eNeuro最新文献

{"title":"Population-genetic and evolutionary context of a <i>CRIP3</i> variant associated with age-related hearing loss.","authors":"Sydney E Brongo, Alber Aqil, Matthew A Xu-Friedman, Omer Gokcumen","doi":"10.1523/ENEURO.0092-26.2026","DOIUrl":"https://doi.org/10.1523/ENEURO.0092-26.2026","url":null,"abstract":"<p><p>Age-related hearing loss is a widespread sensory impairment affecting one third of the elderly population, yet the genetic underpinnings of this condition remain incompletely understood. In this study, we investigate the evolutionary context of a non-synonymous variant (rs2242416) in the <i>CRIP3</i> gene, which is expressed in auditory hair cells, and previously associated with hearing loss. We first confirm that rs2242416 shows strong and consistent association with hearing loss across multiple genome-wide association studies. Notably, rs2242416 is also associated with reduced risk of heart related phenotypes, suggesting potential pleiotropic effects. The variant substitutes the nonpolar isoleucine for the polar threonine at an amino acid site that is otherwise highly conserved across placental mammals. By causing the amino acid change, the variant is predicted to subtly alter the structure of the CRIP3 protein. Moreover, the population genetics of the <i>CRIP3</i> locus reveals an increased frequency of the derived threonine allele of rs2242416 in Eurasian populations following the out-of-Africa migration of humans more than 50,000 years ago. Nevertheless, the role of natural selection in generating this increased allele frequency in Eurasians remains inconclusive. Together, these results provide phenotypic, evolutionary, and molecular context for <i>CRIP3</i> variation and highlight rs2242416 as a promising candidate for functional studies.<b>Significance Statement</b> Age-related hearing loss is highly prevalent, yet the specific genetic variants that contribute to disease risk remain poorly understood. Here, we investigate a variant (rs2242416) that causes an amino acid change in the <i>CRIP3</i> gene. While this variant is associated with hearing loss in multiple genome-wide association studies (GWAS), virtually no focused attention has been given to it. By integrating GWAS findings with evolutionary and population genetic analyses, we provide broader context for interpreting this variant. Our results support rs2242416 as a candidate functional variant increasing hearing loss risk in humans. Overall, this study demonstrates the value of combining population genetics with human GWAS to prioritize variants for functional validation.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Progression of Prion Diseases Is Not Altered in the Absence of TMEM106B.","authors":"Francisca Bravo-Risi, Gabriela Alburquerque Orta, Peter J Kim, Hannah Wylie-Young, Tucker H Stimming, Paulina Soto, Lisbell Estrada, Joanna L Jankowsky, Rodrigo Morales","doi":"10.1523/ENEURO.0043-26.2026","DOIUrl":"10.1523/ENEURO.0043-26.2026","url":null,"abstract":"<p><p>Transmembrane protein 106B (TMEM106B) is a type II transmembrane glycoprotein localized in late endosomes and lysosomes. This protein has been attributed to relevant roles in disease risk and progression of multiple neurodegenerative disorders. In experimental models, TMEM106B has been linked with the prion-like spread of misfolded tau proteins responsible for Alzheimer's disease and other tauopathies. The role of this protein in the spread of other misfolded proteins, like prions, has not been explored. Here, we tested whether the removal of TMEM106B altered the progression of prion diseases using animal mouse models (male and female). This was carefully tested using different prion dosages, strains, and routes of administration. Our results demonstrate that the absence of TMEM106B does not alter the progression of prion diseases in any of the tested conditions. This data provides supportive evidence on the specificity of TMEM106B in neurodegenerative conditions.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":"13 10","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13645488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiopulmonary Effects of Vagus Nerve Stimulation in Mice.","authors":"Chris D Phillips, Christopher M Driskill, Meena Rajendran, Deepika G Krishnan, Sven Kroener, Catherine A Thorn","doi":"10.1523/ENEURO.0086-26.2026","DOIUrl":"10.1523/ENEURO.0086-26.2026","url":null,"abstract":"<p><p>Vagus nerve stimulation (VNS) is an FDA-approved treatment for epilepsy, depression, and chronic stroke. While the effects of VNS are widely studied in rats and large animal models, few studies have characterized VNS in mice due to the practical challenges associated with their small size. However, mouse genetic tools provide a powerful opportunity to elucidate the diverse mechanisms underlying the many effects of VNS. Therefore, to inform the expanding use of mouse models in VNS research, we characterized the cardiopulmonary effects of left versus right VNS in anesthetized C57BL/6 mice. VNS robustly drove decreases in heart rate (HR) and breathing rate (BR) in the majority of mice. VNS-driven changes in BR were not correlated with changes in HR. We found no differences between male and female mice nor in the effects of left versus right VNS. VNS-induced bradycardia was abolished by transection of efferent vagal fibers, consistent with direct descending vagal control of cardiac rhythmicity. In contrast, VNS-driven changes in BR were abolished by both afferent and efferent vagotomies, consistent with the involvement of central feedback circuits in bilaterally coordinated vagal modulation of respiration. These results further our understanding of VNS effects in mice and help inform experimental design and cuff validation protocols for vagal modulation of peripheral versus central circuits in this species.