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Matt is an unusually talented scholar, with seminal contributions in many areas (cognitive ability, environmental influences, substance use, etc.). One key theme that undergirds and unites his work is his development of novel research designs and experiments of nature capable of estimating causal inferences with unusual precision. In this contribution to his Festshrift, I illuminate key models and experiments developed by Matt and their contributions to the field. In lieu of new empirical data, I also present a new idiographic behavioral genetic research design - to be called 'narrative non-shared environmental identification' - in which we leverage idiographic, person-specific measurement tools to meaningfully study the effective non-shared environment for the first time.
Agonistic behaviors are crucial and common among animals due to their importance in securing an individual's fitness, and neural signaling molecules are known to mediate these behaviors. Stenopus, a genus of shrimp-like decapod crustaceans characterized by a pair of enlarged pereiopods, exhibits prominent agonistic behaviors when encountering conspecifics of the same sex owing to its monogamous social structure. These shrimps represent another potentially excellent model organism for investigating the neural signaling basis of agonistic behaviors in crustaceans aside from traditional models. Yet, their underpinning molecular aspects have never been studied. Using S. hispidus and S. cyanoscelis as representatives, the present study is the first that systematically examines the genetics of agonistic behaviors in Stenopus. Three organs, including (1) antennae + antennules, (2) central nervous system, and (3) eyestalk ganglia, were RNA-sequenced to identify the differentially expressed genes (DEGs) and pathways potentially conserved in winners and losers of Stenopus after fighting interactions. Our results suggested that Stenopus agonistic interactions might be systemic activities involving the simultaneous modulation and interplay of multiple signaling cascades, organismal systems, and metabolic pathways. In particular, winners and losers typically exhibited enriched gene ontologies involved in neural signaling, and sensory and behavioral processes. Regarding enriched pathways, while those related to glycan biosynthesis and metabolism were enriched in winners, cholesterol metabolism and one-carbon pool by folate were enriched in losers. These different sets of pathways suggested that while fighting interactions in Stenopus were injurious to both combatants, the damage in losers appeared to be more traumatic. Furthermore, four neural signaling systems, including dopamine, acetylcholine, octopamine, and glutamate, were identified as potentially major mediators of agonistic behaviors and fighting interactions in both Stenopus species, with the first two appearing to be relatively more important. A comparison of the neural signaling systems involved in mediating aggression among pan-crustaceans suggested that Stenopus appeared to stand out by its seemingly major reliance on dopamine and acetylcholine, as opposed to the primarily serotonin-based regulation of aggression observed in most examined pan-crustaceans. The different metabolic responses between winners and losers in Stenopus highlight the profound, asymmetric physiological costs of social conflict at the molecular level. Furthermore, their unique reliance on dopamine and acetylcholine reveals diverse evolutionary trajectories in the neuroendocrine regulation of aggression, providing new insights into the current paradigms of invertebrate social behavior.
Phosphodiesterase 7 A (PDE7A) is a key regulator of cyclic adenosine monophosphate (cAMP) signaling, expressed prominently in brain regions associated with reward and addiction. Despite its strategic localization within reward-related neurocircuitry, the functional contribution of PDE7A to substance use disorders remains poorly defined. We investigated the role of PDE7A in morphine-induced behavioral plasticity using a combination of genetic deletion (Nestin-Cre-mediated neuronal PDE7A knockout) and pharmacological inhibition (BRL-50481) in male C57BL/6J mice (8-10 weeks of age). Behavioral assessments included conditioned place preference (CPP) and locomotor sensitization. Biochemical analyses (ELISA, Western blotting, co-immunoprecipitation) were performed on striatal tissue to assess dopamine levels, cAMP levels, and signaling pathways (AKT/GSK3β, D2R-β-arrestin2 complex). Mice with neuronal PDE7A deficiency failed to develop morphine-induced CPP, highlighting a critical requirement for PDE7A in drug-associated memory formation. Consistently, administration of the PDE7 inhibitor BRL-50,481 (10 mg/kg, i.p.) significantly disrupted established drug memories and attenuated morphine-induced behavioral sensitization in wild-type mice. Mechanistically, PDE7A deletion led to a hyper-dopaminergic state in the striatum, characterized by elevated dopamine levels and D1 receptor expression, yet a paradoxical impairment in downstream signaling. Specifically, the behavioral effects of PDE7 inhibition were reversed by the D2 receptor antagonist haloperidol and the AKT inhibitor oridonin, suggesting a reliance on the D2R-AKT-GSK3β axis. Biochemical analyses further revealed that PDE7A deficiency suppresses the AKT/GSK3β signaling pathway, a defect validated through pharmacological manipulation of PDE7, D2R, and AKT. Collectively, these findings identify PDE7A as a pivotal modulator of morphine-induced addiction and suggest that targeting the PDE7A-D2R-AKT signaling cascade represents a novel therapeutic strategy for managing substance use disorders.
