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Science (New York, N.Y.) 2025年第6736期387卷 827-828页

作者： William M Sheeran Zoe R Donaldson Department of Molecular Cellular and Developmental Biology University of Colorado Boulder Boulder CO USA. Medical Scientist Training Program University of Colorado School of Medicine Aurora CO USA. Department of Psychology and Neuroscience University of Colorado Boulder Boulder CO USA.

In mice, two brain regions drive the impulse to revive an unconscious companion.

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Epigenetic Control of an Auxiliary Subunit of Voltage-Gated Sodium Channels Regulates the Strength of Drug-Cue Associations and Relapse-Like Cocaine Seeking

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Biological Psychiatry 2025年

作者： Wood, Daniel J. Tsvetkov, Evgeny Comte-Walters, Susana Welsh, Colin L. Bloyd, Michelle Wood, Timothy G. Akiki, Rose Marie Anderson, Ethan M. Penrod, Rachel D. Madan, Lalima K. Ball, Lauren E. Taniguchi, Makoto Cowan, Christopher W. Department of Neuroscience Medical University of South Carolina Charleston South Carolina United States Medical Scientist Training Program Medical University of South Carolina Charleston South Carolina United States Department of Pharmacology and Immunology Medical University of South Carolina Charleston South Carolina United States

Background: Repeated use of addictive drugs produces long-lasting and prepotent drug-cue associations that increase vulnerability for relapse in individuals with a substance use disorder. Epigenetic factors, such as HDAC5 (histone deacetylase 5), play a key role in regulating the formation of drug-cue associations, but the underlying mechanisms remain unclear. Methods: We used a combination of molecular biology, cultured cells, tandem mass spectrometry, deacetylase activity measurements, co-immunoprecipitation, and molecular dynamics simulations to assess HDAC5 structure-activity relationships. In male and female Long Evans rats, we used viral-mediated expression of HDAC5 mutants in the nucleus accumbens (NAc) to test effects on cocaine intravenous self-administration and cue-reinstated cocaine seeking. We also used in silico analysis of single-nucleus RNA sequencing data, quantitative reverse transcriptase–polymerase chain reaction, viral-mediated expression of Scn4b short hairpin RNA, patch-clamp electrophysiology, and rat cocaine or sucrose SA to assess Scn4b's effects on NAc intrinsic excitability and cued reward seeking. Results: We discovered that 2 conserved cysteines located near HDAC5’s catalytic domain were required for its intrinsic deacetylase activity and that HDAC5’s deacetylase activity was required in NAc medium spiny neurons (MSNs) to limit relapse-like cue-reinstated cocaine seeking. Moreover, we found that HDAC5 limited cocaine-seeking, but not sucrose-seeking, behavior by reducing NAc MSN intrinsic excitability through the deacetylase-dependent repression of Scn4b, which codes for an auxiliary subunit of voltage-gated sodium channels. Conclusions: Our findings suggest that HDAC5’s control of NAc Scn4b expression governs the formation of cocaine-cue, but not sucrose-cue, associations through modulation of NAc MSN intrinsic excitability and drug-induced NAc plasticity mechanisms. © 2025 Society of Biological Psychiatry

关键词： Epigenetics Neuronal excitability Nucleus accumbens Reinstatement behavior Substance use disorder

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Orderly specification and precise laminar deployment of mouse cortical projection neuron types through intermediate progenitors

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Developmental Cell 2025年

作者： Huilgol, Dhananjay Levine, Jesse M. Galbavy, William Wang, Bor-Shuen Huang, Z. Josh Department of Neurobiology Duke University Medical Center Durham NC United States Department of Biomedical Engineering Duke University Durham NC United States Cold Spring Harbor Laboratory Cold Spring Harbor NY United States Program in Neuroscience and Medical Scientist Training Program Stony Brook University Stony Brook NY United States Program in Neuroscience Department of Neurobiology and Behavior Stony Brook University Stony Brook NY United States

The cerebral cortex comprises diverse types of glutamatergic projection neurons (PNs) generated from radial glial progenitors (RGs) through either direct neurogenesis (dNG) or indirect neurogenesis (iNG) via intermediate progenitors (IPs). A foundational concept in corticogenesis is the “inside-out” model, whereby successive generations of PNs sequentially migrate first to deep and then progressively to more superficial layers. However, its biological significance remains unclear, and the role of iNG in this process is unknown. Using genetic strategies linking PN birth dating to projection mapping in mice, we found that the laminar deployment of IP-derived PNs substantially deviates from a stringent inside-out rule: PNs destined to non-consecutive layers are generated at the same time, and different PN types of the same layer are generated at non-contiguous times. The overarching scheme of iNG is the sequential specification and precise laminar deployment of projection-defined PN types, which may contribute to the orderly assembly of cortical output channels and processing streams. © 2025 Elsevier Inc.

