recent advances and future directions","authors":"Kota Tamada, Toru Takumi","doi":"10.1016/j.conb.2025.103001","DOIUrl":"10.1016/j.conb.2025.103001","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication impairments and restricted, repetitive behaviors. ASD exhibits a strong genetic basis, with rare and common genetic variants contributing to its etiology. Copy number variations (CNVs), deletions or duplications of chromosomal segments, have emerged as key contributors to ASD risk. Rare CNVs often demonstrate large effect sizes and can directly cause ASD, while common variants collectively exert subtle influences. Recent advances have identified numerous ASD-associated CNVs, including recurrent loci such as 1q21.1, 2p16.3, 7q11.23, 15q11.2, 15q11-q13, 16p11.2 and 22q11.2. Mouse models carrying these CNVs have provided profound insights into the underlying neurobiological mechanisms. Recent studies integrating transcriptomic, proteomic, and functional imaging approaches have revealed alterations in synaptic function, neuronal differentiation, myelination, metabolic pathways, and circuit connectivity. Notably, investigations leveraging conditional knockout models, high magnetic field MRI, and single-cell analyses highlight disruptions in excitatory-inhibitory balance, white matter integrity, and dynamic gene regulatory networks. Parallel human-based approaches, including iPSC-derived neurons, cerebral organoids, and large-scale single-nucleus sequencing, are combined with animal model data. These integrative strategies promise to refine our understanding of ASD's genetic architecture, bridging the gap between fundamental discoveries in model organisms and clinically relevant biomarkers, subtypes, and therapeutic targets in humans. This review summarizes key findings from recent CNV mouse model studies and highlights emerging technologies applied to human ASD samples. Finally, we outline prospects for translating findings from mouse studies to humans. By illuminating both unique and convergent genetic mechanisms, these advances offer a critical framework for unraveling etiological complexity in ASD.</div></div>","PeriodicalId":10999,"journal":{"name":"Current Opinion in Neurobiology","volume":"92 ","pages":"Article 103001"},"PeriodicalIF":4.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Serotonin signaling at cilia synapses","authors":"Katherine DeLong , Shu-Hsien Sheu","doi":"10.1016/j.conb.2025.102994","DOIUrl":"10.1016/j.conb.2025.102994","url":null,"abstract":"<div><div>Serotonin (5-HT) is a key neuromodulator influencing cognition, mood, and sleep, yet the structural and molecular mechanisms of serotonergic signaling remain incompletely understood. Recent findings have identified a novel mode of serotonergic transmission via axo-ciliary synapses, where serotonergic axons directly contact the primary cilia of hippocampal pyramidal neurons. These synapses facilitate localized 5-HT release, activating ciliary 5-HT6R receptors and triggering intracellular signaling cascades distinct from conventional synaptic mechanisms. This pathway leads to chromatin remodeling and transcriptional regulation, providing a direct link between serotonergic signaling and neuronal gene expression. Additional volume electron microscopy studies have revealed the prevalence of axo-ciliary contacts across different brain regions, suggesting a broad role in neuromodulation. Further investigation into axo-ciliary synapses may provide critical insights into serotonergic function and its implications for neuropsychiatric disorders.</div></div>","PeriodicalId":10999,"journal":{"name":"Current Opinion in Neurobiology","volume":"92 ","pages":"Article 102994"},"PeriodicalIF":4.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Building and modifying diverse synaptic properties: Insights from Drosophila","authors":"Kaikai He, Dion Dickman","doi":"10.1016/j.conb.2025.102995","DOIUrl":"10.1016/j.conb.2025.102995","url":null,"abstract":"<div><div>Neuronal synapses are endowed with tremendous structural, functional, and molecular diversity, honed according to the physiological needs of the circuits in which they are embedded. This diversity, once established in development, can subsequently be further modified by plasticity. It is now widely appreciated that even closely related neurons sharing the same molecular machinery can exhibit remarkable diversity in synaptic structure, function, and plasticity. How such synaptic heterogeneity is achieved is now beginning to be elucidated in a powerful model system, the glutamatergic Drosophila neuromuscular junction (NMJ). In this review, we will first discuss recent discoveries about the structural, functional, and genetic diversity at synapses made by two closely related glutamatergic motor neurons at the Drosophila NMJ, MN-Ib and -Is. Next, we detail how inherent synaptic diversity can be subsequently modified by plasticity in response to altered synaptic growth, excess glutamate release, diminished glutamate receptor functionality, and disease. Together, these insights at the Drosophila NMJ have revealed fundamental principles about how closely related synapses are differentially sculpted in development and remodeled through plasticity to ultimately stabilize neural circuit function.