Ovarian cancer (OC) exhibits significant ethnic and geographic disparities, with rising incidence in Asia contrasting global declines. While non-modifiable risk factors (e.g., genetics) are well-established, evidence for the role of modifiable factors like physical activity remains inconsistent, especially in Asian populations. This study systematically evaluates the association between physical activity, sedentary behavior, and OC risk in Asia. We conducted a meta-analysis of seven studies (156,910 participants, 1,585 OC cases) from Japan, Korea, and China. Physical activity and sedentary behavior were assessed via self-reports. Meta-analysis was performed to pool RR estimates together with their 95% CI. Regular physical activity was associated with a 24% lower OC risk (RR = 0.76, 95% CI: 0.64-0.91; P = 0.002), despite high heterogeneity (I2 = 75%). Sedentary behaviour was associated with a 55% higher OC risk (RR = 1.55, 95% CI: 1.23-1.96; P = 0.0002). In Asian populations, physical activity may protect against OC, while sedentary behavior may elevate risk. These findings underscore the need for dual public health strategies: promoting exercise and reducing sedentary time. Future research should standardize exposure assessments and include diverse Asian subpopulations to refine prevention guidelines.
Aedes aegypti is widely distributed in the tropics and sub-tropics and is a major vector of several arboviruses, such as dengue and chikungunya viruses. Mapping the behavioral and genetic divergence among the mosquito populations can enhance our understanding of spatiotemporal variation in disease transmission. Cross-sectional surveys were carried out between 2022 and 2023 to investigate egg-laying abundance in ovitraps as well as adult abundance in BG Sentinel traps baited with carbon dioxide. Both trap types were deployed in outdoor environments in two peri-urban areas in the Rift Valley and coastal regions of Kenya. A subset of the adult specimens was screened for arbovirus infections, and the mitochondrial cox-1 gene was analyzed to estimate genetic differences between the populations. Engorged specimens were also typed to determine host feeding sources. Aedes egg density was significantly higher in Marigat in the Rift Valley than in Ukunda at the coast (p = 0.006), despite recording a lower ovitrap positivity rate. By contrast, adult female abundance was twofold greater in Ukunda than in Marigat (p < 0.0001). A higher human blood feeding rate (HBI = 0.68) in Ukunda compared to Marigat (HBI = 0.29) correlated with higher proportional abundance of the domestic than of the forest Ae. aegypti ecotype. Haplotype network analysis revealed a high mitochondrial diversity dominated by population-specific haplotypes. Limited haplotype sharing between Ukunda and Marigat populations suggests a restricted maternal gene flow and localized population structuring. While all the samples tested negative for pathogenic arboviruses, insect-specific viruses (ISVs) in the families Flaviviridae (Cell fusing agent virus and uncharacterized flavivirus-like sequences (Flaviviridae sp.)) and Phenuiviridae (Phasi Charoen-like virus) were detected, which varied between the two ecological environments. We observed geographic differences in egg and adult capture rates of Ae. aegypti, which correlate poorly, providing valuable information for Aedes surveillance and control. Heterogeneity in entomological, genetic and virological factors likely shapes geographic differences in dengue occurrence and spread.