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Goal Location Beta Oscillations and Sharp Wave-Ripples Are Complementary Markers of Learning-Related Changes in Hippocampal-Neocortical Networks.","authors":"Sameera Shridhar, Zachary M Leveroni, Nan Zhou, Ellie Quattrocchi, Audrey E Kaye, Jaquelin Gutierrez, Amanda Rodríguez León, Leslie M Kay, Jai Y Yu","doi":"10.1523/ENEURO.0048-26.2026","DOIUrl":"10.1523/ENEURO.0048-26.2026","url":null,"abstract":"<p><p>The hippocampus and neocortex are thought to undergo reorganization to incorporate new information during learning. How can we identify network states that indicate learning is occurring? In the hippocampus, one network signature with these properties is the sharp wave-ripple (SWR), which occurs more frequently during initial learning. However, it remains unclear which neural signatures track changes in neocortical networks during learning. We therefore recorded local field potentials simultaneously from the dorsal hippocampus (CA1) and prefrontal cortex (PFC) as male rats learned spatial navigation tasks. After animals reached goal locations, we found beta frequency (∼20 Hz) oscillations in PFC that increased in power with improvements in performance across days of training. In contrast, the rate and size of hippocampal SWRs decreased over the same period. Furthermore, goal-entry beta in PFC but not in CA1 was correlated with reward likelihood. Our results suggest that neocortical beta oscillations develop gradually as learning occurs, which stands in contrast to the reduction in hippocampal SWRs as the task becomes familiar. We hypothesize that PFC beta oscillations and hippocampal SWRs are complementary markers of experience-dependent change in hippocampal-neocortical networks during learning.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13626293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epidermal and ECM Damage Following Pinch Injury Restricts Dendrite Regeneration in <i>Drosophila</i>.","authors":"Mia A Brantley, Avantika Pandiyan, Annie C Danh, Sydney E Prange, Dario S Rimicci, Katherine L Thompson-Peer","doi":"10.1523/ENEURO.0058-26.2026","DOIUrl":"10.1523/ENEURO.0058-26.2026","url":null,"abstract":"<p><p>Neuronal dendrites can be injured by a number of insults, but the cellular mechanism by which dendrites respond to tissue injury and undergo repair is poorly understood. Much of the field's progress has evaluated dendrite regeneration following laser injury. While precise, laser injury does not accurately model the real-world damage to surrounding tissue that would accompany neuronal injury. Here, we modify a pinch injury technique to injure both the dendrites and their surrounding tissues in both female and male <i>Drosophila melanogaster</i> larvae to better model what is observed following real-world neuronal trauma. We refined this technique such that only half of a sensory neuron's dendrites are injured, leaving the other half uninjured. Our data indicate that both dynamic and stable dendritic arbors regrow dendrites in response to pinch injury, and neurons primarily engage in compensatory regeneration whereby new branches are added on the uninjured half of the arbor. Comparing the regenerative response following pinch injury versus laser injury revealed that dendrites preferentially regrow into areas where the surrounding tissue was left intact and not into areas where the surrounding tissue was damaged by pinch. These results prompted us to evaluate the damage sustained to surrounding tissues. In examining non-neuronal tissues after pinch injury, we found damage to the epidermis and ECM, but not glia. We also observed a robust immune response in the pinched hemisegment. We conclude that the surrounding tissue damage combined with a sustained immune response creates a nonpermissive environment for dendrite regeneration following pinch injury.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"uniSynK: A Ratio-Optimized Bicistronic Chemically Induced Dimerization Tool for Robust Induction of Dendritic Spine Enlargement.","authors":"Kota Homma, Masanari Ohtsuka, Siqi Zhou, Hitoshi Okazaki, Tomoki Arima, Haruo Kasai, Takeshi Sawada","doi":"10.1523/ENEURO.0157-26.2026","DOIUrl":"10.1523/ENEURO.0157-26.2026","url":null,"abstract":"<p><p>Synaptic plasticity is widely implicated in learning and brain-state regulation. Although correlations between synaptic modifications and diverse brain functions have been extensively reported, establishing causality requires tools that can directly and selectively perturb synapses in vivo. Recently, the chemogenetic actuator SYNCit-K (SynK) enabled causal induction of dendritic spine enlargement and synaptic potentiation. However, SynK relies on the coexpression of two independent components delivered by separate viral vectors, making it difficult to reliably achieve appropriate expression levels of both components within the same neuron. Here, using neocortical dissociated cultures from mouse embryos of undetermined sex, we sought to develop a unified, single-vector version of SynK (uniSynK) that enables robust and safe