</div></div>","PeriodicalId":10999,"journal":{"name":"Current Opinion in Neurobiology","volume":"92 ","pages":"Article 102995"},"PeriodicalIF":4.8,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cutting-edge methodologies for tagging and tracing active neuronal coding in the brain","authors":"Kenichiro Nagahama , Veronica Hyeyoon Jung , Hyung-Bae Kwon","doi":"10.1016/j.conb.2025.102997","DOIUrl":"10.1016/j.conb.2025.102997","url":null,"abstract":"<div><div>Decoding the neural substrates that underlie learning and behavior is a fundamental goal in neuroscience. Identifying “key players” at the molecular, cellular, and circuit levels has become possible with recent advancements in molecular technologies offering high spatiotemporal resolution. Immediate-early genes are effective markers of neural activity and plasticity, allowing for the identification of active cells involved in memory-based behavior. A calcium-dependent labeling system coupled with light or biochemical proximity labeling allows characterization of active cell ensembles and circuitry across broader brain regions within short time windows, particularly during transient behaviors. The integration of these systems expands the ability to address diverse research questions across behavioral paradigms. This review examines current molecular systems for activity-dependent labeling, highlighting their applications in identifying specific cell ensembles and circuits relevant to various scientific questions and further discuss their significance, along with future directions for the development of innovative methodologies.</div></div>","PeriodicalId":10999,"journal":{"name":"Current Opinion in Neurobiology","volume":"92 ","pages":"Article 102997"},"PeriodicalIF":4.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Diverse synaptic mechanisms underlying learning and memory consolidation","authors":"Yuki Murai , Akihiro Goto","doi":"10.1016/j.conb.2025.102996","DOIUrl":"10.1016/j.conb.2025.102996","url":null,"abstract":"<div><div>Memory consolidation is defined as the process by which labile short-term memories are stabilized and transformed into persistent long-term memories. This process relies heavily on synaptic plasticity, particularly long-term potentiation and depression (LTP and LTD, respectively), which have been extensively investigated in previous studies. The advent of optical tools that allow the observation and manipulation of LTP and LTD <em>in vivo</em> has advanced our understanding of their roles in learning and memory consolidation. In addition to LTP and LTD, recent research has indicated the presence of a more rapid plasticity mechanism, termed behavioral timescale synaptic plasticity (BTSP), which is crucial for encoding space and context. Sharp-wave ripples and sleep also play indispensable roles in memory consolidation, with some studies alternately linking them to LTP and LTD. At the systems level, sharp-wave ripples and sleep contribute to the transmission of information to broader brain areas, as well as the modification of synaptic strength in cortical areas for the long-term storage of memory. Furthermore, recent findings have highlighted the role of non-neuronal cells in learning, as they modulate synaptic plasticity in various ways.</div></div>","PeriodicalId":10999,"journal":{"name":"Current Opinion in Neurobiology","volume":"92 ","pages":"Article 102996"},"PeriodicalIF":4.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143551714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Comparative approaches to the neurobiology of avian vocal learning","authors":"Zhilei Zhao, Jesse H. Goldberg","doi":"10.1016/j.conb.2025.102993","DOIUrl":"10.1016/j.conb.2025.102993","url":null,"abstract":"<div><div>Birdsong provides an opportunity to study sensorimotor learning in the context of brain evolution. Despite the vast diversity in song behavior across species, mechanistic understanding of birdsong comes primarily from the zebra finch, a closed-ended songbird that learns one simple and stereotyped song, which it keeps singing throughout adulthood. It remains unclear if neural mechanisms of finch song production and learning generalize with other species, including open-ended learners with more complex and variable vocalizations. Here we review finch communication alongside both closely and distantly related avian species. We propose that comparing songbirds and parrots, sister clades that diverged over 50 million years ago and those that exhibit both similarities and differences in behavior and neural circuits, will be particularly useful in distinguishing general principles from neural solutions to species-specific needs.</div></div>","PeriodicalId":10999,"journal":{"name":"Current Opinion in Neurobiology","volume":"92 ","pages":"Article 102993"},"PeriodicalIF":4.8,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143551715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joseph D. Dougherty , Simona Sarafinovska , Sneha M. Chaturvedi , Travis E. Law , Titilope M. Akinwe , Harrison W. Gabel
{"title":"Single-cell technology grows up: Leveraging high-resolution omics approaches to understand neurodevelopmental disorders","authors":"Joseph D. Dougherty , Simona Sarafinovska , Sneha M. Chaturvedi , Travis E. Law , Titilope M. Akinwe , Harrison W. Gabel","doi":"10.1016/j.conb.2025.102990","DOIUrl":"10.1016/j.conb.2025.102990","url":null,"abstract":"<div><div>The identification of hundreds of neurodevelopmental disorder (NDD) genes in the last decade led to numerous genetic models for understanding NDD gene mutation consequences and delineating putative neurobiological mediators of disease. In parallel, single-cell and single-nucleus genomic technologies have been developed and implemented to create high-resolution atlases of cell composition, gene expression, and circuit connectivity in the brain. Here, we discuss the opportunities to leverage mutant models (or human tissue, where available) and genomics approaches to systematically define NDD etiology at cellular resolution. We review progress in applying single-cell and spatial transcriptomics to interrogate developmental trajectories, cellular composition, circuit activity, and connectivity across human tissue and NDD models. We discuss considerations for implementing these approaches at scale to maximize insights and facilitate reproducibility. Finally, we highlight how standardized application of these technologies promises to not only define etiologies of individual disorders but also identify molecular, cellular, and circuit level convergence across NDDs.</div></div>","PeriodicalId":10999,"journal":{"name":"Current Opinion in Neurobiology","volume":"92 ","pages":"Article 102990"},"PeriodicalIF":4.8,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143551713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}