During pregnancy, estrogen levels rise dramatically, but quickly drop to prepartum levels following birth and remain suppressed until ovulation resumes. This "postpartum estrogen withdrawal" state has been linked to changes in the brain and behavior in humans and rodents. Previous research has demonstrated that following a hormone-simulated pseudopregnancy (HSP), an experimental model of postpartum estrogen withdrawal, female mice show increased anxiety-like behaviors and decreased social motivation. Further, these behavioral changes occur concurrently with an increase in ∆FOSB, a transcription factor associated with stable long-term plasticity, in the nucleus accumbens core. To test whether this increase in ∆FOSB is required for these behavioral changes, we used a viral-mediated gene transfer approach to prevent ∆FOSB-mediated transcription in the NAcC during HSP and found that it reduced the high-anxiety behavioral phenotype in estrogen-withdrawn females. However, preventing ∆FOSB-mediated transcription had little effect on social motivation. Together, these results suggest that postpartum estrogen withdrawal increases ∆FOSB in the NAc core to impact anxiety-like behaviors but not social motivation following estrogen withdrawal.
Efficient and markerless allele-coupled exchange (ACE) mutagenesis is possible in a wild-type C. difficile background by using a synthetic riboswitch to indirectly control replication of the mutagenesis plasmid. Controlling plasmid replication gives the user the ability to introduce selective pressure for recombination of the mutagenesis plasmid into the chromosome (integration) followed by recombination of plasmid DNA out of the chromosome (excision) reliably. ACE has been successfully used in C. difficile research for over a decade, mostly with unstably replicating plasmids using toxic pyrimidine precursors or toxin/antitoxin systems to select for recombination events. The advantages of using a riboswitch to control plasmid replication include the ability to begin with a wild-type parent strain, use of a higher copy number origin of replication, and generation of mutants on rich medium. A wild-type progenitor means there is no need to complement pyrE into newly made mutants, increasing ease of use. The inclusion of the more stable, pCD6-derived origin of replication in the mutagenesis vector should increase efficiency of conjugal transfer, and its higher plasmid copy number should increase the frequency of crossover events. The efficacy of the riboswitch in rich media also avoids the use of minimal or defined media, increasing growth rates and ease of use.
Background/Objectives: Elevated central adiposity (ECA) in childhood is associated with early cardiometabolic risk and hemodynamic alterations. However, evidence in Spanish schoolchildren regarding the relationship between eating behavior traits and central adiposity is limited, particularly across developmental stages. This study aimed to examine the association between Children's Eating Behaviour Questionnaire (CEBQ) subscales and ECA, and to explore potential differences by age group. Methods: A cross-sectional study was conducted in 496 rural schoolchildren aged 6-15 years. ECA was defined using the waist-to-height ratio (WHtR) and sex-specific cut-offs validated for the Spanish pediatric population. Eating behavior was assessed with the CEBQ (Z-scores), and diet quality was measured using the KIDMED index. Multivariable logistic regression models were adjusted for sex, KIDMED score, and maternal education. Analyses were subsequently stratified by age (6-9 and 10-15 years). Results: The prevalence of ECA was 45.90%. In fully adjusted models, higher Food Responsiveness (FR) was associated with increased odds of ECA, while Satiety Responsiveness (SR) acted as a protective factor; sex also showed an independent association. After stratification, sex remained the only significant predictor in children aged 6-9 years. Among those aged 10-15 years, FR was significantly associated with ECA (p = 0.008), while Slowness in Eating (SE) showed a borderline positive association in the adjusted model (p = 0.049) and was therefore interpreted cautiously. SR and Emotional Undereating (EU) showed protective trends near significance (p = 0.081 and p = 0.082, respectively). Conclusions: The association between eating behavior traits and ECA varies by age. In older children, FR showed a robust association with ECA, whereas no behavioral predictors were observed in younger children. The protective role of SR in the global model and the emergence of behavioral predictors in older participants highlight the importance of targeted interventions during late childhood.