induction of dendritic spine enlargement. We first found that each SynK component induces distinct, concentration-dependent abnormalities in neuronal morphology when overexpressed, underscoring the need for precise control of their expression ratio. To address this challenge, we engineered a single construct in which the two components are linked by internal ribosome entry site (IRES) variants with graded translational efficiencies. Systematic screening of IRES variants identified an optimized configuration that preferentially drives each component within its respective concentration range that preserves normal spine morphology. The optimized uniSynK efficiently induces dendritic spine enlargement while exhibiting fewer off-target morphological abnormalities than observed in the multivector system when expression levels were not properly controlled. By simplifying experimental design, this single-vector, ratio-optimized synaptic chemogenetic tool provides a practical and broadly applicable platform that should facilitate causal interrogation of synaptic plasticity across neural circuits and behavior.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transgenic Expression of BK Channel Auxiliary LRRC26 Subunit in the Forebrain Causes Locomotor Hyperactivity and Cognitive Defects.","authors":"Guanxing Chen, Xin Guan, Hua Wei, Youqing Cai, Zhizhong Pan, Hui-Lin Pan, Jiusheng Yan","doi":"10.1523/ENEURO.0053-25.2026","DOIUrl":"10.1523/ENEURO.0053-25.2026","url":null,"abstract":"<p><p>The large-conductance, Ca²⁺- and voltage-activated K⁺ (BK) channels are widely distributed in the central nervous system, where they play diverse roles in regulating brain activity. The γ1 (LRRC26) subunit functions as a potent activator of BK channels, inducing a large shift in the voltage dependence of channel activation toward the hyperpolarized direction. Given the large conductance of BK channels, their activators have therapeutic potential for various diseases. To investigate the impact of activator-induced hyperactivity of BK channels on brain function, we generated conditional hLRRC26 transgenic mice in which recombinant human LRRC26 is expressed in the forebrain under the control of the CaMKIIα promoter and the tetracycline Tet-Off system. Experiments included mice of both sexes and data were pooled, as no obvious sex-dependent effects were detected. Histological analysis following postweaning doxycycline withdrawal confirmed hLRRC26 expression in the forebrain, with strong expression in the hippocampus, isocortex, and striatum. Behavioral tests demonstrated that long-term hLRRC26 expression resulted in locomotor hyperactivity, cognitive deficits, and some anxiety- and depression-like behaviors. At 2-4 months of age, hLRRC26 transgenic mice exhibited significantly elevated locomotor activity, with increased movement distance in the open-field test, despite shorter strides in the footprint test. These mice also showed impaired learning performance in the water maze, novel object recognition, and rotarod tests compared with controls. At 12-14 months, transgenic mice continued to display locomotor hyperactivity and cognitive deficits. In conclusion, hLRRC26 transgenic mice demonstrated heightened locomotor activity and cognitive impairments, revealing potential ADHD-like neurological consequences of BK channel hyperactivity.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148911140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PTEN Regulates Microtubule Polymerization via mTORC2, But Not mTORC1, in Peripheral Sensory Neurons.","authors":"Simone Evans, Julia Reglewski, Haley Rose, Cara Lewis, Anika Nayak, Cole Minsky, Evan McNeil, Brizha Knowles, Wei Wang, Meijie Li, Bryan W Luikart, Jennifer Hong","doi":"10.1523/ENEURO.0116-26.2026","DOIUrl":"10.1523/ENEURO.0116-26.2026","url":null,"abstract":"<p><p>Peripheral neuropathy affects over 18 million adults in the United States ( Hicks et al., 2021), but therapeutic outcomes are poor due to a lack of regenerative treatments. Development of novel, disease-modifying therapies is hindered by poor understanding of the mechanisms promoting axonal regeneration in peripheral neurons. Pten is a strong negative regulator of cell growth, and Pten-KO drives axonal regeneration in various neuronal subtypes potentially via downstream regulation of stability of the microtubule (MT) cytoskeleton, a vital component of axonal growth. While Pten-KO accelerates MT polymerization rates in the axonal growth cone, it remains unknown whether this action is dependent on mTORC1 or mTORC2 signaling and regeneration under Pten-KO is dependent on MT activation. Here, we perform in vitro codeletions of either Raptor (mTORC1) or Rictor (mTORC2) alongside Pten-KO in mouse peripheral sensory neuron cultures of either sex to isolate the effects of each pathway on the MT cytoskeleton. We use Pten-KO to increase MT polymerization and neuronal outgrowth and then show that suppression of mTORC2, but not mTORC1, is sufficient to reduce the accelerated MT polymerization and neuronal hypertrophy to wild-type levels. These results are specific to the axonal growth cone, and MT dynamics in the proximal axon shaft are not impacted by Pten-KO, mTORC1 suppression, or mTORC2 suppression. Our results help elucidate the mechanism by which Pten regulates the MT cytoskeleton and axonal outgrowth in peripheral sensory neurons, localize where this occurs in the axon, and highlight the MT cytoskeleton as a potential molecular target for regenerative therapies.