Pub Date : 2025-12-23DOI: 10.1016/j.conb.2025.103151
Xia-Jing Tong , Fei Wang , Xiaohong Xu
In sexually reproducing animals, males and females are biologically specialized to produce sperm or eggs, which must unite through mating to ensure successful reproduction. To facilitate this, each sex displays sex-specific, often stereotyped, mating behaviors orchestrated by neural circuits that undergo sexual differentiation during development. Extensive anatomical mapping and functional dissection in genetically tractable model organisms, including Caenorhabditis elegans, Drosophila melanogaster, and Mus musculus, have revealed many sexually dimorphic neuronal populations and neural circuits. While previous reviews have offered broad cross-species comparisons of such sex differences in the nervous system [1,2], here we take a more focused approach. We specifically examine the neural substrates underlying mating behaviors across these three species, aiming to highlight shared principles in circuit architecture and to advance the emerging concept of connectome sex.
{"title":"Sexually dimorphic neural circuits underlying mating behaviors: Insights from worms, flies, and mice","authors":"Xia-Jing Tong , Fei Wang , Xiaohong Xu","doi":"10.1016/j.conb.2025.103151","DOIUrl":"10.1016/j.conb.2025.103151","url":null,"abstract":"<div><div>In sexually reproducing animals, males and females are biologically specialized to produce sperm or eggs, which must unite through mating to ensure successful reproduction. To facilitate this, each sex displays sex-specific, often stereotyped, mating behaviors orchestrated by neural circuits that undergo sexual differentiation during development. Extensive anatomical mapping and functional dissection in genetically tractable model organisms, including <em>Caenorhabditis elegans</em>, <em>Drosophila melanogaster</em>, and <em>Mus musculus</em>, have revealed many sexually dimorphic neuronal populations and neural circuits. While previous reviews have offered broad cross-species comparisons of such sex differences in the nervous system [<span><span>1</span></span>,<span><span>2</span></span>], here we take a more focused approach. We specifically examine the neural substrates underlying mating behaviors across these three species, aiming to highlight shared principles in circuit architecture and to advance the emerging concept of <em>connectome sex</em>.</div></div>","PeriodicalId":10999,"journal":{"name":"Current Opinion in Neurobiology","volume":"96 ","pages":"Article 103151"},"PeriodicalIF":5.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827132","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}
Pub Date : 2025-12-20DOI: 10.1016/j.conb.2025.103159
Nolwenn Adam, Jessica Tollkuhn
Social behaviors are crucial for reproductive success and survival. In vertebrates, these behaviors are sexually dimorphic due to distinct hormonal environments in development and adulthood. The underlying neural pathways, collectively known as the social behavior network (SBN), consist of interconnected regions exhibiting sex-variable genomic, anatomical, and functional characteristics. While the structure and function of the adult SBN is increasingly well described, its embryonic origins and development remain poorly understood. All neural networks undergo extensive genomic and functional changes during development, but a unique feature of the SBN is its sensitivity to gonadal hormones. Transient developmental hormone signaling ultimately results in anatomic SBN sexual dimorphism and sex-variable behavioral repertoires. However, the precise mechanisms linking early life hormone signaling to the establishment of neural sex differences remain elusive. This review highlights recent findings on SBN development spanning embryonic timepoints to puberty, offering valuable perspectives to address this critical topic.