Lifestyle behaviors such as smoking, vaping, and physical activity can induce epigenetic modifications that influence health trajectories and may provide forensic value. DNA methylation signatures linked to these behaviors offer potential for behavioral inference, personalized health assessment, and improved investigative practices. This study aimed to characterize methylation patterns associated with nicotine exposure and exercise using buccal cell DNA profiling, and to evaluate the extent to which these patterns differentiate harmful and protective lifestyle habits. Buccal epithelial DNA was analyzed using the Illumina Infinium MethylationEPIC v2 BeadChip to assess genome-wide methylation. Participants were categorized by smoking status, vaping behavior, and exercise activity. Differentially methylated regions (DMRs) and CpG sites were identified through pairwise comparisons among smokers, vapers, non-smokers/non-vapers, athletes, and sedentary individuals. A threshold of p < 1 × 10-4 was applied for significant differentially methylated CpG sites. Distinct epigenetic profiles were associated with smoking/vaping and physical activity. Five DMRs differentiated smokers from non-smokers/non vapers, while 11 DMRs distinguished vapers from the same reference group. Twenty-eight DMRs displayed divergent methylation patterns between smokers and vapers. Exercise also showed measurable epigenetic influence: control athletes exhibited 26 significantly differentially methylated CpG sites relative to non-athletes, and smoker athletes demonstrated 126 suggestive differential sites compared to sedentary smokers. Additionally, 63 sites differentiated smoker athletes from non-smoker/non-vaper non-athletes, indicating interactions between risk-associated and health-promoting behaviors. Buccal cell DNA methylation profiling effectively captured signatures associated with smoking, vaping, and physical activity. These findings underscore the potential of epigenetic markers for lifestyle assessment in both personalized medicine and forensic investigations.
Although dietary intake is a leading risk factor for many common diseases, adherence to dietary recommendations remains low. This may partly reflect limited consideration of individual differences in eating behavior that arise from both environmental and genetic factors. While genome-wide association studies (GWAS) of dietary intake have identified hundreds of associated loci, the X chromosome has largely been ignored. To address this gap, we applied multiple X-chromosome-wide association study (X-WAS) models on dietary intake phenotypes to identify novel associations. We performed X-WAS of 46 dietary intake traits from food frequency questionnaires in up to 424,758 European participants from the UK Biobank. Phenotypes included quantitative measures (e.g., fruit intake), binary traits (e.g., decaffeinated vs caffeinated coffee), and principal component-derived food groups. We tested for genetic associations using several models: a traditional sex-combined additive GWAS, additive models stratified by sex, and two joint models accounting for sex-interaction effects and non-additivity. We also conducted X-WAS in five additional genetic ancestry groups and performed a sex-combined multi-ancestry additive GWAS meta-analysis with up to 445,773 individuals. We identified 18 loci associated with 20 dietary intake traits ( P < 5×10 -8 ), including 17 variants without prior associations in the GWAS Catalog. Among these loci, 10 were significant across multiple X-WAS models, and 5 were strongest in a model other than the traditional sex-combined additive GWAS, highlighting the value of approaches that address known complexities of the X chromosome. These results demonstrate that incorporating the X chromosome in GWAS can reveal novel loci, even for complex behavioral traits such as dietary intake. Applying multiple association models further improves discovery by accounting for unique features of the X chromosome. Although diet is a major risk factor for many common diseases, adherence to healthy eating guidelines remains low. One reason is that current recommendations do not account for individual differences in food choice that arise from environmental or genetic factors. Previous genetic studies have identified hundreds of genetic variants associated with dietary behaviors, but most have excluded the X chromosome due to its analytical complexity and differences between males and females. However, accumulating evidence suggests that the X chromosome contains important genetic variation that impacts complex traits.We analyzed data from hundreds of thousands of individuals to identify genetic variants on the X chromosome associated with dietary intake. To address the unique features of the X chromosome, we applied multiple different models that account for sex-differences and non-additive genetic effects. We identified 18 regions in the genome associated with at least one dietary intake trait. These results reveal new insights into the genetics underlying eating behavior and highlight the importance of incorporating the X chromosome in genetic studies of complex traits.
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive synaptic dysfunction, axonal pathology, and cognitive decline, with the hippocampal circuits showing particular vulnerability during disease progression. However, early-life nutritional interventions may influence long-term synaptic resilience. In this study, we investigated the long-term effects of prenatal and lactational supplementation with choline, UMP, and fish oil in the 5XFAD mouse model. To this end, hippocampal synaptic and axonal pathology was assessed at 3, 6, and 9 months using Western blotting and immunofluorescence to measure synaptophysin, PSD-95, and neurofilament medium chain (NF-M), alongside a multidimensional behavioral battery that evaluated cognitive, affective, motor, and sensory outcomes. Results showed that early-life supplementation did not significantly improve the learning performance decline, increase nociception, or reverse changes in anxiety behavior in transgenic mice. However, it attenuated synaptic decline in transgenic animals by partially preserving synaptophysin and PSD-95 levels and reducing NF-M elevations. These molecular effects were accompanied by selective behavioral modulation, including preserved learning dynamics, altered anxiety-like behavior, and delayed nociceptive hypersensitivity, while late-stage motor impairments remained largely unaffected. Overall, prenatal and lactational supplementation produced modest, age-dependent effects on synaptic markers and partially prevented neurodegenerative progression in the 5XFAD model.