关键词： fate mapping indirect neurogenesis intermediate progenitors neocortex projection neurons

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Whole-body hyperthermia as a novel antidepressant therapy

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Biomarkers in Neuropsychiatry 2025年 12卷 100124-100124页

作者： Gaitonde, Kevin D. Nasrallah, Henry A. Medical Scientist Training Program University of Cincinnati College of Medicine 3230 Eden Avenue Cincinnati 45267 OH United States Department of Psychiatry and Behavioral Neuroscience University of Cincinnati College of Medicine 260 Stetson Street Suite 3200 Cincinnati 45219 OH United States

First-line treatments for major depressive disorder include medication and cognitive behavioral therapy. While effective, pharmacotherapy often takes time to start demonstrating efficacy in symptomatic improvement and may be accompanied by adverse effects, indicating an ongoing need for new therapeutic approaches. A recently emerging somatic antidepressant intervention is whole-body hyperthermia, in which subjects are temporarily exposed to heat and then allowed to cool down. Recent studies employing hyperthermia-based strategies appear to show mood improvements both immediately and several weeks after the conclusion of treatment. However, published studies are often limited by their sample sizes and by their selection criteria. In this article, we review the literature on this novel approach and propose ideas regarding the possible physiological basis of this novel intervention and how it may be used in the future as adjunctive therapy with the current standard of care. © 2025 The Authors

关键词： Depression Hyperthermia Temperature Thermoregulation

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Semaphorin7A and PD-L1 cooperatively drive immunosuppression during mammary involution and breast cancer

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Cell Reports 2025年第5期44卷 115676页

作者： Elder, Alan M. Fairchild, Heather R. Kines, Kelsey T. Cozzens, Lauren M. Becks, Alexandria R. Slansky, Jill E. Anderson, Steven M. Lyons, Traci R. Division of Medical Oncology Department of Medicine School of Medicine University of Colorado Anschutz Medical Campus Aurora CO United States Cancer Biology Graduate Training Program University of Colorado Anschutz Medical Campus Aurora CO United States Medical Scientist Training Program University of Colorado Anschutz Medical Campus Aurora CO United States University of Colorado Cancer Center Aurora CO United States Department of Immunology and Microbiology School of Medicine University of Colorado Anschutz Medical Campus Aurora CO United States Young Women's Breast Cancer Translational Program University of Colorado Anschutz Medical Campus Aurora CO United States

Postpartum mammary gland remodeling after a pregnancy/lactation cycle is characterized by mechanisms of cell death and inflammation. Here, we show that SEMA7A promotes PD-L1 expression in immune cells of the mammary tissue during involution. These same phenotypes are mimicked in the microenvironment of SEMA7A-expressing tumors, which partially respond to αPD-1/αPD-L1 treatments in vivo. However, cells that remain after treatment are enriched for SEMA7A expression. Therefore, we tested a monoclonal antibody that directly targets SEMA7A-expressing tumors, in part, by reducing SEMA7A-mediated upregulation of PD-L1. In vivo, the SEMA7A monoclonal antibody reduces tumor growth and/or promotes complete regression of mouse mammary tumors, reduces some immunosuppressive phenotypes in the tumor microenvironment, and restores cytotoxic T cells, suggesting that SEMA7A may be a candidate for immune-based therapy for breast cancer patients. © 2025 The Author(s)

关键词： breast cancer CP: Cancer macrophage mammary gland involution PD-L1 semaphorin 7a tumor immunology tumor microenvironment

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Variable Presence of an Evolutionarily New Brain Structure Is Related to Trait Impulsivity

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Biological Psychiatry: Cognitive neuroscience and Neuroimaging 2025年

作者： Willbrand, Ethan H. Maboudian, Samira A. Elliott, Matthew V. Kellerman, Gabby M. Johnson, Sheri L. Weiner, Kevin S. Medical Scientist Training Program School of Medicine and Public Health University of Wisconsin-Madison Madison WI United States Helen Wills Neuroscience Institute University of California Berkeley Berkeley California United States Department of Neuroscience University of California Berkeley Berkeley California United States Department of Psychology University of California Berkeley Berkeley California United States