{"title":"Development of the social behavior network","authors":"Nolwenn Adam, Jessica Tollkuhn","doi":"10.1016/j.conb.2025.103159","DOIUrl":"10.1016/j.conb.2025.103159","url":null,"abstract":"<div><div>Social behaviors are crucial for reproductive success and survival. In vertebrates, these behaviors are sexually dimorphic due to distinct hormonal environments in development and adulthood. The underlying neural pathways, collectively known as the social behavior network (SBN), consist of interconnected regions exhibiting sex-variable genomic, anatomical, and functional characteristics. While the structure and function of the adult SBN is increasingly well described, its embryonic origins and development remain poorly understood. All neural networks undergo extensive genomic and functional changes during development, but a unique feature of the SBN is its sensitivity to gonadal hormones. Transient developmental hormone signaling ultimately results in anatomic SBN sexual dimorphism and sex-variable behavioral repertoires. However, the precise mechanisms linking early life hormone signaling to the establishment of neural sex differences remain elusive. This review highlights recent findings on SBN development spanning embryonic timepoints to puberty, offering valuable perspectives to address this critical topic.</div></div>","PeriodicalId":10999,"journal":{"name":"Current Opinion in Neurobiology","volume":"96 ","pages":"Article 103159"},"PeriodicalIF":5.2,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797661","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}
Pub Date : 2025-12-19DOI: 10.1016/j.conb.2025.103150
Ivette M. Sandoval , Michael F. Salvatore , Fredric P. Manfredsson
The prospect of successful use of gene therapy to treat neurological disorders, including Parkinson’s disease (PD), can be increased by understanding the molecular etiology underlying disease symptoms and neurodegeneration. The major hurdle of safety for gene therapy use in central nervous system disorders has been cleared; with now ∼20 years since the first gene therapy clinical trial for PD, and with a large number of patients having received various treatments, the field has generated a large body of data with an impeccable safety record. As our understanding of the targetable components of disease processes evolves, so too do the tools available to target these processes. Viral vectors based on adeno-associated virus have undergone significant advancements in the last decade, including capsid improvements, enhanced production methods, and recombinant genome design. Although the etiopathology(ies) underlying PD is (are) yet to be defined, a number of therapeutic modalities with broad preclinical support have been, and are being, tested in humans. This includes proteins providing symptomatic relief, neuromodulation, monogenic correction, and neurotrophic support. The leading therapeutic gene therapy candidate has been glial cell line–derived neurotrophic factor (GDNF) or the closely related protein neurturin. Although clinical studies are still ongoing, recent work shows that protein levels of GDNF receptors (GDNF family receptor alpha1 and receptor tyrosine kinase) decrease with disease. Therefore, it is possible that optimal use of gene therapy using GDNF, and other protective pathways, can only be realized with an incisive assessment of all components of a targeted signaling pathway. Nevertheless, current clinical candidates, paired with a strong upcoming preclinical data pipeline, are setting the stage for an exciting future for PD gene therapy.
{"title":"Gene therapy for Parkinson’s disease—Ample room for optimism","authors":"Ivette M. Sandoval , Michael F. Salvatore , Fredric P. Manfredsson","doi":"10.1016/j.conb.2025.103150","DOIUrl":"10.1016/j.conb.2025.103150","url":null,"abstract":"<div><div>The prospect of successful use of gene therapy to treat neurological disorders, including Parkinson’s disease (PD), can be increased by understanding the molecular etiology underlying disease symptoms and neurodegeneration. The major hurdle of safety for gene therapy use in central nervous system disorders has been cleared; with now ∼20 years since the first gene therapy clinical trial for PD, and with a large number of patients having received various treatments, the field has generated a large body of data with an impeccable safety record. As our understanding of the targetable components of disease processes evolves, so too do the tools available to target these processes. Viral vectors based on adeno-associated virus have undergone significant advancements in the last decade, including capsid improvements, enhanced production methods, and recombinant genome design. Although the etiopathology(ies) underlying PD is (are) yet to be defined, a number of therapeutic modalities with broad preclinical support have been, and are being, tested