Mutations in SHANK3 are a leading monogenic cause of autism spectrum disorder (ASD), often associated with profound sensory abnormalities. However, the impact of SHANK3 deficiency on olfactory processing and the underlying neural mechanisms remains unclear. Here, we identify a cross-species disruption of olfactory valence perception in individuals with SHANK3 mutations and in Shank3 mutant mice. Patients carrying SHANK3 mutations exhibited impaired valence-oriented sniffing and electroencephalography (EEG) responses, whereas Shank3B-/- mice displayed blunted behavioral responses to both attractive and aversive odors. In mice, these behavioral deficits were associated with attenuated odor-evoked calcium signals and reduced excitatory synaptic transmission in the cortical amygdala (CoA), a key node for olfactory valence processing. Acute CoA-specific Shank3 deletion recapitulated these deficits, whereas targeted restoration of CoA Shank3 expression rescued odor-induced appetitive and aversive behaviors. Our findings reveal a conserved function for SHANK3 in encoding olfactory valence and identify CoA dysfunction as a circuit mechanism in mice.
Alzheimer's disease (AD) is a complex neurodegenerative condition involving β-amyloid (Aβ) deposition, tau abnormalities, neuroinflammation, neuronal degeneration, and progressive impairment of cognitive functions. Despite extensive research, effective disease-modifying therapies remain limited, highlighting the need for translationally relevant models and repurposable therapeutic candidates. Dexmedetomidine (DEX), an α2-adrenergic receptor agonist with known neuroprotective properties, was investigated in an adult zebrafish model of AD established through cerebroventricular administration of Aβ42. DEX treatment significantly reduced Aβ accumulation and was associated with reduced amyloidogenic gene expression, indicating transcriptional changes in amyloidogenic pathway-related genes. DEX attenuated neuroinflammation by reducing glial activation, lowering pro-inflammatory cytokine gene expression, and increasing expression of the anti-inflammatory gene il10. Immunofluorescence assessment further demonstrated reduced astrogliosis and preserved neuronal marker integrity, as indicated by increased HuC/D levels. Interestingly, DEX attenuated Aβ-induced proliferative responses, characterized by decreased PCNA expression, while enhancing cleaved caspase-3 levels, suggesting changes in proliferation and apoptotic signaling under Aβ stress conditions. Behavioral assessments further demonstrated that DEX alleviated Aβ42-induced anxiety- and aggression-like behaviors, improving behavioral phenotypes in this model. Overall, these findings underscore the multi-level effects of DEX in modulating AD-related pathological features. As a clinically available agent, DEX represents a promising candidate for repurposing in neurodegenerative disease contexts. Further preclinical studies in mammalian models are warranted to validate its translational relevance and therapeutic potential.
Taste sensation plays a crucial role in shaping feeding behavior and is intricately influenced by internal states like hunger or satiety. Despite the identification of numerous neural substrates regulating feeding behavior, the central neural substrate that linked energy-sensing and taste sensation remained elusive. Here, we identified a novel neural circuitry that could directly sense internal energy state and modulate sweet sensation in the Drosophila brain. Specifically, a subset of neuropeptidergic neurons expressing hugin directly detected elevated levels of circulating glucose via glucose transporter Glut1 and ATP-sensitive potassium channels. Upon activation, these neurons released hugin peptide and activated downstream Allatostatin A (AstA)+ neurons via its cognate receptor PK2-R1. Subsequently, the activation of AstA+ neurons then directly inhibited sweet sensation via AstA peptide and its cognate receptor AstA-R1 expressed in sweet-sensing Gr5a+ neurons. We also showed that Neuromedin U (NMU), the mammalian homolog of fly hugin, served as an energy sensor to suppress sweet sensation. Therefore, these data identify hugin+ neuron as a glucose-responsive central energy-sensing module that modulates sweet sensation across species.