Background: Impulsivity is a multidimensional construct reflecting poor constraint over one's behaviors. Clinical psychology research has identified separable impulsivity dimensions that are each unique transdiagnostic indicators for psychopathology. However, despite this apparent clinical importance, the shared and unique neuroanatomical correlates of these factors remain largely unknown. Concomitantly, neuroimaging research has identified variably present human brain structures implicated in cognition and disorder: the folds (sulci) of the cerebral cortex located in the latest-developing and most evolutionarily expanded hominoid-specific association cortices. Methods: We tethered these 2 fields to test whether variability in one such structure in the anterior cingulate cortex (ACC)—the paracingulate sulcus (PCGS)—was related to individual differences in trait impulsivity. A total of 120 adult participants with internalizing or externalizing psychopathology completed a magnetic resonance imaging scan and the Three-Factor Impulsivity Index. Using precision imaging techniques, we manually identified the PCGS, when present, and acquired quantitative folding metrics (PCGS length and ACC local gyrification index). Results: Neuroanatomical-behavioral analyses revealed that participants with leftward or symmetrical PCGS patterns had greater severity of Lack of Follow Through (LFT)—which captures inattention and lack of perseverance—than those with rightward asymmetry. Neuroanatomical-functional analyses identified that the PCGS colocalized with a focal locus found in a neuroimaging meta-analysis on a feature underlying LFT. Neither quantitative folding metric related to any impulsivity dimension. Conclusions: This study advances understanding of the neuroanatomical correlates of impulsivity and establishes the notion that the topographical organization of distinct, hominoid-specific cortical expanses underlies separable impulsivity dimensions with robust, transdiagnostic

关键词： Cingulate cortex Impulsivity Neuroanatomy Neuroimaging Psychopathology Transdiagnostic

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The emerging role of microbiota derived SCFAs in neurodegenerative disorders

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Brain, Behavior, & Immunity - Health 2025年 46卷 101012-101012页

作者： Samuel Wachamo Alban Gaultier Department of Neuroscience University of Virginia Charlottesville VA USA Neuroscience Graduate Program University of Virginia Charlottesville VA USA Center for Brain Immunology and Glia University of Virginia Charlottesville VA USA Medical Scientist Training Program School of Medicine University of Virginia Charlottesville VA USA

The microbiota-gut-brain axis (MGBA), the bidirectional communication network between the gastrointestinal tract and the central nervous system, plays a significant role in the pathophysiology of neurodegenerative disorders. Emerging research highlights how gut microbiota dysbiosis, or an imbalance in the microbial community, is linked to the etiology and pathology of these conditions. Microbiota dysbiosis leads to changes in the production of microbial metabolites, such as short-chain fatty acids (SCFAs), which can cross the intestinal barrier and influence the brain either directly or indirectly. Understanding the mechanisms by which dysfunction in the MGBA contributes to neurodegeneration opens potential avenues for novel therapeutic strategies, including microbiota-targeted interventions. This review introduces the MGBA, discusses the role of SCFAs within the MGBA in the context of neurodegenerative disorders, and suggests future research directions.

关键词： Microbiota Microbiota-gut-brain axis (MGBA) Dysbiosis Short-chain fatty acids (SCFAs) Neurodegenerative disorders

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Clusterin induced by OPC phagocytosis blocks IL-9 secretion to inhibit myelination in a model of Alzheimer's disease

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Heliyon 2025年第1期11卷 e41635页

作者： Beiter, Rebecca M. Raghavan, Tula P. Suchocki, Olivia Ennerfelt, Hannah E. Rivet-Noor, Courtney R. Merchak, Andrea R. Phillips, Jennifer L. Bathe, Tim Lukens, John R. Prokop, Stefan Dupree, Jeffrey L. Gaultier, Alban Center for Brain Immunology and Glia Department of Neuroscience Charlottesville 22908 VA United States Graduate Program in Neuroscience Charlottesville 22908 VA United States Department of Neurobiology UMass Chan Medical School Worcester 01655 MA United States Medical Scientist Training Program University of Virginia School of Medicine Charlottesville 22908 VA United States Center for Translational Research in Neurodegenerative Disease College of Medicine University of Florida Gainesville 32610 FL United States Department of Pathology College of Medicine University of Florida Gainesville 32610 United States McKnight Brain Institute College of Medicine University of Florida Gainesville 32610 FL United States Department of Anatomy and Neurobiology Virginia Commonwealth University Richmond 23298 VA United States

Background: Variants in the CLUSTERIN gene have been identified as a risk factor for late-onset Alzheimer's disease and are linked to decreased white matter integrity in healthy adults. However, the specific role for clusterin in myelin maintenance in the context of Alzheimer's disease remains unclear. Methods: We employed a combination of immunofluorescence and transmission electron microscopy techniques, primary culture of OPCs, and an animal model of Alzheimer's disease. Results: We found that phagocytosis of debris such as amyloid beta, myelin, and apoptotic cells, increases clusterin expression in oligodendrocyte progenitors. We further discovered that exposure to clusterin inhibits differentiation of oligodendrocyte progenitors. Mechanistically, clusterin blunts production of IL-9 and addition of exogenous IL-9 can rescue clusterin-inhibited myelination. Lastly, we demonstrate that clusterin deletion in mice prevents myelin loss in the 5XFAD model. Discussion: Our data suggest that clusterin could play a key role in Alzheimer's disease myelin pathology. © 2025 The Authors