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13640863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The orbitofrontal-anterior temporal network complements the attention network for where to look in social situations.","authors":"Nico Marek, Radha Nila Meghanathan, Stefan Pollmann","doi":"10.1523/ENEURO.0203-26.2026","DOIUrl":"10.1523/ENEURO.0203-26.2026","url":null,"abstract":"<p><p>Human neuroimaging experiments have consistently found dorsal and ventral attention networks subserving spatial shifts of covert attention or eye movements. However, these experiments used abstract, artificial stimuli for better experimental stimulus control and clearly defined instructions about where to attend or what to search for. This clearly is not an adequate model of eye movement control in natural environments full of semantic and social information. Here, we show that during movie viewing, activation of the dorsal and ventral attention networks was complemented by activation patterns in orbitofrontal and anterior temporal cortex, previously not implicated in human eye movement control, supporting individual decisions where to look. This effect was largely driven by looking at faces. We compared similarity relationships between eye fixation patterns on the one hand and brain activity patterns on the other hand in human participants of either sex. Searching for between-scenes changes in activation patterns that mirrored changes in fixation patterns, we were able to identify the attention networks defined by previous experiments with artificial stimuli. In contrast, interindividual differences in fixation patterns, indicative of endogenous decisions about where to look, were mirrored by activation pattern differences in orbitofrontal and anterior temporal cortex, particularly for scenes presenting faces. Thus, we could precisely replicate the role of the attention networks in a more natural viewing environment. Crucially, we also showed that previous lab experiments, lacking the complexity of free viewing in a naturalistic environment, overlooked the importance of the orbitofrontal - anterior temporal network for individual differences in active vision. Our findings show that the orbitofrontal - anterior temporal network needs to be considered in studies of active vision, particularly in social situations.<b>Significance Statement</b> Human attention networks have been replicated in a naturalistic setting. The attention networks could be mapped by comparing the similarity of fixation patterns and local brain activation patterns between scenes of a movie. In contrast, searching for brain activation reflecting interindividual differences in fixation patterns yielded an orbitofrontal-anterior temporal network. This network showed the highest similarity of fixation and brain activation patterns during scens containing faces, in line with its known function for social communication.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Allometric Approach to Fine-Mapping Subcortical Volume Alterations in RASopathies.","authors":"Chloe A McGhee-Deakin, Odeya Russo, Julia R Plank, Tamar Green","doi":"10.1523/ENEURO.0017-26.2026","DOIUrl":"10.1523/ENEURO.0017-26.2026","url":null,"abstract":"<p><p>Structural neuroimaging in youth with RASopathies has shown alterations in total brain volume (TBV) and subcortical structures. However, whether these subcortical differences scale proportionately with TBV or follow nonlinear allometric relationships remains unclear, limiting accurate interpretation of neuroanatomical findings and their relevance to cognition. Using an allometric framework, this study aimed to determine whether (1) subcortical volumes exhibit deviations from normative scaling in RASopathies and (2) methods used to account for TBV influence the detection of subcortical volume alterations. We examined youth with RASopathies (<i>N</i> = 132), including neurofibromatosis type 1 (NF1; <i>N</i> = 27), Noonan syndrome (<i>N</i> = 100; <i>PTPN11</i>, 72; <i>SOS1</i>, 22; <i>RAF1</i>, 6), and Noonan syndrome with multiple lentigines (NSML; <i>N</i> = 5), compared with 80 age- and sex-matched controls. Subcortical volumes were analyzed using an allometric framework, compared with linear TBV correction methods (normalization and covariation), and explored in sex-stratified analyses. Allometric analyses revealed deviations from normative scaling in the thalamus for NF1; the caudate, putamen, ventral striatum, and pallidum for <i>PTPN11</i>; and the ventral striatum for <i>SOS1</i> No significant deviations were observed for NSML or <i>RAF1</i> Exploratory sex-stratified analyses suggested similar directional scaling patterns across sexes, with greater deviations in females, although subgroup sizes were small. Comparisons across correction methods demonstrated that linear approaches may overestimate regional differences, whereas thalamic alterations in NF1 and striatal alterations in <i>PTPN11</i> were consistent across methods, suggesting robust, region-specific genetic effects beyond scaling. These findings highlight genotype-specific deviations from normative allometric scaling and underscore the importance of nonlinear scaling frameworks to accurately characterize neuroanatomical differences in RASopathies.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13592736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148911204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}