Copyright: © 2026 Speyer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Gastrointestinal stromal tumors (GISTs) are molecularly defined by oncogenic alterations that predict clinical behavior and response to therapy. Activating mutations in KIT or PDGFRA characterize most GISTs and confer sensitivity to imatinib, whereas succinate dehydrogenase (SDH)–deficient GISTs lack these mutations and are typically imatinib resistant. These molecular subtypes are generally considered mutually exclusive. We report a rare case of a small bowel GIST harboring both a somatic KIT exon 9 A502_Y503 duplication and a germline inactivating SDHC mutation (p.R50C). The patient received neoadjuvant high-dose imatinib with a marked radiographic and metabolic response, followed by complete surgical resection. Pathology demonstrated spindle cell GIST with significant treatment effect and retained SDHB expression. This case suggests that oncogenic KIT signaling may remain the dominant driver of GIST behavior despite the presence of a germline SDHC mutation and highlights the importance of integrated molecular interpretation in GIST management.
Mosquito larvae depend on light detection for predator evasion and habitat selection; however, the molecular functions underlying larval photoreception remain largely unexplored. In this paper, we describe in detail the long-wavelength-sensitive opsin GPROP3 in Aedes mosquitoes by investigating its evolutionary conservation, expression patterns, and functional role in phototactic behavior. Using phylogenetic analyses, expression profiling across different developmental stages and tissues, and functional RNAi assays, we show that GPROP3 is required for larval negative phototaxis. These studies demonstrate stage-specific expression patterns and light-dependent subcellular dynamics and identify GPROP3 as a principal photosensor necessary for larval survival behaviors. These findings advance understanding of mosquito larval sensory systems and indicate their potential for vector control strategies targeting early developmental stages.
Atlantic bluefin tuna (Thunnus thynnus) are a highly migratory scombrid that traverse the north Atlantic Ocean. During the extensive history of exploitation of Atlantic bluefin tuna as a resource, several paradigms have been proposed in describing population structure. Currently, a two-stock model exists that defines separation between an eastern and western stock, with dominant spawning sites in the Mediterranean Sea and Gulf of Mexico, respectively. The discovery and continued collection of larvae in the Slope Sea renews research interest into spawning at alternative sites. Evidence for spawning outside of the Mediterranean Sea and Gulf of Mexico is well-supported in historical literature. Sites of interest that are included in this review are: 1) Historically recognized spawning sites of the Mediterranean Sea and Gulf of Mexico; 2) Recently confirmed spawning, in the Slope Sea; 3) Plausible spawning sites in the western Atlantic: the Straits of Florida-Caribbean Margin, South Atlantic Bight-Blake Plateau, and Yucatán-Western Caribbean; 4) Plausible spawning sites in the eastern Atlantic: the Bay of Biscay, off mainland Portugal, South Macaronesia, and North Macaronesia; and 5) Presumed collapsed sites, of the Black Sea, Gulf of Guinea, and Brazil. This review aims to compile references relevant to the likelihood of Atlantic bluefin tuna spawning in alternative spawning sites, including collections of larvae, presence of mature adults in spawning condition, captures of young-of-year juveniles, and supporting evidence in tagging studies, genetics, stock-mixing and population modeling, and microchemistry. Oceanographic conditions of areas of interest, including sea surface temperature, salinity, height anomaly, current velocity, and chlorophyll are described, and regional suitability for spawning and larval survival is discussed. In compiling this review, uncertainties in Atlantic bluefin tuna spawning are highlighted and gaps in knowledge addressed. Future work to resolve questions related to spawning, both spatially and temporally, is crucial for improving our understanding of the population. Sustainable management of this species is reliant upon accurate analysis of their structure and spawning behavior.