关键词： Alzheimer's disease Astrocyte Clusterin IL-9 Myelin Oligodendrocyte progenitor cells

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Machine learning identification of enhancers in the rhesus macaque genome

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Neuron 2025年第10期113卷 1548-1561.e8页

作者： He, Jing Phan, BaDoi N. Kerkhoff, Willa G. Alikaya, Aydin Hong, Tao Brull, Olivia R. Fredericks, J. Megan Sedorovitz, Morgan Srinivasan, Chaitanya Leone, Michael J. Wirfel, Olivia M. Brown, Ashley Dauby, Samuel Tittle, Rachel K. Lin, Meng K. Hooks, Bryan M. Bostan, Andreea C. Gharbawie, Omar A. Byrne, Leah C. Pfenning, Andreas R. Stauffer, William R. Department of Neurobiology University of Pittsburgh Pittsburgh 15213 PA United States Computational Biology Department Carnegie Mellon University Pittsburgh 15213 PA United States Neuroscience Institute Carnegie Mellon University Pittsburgh 15213 PA United States University of Pittsburgh-Carnegie Mellon University Medical Scientist Training Program Pittsburgh 15213 PA United States Program in Neural Computation Carnegie Mellon University Pittsburgh 15213 PA United States Department of Ophthalmology University of Pittsburgh Pittsburgh 15213 PA United States

Nonhuman primate (NHP) neuroanatomy and cognitive complexity make NHPs ideal models to study human neurobiology and disease. However, NHP circuit-function investigations are limited by the availability of molecular reagents that are effective in NHPs. This calls for reagent development approaches that prioritize NHPs. Therefore, we derived enhancers from the NHP genome. We defined cell-type-specific open chromatin regions (OCRs) in single-cell data from rhesus macaques. We trained machine-learning models to rank those OCRs according to their potential as cell-type-specific enhancers for cells in the dorsolateral prefrontal cortex (DLPFC). We packaged the top-ranked layer-3-pyramidal-neuron enhancer into AAV and injected it into the macaque DLPFC. Expression was mostly restricted to layers 2 and 3 and confirmed with light-driven activation of channelrhodopsin. These results provide a crucial tool for studying the causal functions of DLPFC and provide a roadmap for optimized gene delivery in primates. © 2025 The Authors

关键词： AAV cell types cell-type-specific cognition DLPFC dorsolateral prefrontal cortex enhancer machine learning optogenetics rhesus monkey

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Computational design of serine hydrolases

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Science (New York, N.Y.) 2025年第6744期388卷 eadu2454页

作者： Lauko, Anna Pellock, Samuel J. Sumida, Kiera H. Anishchenko, Ivan Juergens, David Ahern, Woody Jeung, Jihun Shida, Alexander F. Hunt, Andrew Kalvet, Indrek Norn, Christoffer Humphreys, Ian R. Jamieson, Cooper Krishna, Rohith Kipnis, Yakov Kang, Alex Brackenbrough, Evans Bera, Asim K. Sankaran, Banumathi Houk, K.N. Baker, David Department of Biochemistry University of Washington Seattle WA United States Institute for Protein Design University of Washington Seattle WA United States Graduate Program in Biological Physics Structure and Design University of Washington Seattle WA United States Department of Chemistry University of Washington Seattle WA United States Graduate Program in Molecular Engineering University of Washington Seattle WA United States Paul G. Allen School of Computer Science and Engineering University of Washington Seattle WA United States Medical Scientist Training Program University of Washington Seattle WA United States Howard Hughes Medical Institute University of Washington Seattle WA United States Department of Chemistry and Biochemistry University of California Los Angeles CA United States

The design of enzymes with complex active sites that mediate multistep reactions remains an outstanding challenge. With serine hydrolases as a model system, we combined the generative capabilities of RFdiffusion with an ensemble generation method for assessing active site preorganization at each step in the reaction to design enzymes starting from minimal active site descriptions. Experimental characterization revealed catalytic efficiencies (kcat/Km) up to 2.2 × 105 M-1 s-1 and crystal structures that closely match the design models (Cα root mean square deviations <1 angstrom). Selection for structural compatibility across the reaction coordinate enabled identification of new catalysts remove with five different folds distinct from those of natural serine hydrolases. Our de novo approach provides insight into the geometric basis of catalysis and a roadmap for designing enzymes that catalyze multistep transformations.

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