in humans. This includes proteins providing symptomatic relief, neuromodulation, monogenic correction, and neurotrophic support. The leading therapeutic gene therapy candidate has been glial cell line–derived neurotrophic factor (GDNF) or the closely related protein neurturin. Although clinical studies are still ongoing, recent work shows that protein levels of GDNF receptors (GDNF family receptor alpha1 and receptor tyrosine kinase) decrease with disease. Therefore, it is possible that optimal use of gene therapy using GDNF, and other protective pathways, can only be realized with an incisive assessment of all components of a targeted signaling pathway. Nevertheless, current clinical candidates, paired with a strong upcoming preclinical data pipeline, are setting the stage for an exciting future for PD gene therapy.</div></div>","PeriodicalId":10999,"journal":{"name":"Current Opinion in Neurobiology","volume":"96 ","pages":"Article 103150"},"PeriodicalIF":5.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797662","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}
Pub Date : 2025-12-18DOI: 10.1016/j.conb.2025.103147
Kathryn L. Todd , Kaitlyn M.L. Cramb , Katherine R. Brimblecombe , Stephanie J. Cragg
{"title":"Corrigendum to “New insights into axonal regulators of dopamine transmission in health and disease” [Curr Op Neurobiol 94 (2025) 103093]","authors":"Kathryn L. Todd , Kaitlyn M.L. Cramb , Katherine R. Brimblecombe , Stephanie J. Cragg","doi":"10.1016/j.conb.2025.103147","DOIUrl":"10.1016/j.conb.2025.103147","url":null,"abstract":"","PeriodicalId":10999,"journal":{"name":"Current Opinion in Neurobiology","volume":"96 ","pages":"Article 103147"},"PeriodicalIF":5.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793632","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}
Pub Date : 2025-12-16DOI: 10.1016/j.conb.2025.103149
Jonathan Nulman , Jason D. Ulrich , David M. Holtzman
Interferon-gamma (IFNγ) is a pleiotropic cytokine produced by CD8+ and CD4+ Th1 T cells, natural killer cells, natural killer-T cells, and type 1 innate lymphoid cells. Canonical IFNγ-induced genes include cytokines, chemokines, antigen processing and presentation machinery, and other transcription factors that initiate secondary, cell type-specific IFNγ responses. Originally described as an antiviral molecule, additional roles for IFNγ in development, anti-infection immunity, and neurodegeneration have been described. However, IFNγ′s downstream effects are highly context-dependent. Recent studies have uncovered extensive neuroimmune interactions within the CNS and implicated IFNγ in numerous CNS diseases, although these studies have produced conflicting results. This highlights a need for functional studies accounting for the spatial, temporal, and cellular complexities of CNS IFNγ signaling. Here, we summarize the current understanding of IFNγ signaling in CNS infections, multiple sclerosis/experimental autoimmune encephalomyelitis, and aging-associated neurodegenerative diseases and propose a framework for the design of future studies investigating the role of CNS IFNγ signaling.
{"title":"Context matters: Conflicting roles of interferon-γ signaling in CNS diseases","authors":"Jonathan Nulman , Jason D. Ulrich , David M. Holtzman","doi":"10.1016/j.conb.2025.103149","DOIUrl":"10.1016/j.conb.2025.103149","url":null,"abstract":"<div><div>Interferon-gamma (IFNγ) is a pleiotropic cytokine produced by CD8+ and CD4+ Th1 T cells, natural killer cells, natural killer-T cells, and type 1 innate lymphoid cells. Canonical IFNγ-induced genes include cytokines, chemokines, antigen processing and presentation machinery, and other transcription factors that initiate secondary, cell type-specific IFNγ responses. Originally described as an antiviral molecule, additional roles for IFNγ in development, anti-infection immunity, and neurodegeneration have been described. However, IFNγ′s downstream effects are highly context-dependent. Recent studies have uncovered extensive neuroimmune interactions within the CNS and implicated IFNγ in numerous CNS diseases, although these studies have produced conflicting results. This highlights a need for functional studies accounting for the spatial, temporal, and cellular complexities of CNS IFNγ signaling. Here, we summarize the current understanding of IFNγ signaling in CNS infections, multiple sclerosis/experimental autoimmune encephalomyelitis, and aging-associated neurodegenerative diseases and propose a framework for the design of future studies investigating the role of CNS IFNγ signaling.</div></div>","PeriodicalId":10999,"journal":{"name":"Current Opinion in Neurobiology","volume":"96 ","pages":"Article 103149"},"PeriodicalIF":5.2,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773829","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}
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