Bladder cancer is one of the most common malignancies of the urinary system. Identifying new potential therapeutic targets and exploring molecular mechanisms are crucial for improving treatment and prognosis. The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel 2, known to play a key role in various physiological and pathological processes, has an unclear function and mechanism of action in bladder cancer. We employed bioinformatics analysis and immunohistochemistry to assess the role of HCN2 in bladder cancer, integrating in vitro and in vivo models to evaluate the impact of HCN2 on cell behavior. Molecular interactions were characterized using immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays. Our investigation revealed a significant upregulation of HCN2 in bladder cancer tissues, which was predictive of a poorer clinical outcome. Functionally, HCN2 knockdown in bladder cancer impeded cell proliferation, induced apoptosis, and curtailed migration and invasion. Mechanistically, the overexpression of HCN2 contributed to the translocation of the REST transcription factor into the nucleus and facilitated its binding to the BGN promoter for transcriptional activation of its expression. This regulatory mechanism was shown to suppress ferroptosis, a form of regulated cell death, thereby enhancing the proliferative and tumorigenesis of bladder cancer cells. This study uncovers the novel mechanism by which HCN2 regulates ferroptosis via the REST-BGN axis, affecting bladder cancer cell behavior, and provides new perspectives and strategies for future clinical treatment.
Parkinson's disease (PD) is a common neurodegenerative disorder marked by progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies, intracellular inclusions enriched in α-synuclein. Synphilin-1 interacts with α-synuclein, localizes to Lewy bodies, and has been implicated in inclusion formation and neuroprotection in cellular and animal models; however, its physiological function in vivo remains poorly defined. Here, we generated and characterized a synphilin-1 knockout (Sph-1 KO) mouse by targeted genetic deletion of the Sph-1 locus and performed a comprehensive phenotyping battery including behavioral testing as well as biochemical, histological, structural, and ultrastructural analyses. Sph-1 KO mice survived to nearly two years of age and showed normal body weight, lifespan, motor performance, learning and memory, anxiety-like behavior, attention, and gross brain morphology. Western blot analyses indicated that levels of α-synuclein and synaptic proteins were largely unchanged. While outer mitochondrial membrane proteins were unaffected, the mitochondrial matrix protein HSP60 was reduced, consistent with altered mitochondrial proteostasis in the absence of synphilin-1. Strikingly, histochemical analyses, magnetic resonance imaging, and electron microscopy revealed early-onset hydrocephalus in Sph-1 KO mice associated with severe loss and disorganization of motile ependymal cilia in the ventricular lining, a cell type that normally expresses high levels of synphilin-1. Ultrastructural and immunohistochemical analyses revealed disrupted ependymal architecture, mislocalization of acetylated α-tubulin to the cytoplasm, cellular swelling, and enlarged, aberrant mitochondria, whereas cortical neurons appeared largely structurally unaffected. Together, these findings identify synphilin-1 as a key regulator of microtubule organization and cytoskeletal/organelle homeostasis in ependymal cells, required to maintain motile ciliogenesis, cerebrospinal fluid flow, and ventricular integrity. This unexpected role for synphilin-1 in ciliated brain epithelia, along with a reduction in the critical mitochondrial chaperone HSP60, broadens our understanding of synphilin-1 biology and provides a new framework for its potential relevance to PD-associated pathology.
Modulating brain oscillations has significant therapeutic promise. Traditional non-invasive neuromodulation techniques can alleviate clinical signs of Alzheimer's disease (AD) by restoring normal neural oscillatory activity in certain brain regions. As a novel non-invasive brain modulation technique, temporal interference (TI) has been demonstrated to precisely control hippocampus neural oscillations while minimizing its impact on cortical neural activity, but its exact mechanism of action is still unclear. We simulated and experimentally measured the intracranial electric field under TI to determine the precision of TI intervention. Subsequently, TI stimulation was applied to the APP/PS1 transgenic AD mouse model, and the impact of TI stimulation on the stimulated brain region was compared from the perspectives of behavior, electrophysiology, and cell biology. This work showed that in the APP/PS1 Alzheimer's disease mice model, TI stimulation significantly increased GABA levels and decreased NMDA receptor activation at the targeted region. Following neurotransmitter regulation, the rhythm of the gamma oscillations they associate also changed. This, in turn, influenced other memory-related neural oscillation frequencies and brain regions through cross-frequency coupling and brain connectivity, ultimately improving the behavioral performance of AD model mice. The results of our work demonstrated how TI stimulation alters brain oscillations to enhance memory in mice with Alzheimer's disease, offering a possible theoretical foundation for TI's clinical application.