The psychedelic psilocybin may have lasting therapeutic effects for patients with chronic pain syndromes. Some preclinical data suggest these putative benefits derive from direct analgesic effects; however, this possibility has not been comprehensively tested in preclinical models. Here, we evaluated the analgesic properties of a single exposure to psilocybin at acute and chronic time points in Complete Freund's Adjuvant-induced inflammatory pain, spared nerve injury model of neuropathic pain, and acid-induced muscle pain. Across these models, we tested a range of doses (0.3, 2, and 10 mg/kg i.p.) in male and female mice using multiple behavioral assays evaluating sensory aspects (von Frey, cold plate, Hargreaves, thermal place preference, and muscle withdrawal threshold) and functional aspects of pain (marble burying). We further tested the effects of psilocybin on the affective dimension of pain in a surgical model of acute pain (mouse grimace scale). Except for cold sensitivity, we found no effect of psilocybin across pain models, behavioral assays, drug doses, or sex. The apparent reduction in cold sensitivity may be explained by profound hypothermia induced by psilocybin rather than true analgesia.

Radiation-associated pain (RAP) after head and neck cancer treatment often results in significant discomfort, yet the mechanisms underlying this pain remain poorly understood. Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8) channels, known to mediate cold sensation, have been implicated in RAP. Previous studies suggested that inhibition of TRPM8 might offer a therapeutic approach for alleviating radiation-induced pain. We tested the effects of PBMC, a small molecule inhibitor of TRPM8, on radiation-induced glossitis and associated pain behaviors in C57BL/6J mice following tongue irradiation. We evaluated the impact of phenylethyl(2-aminoethyl)(4-(benzyloxy)-3-methoxybenzyl)carbamate (PBMC) on weight loss, burrowing, grooming behavior, and nest building. Additionally, mRNA expression of TRPM8 and other relevant ion channels was assessed in the trigeminal ganglion (TG) using qRT-PCR and in situ hybridization (ISH). Irradiated mice exhibited significant glossitis, weight loss, and altered behaviors, including impaired burrowing and grooming. PBMC treatment provided no measurable protection against glossitis and only weakly mitigated weight loss and abnormal burrowing behavior. Exposure to radiation led to downregulation of TRPM8 expression in the TG, contrasting with previous findings of upregulation. Interestingly, female mice showed greater susceptibility to RAP than males, highlighting a sex-dependent response. Our findings suggest that TRPM8 inhibition with PBMC does not alleviate radiation-induced pain or glossitis in the C57BL/6J murine model. The observed downregulation of TRPM8 expression challenges prior assumptions, and our results suggest that compensatory mechanisms or model-specific factors may contribute to the failure of PBMC to impact pain outcomes. Future studies incorporating genetic models and evaluating protein expression are necessary to better understand the role of TRPM8 in radiation-induced pain and to explore more effective therapeutic strategies.

The innate immune system is increasingly recognized as a contributor to the development of type 1 diabetes (T1D), but the role of natural killer (NK) cells remains largely unclear. Here, we identify an expanded subset of transcriptionally active CD226+CD56dimCD16+ NK cells at the onset of T1D that contracts in remission. Using single-cell RNA sequencing integrated with cross-sectional and longitudinal analyses in patients with T1D, we show that CD226+ NK cell frequency correlates with disease progression. CD226+ NK cells exhibit enhanced cytotoxicity, inflammation and glucose metabolism. Mechanistically, CD161+CD4+ T cells promote pathogenic NK cell generation through interleukin-21 (IL-21) and mTOR signalling. Inhibition of this pathway by CD226 blockade, IL-21 receptor fusion protein, IL-21 knockout or mTOR inhibition attenuates NK cell activation, reduces pancreatic infiltration and delays diabetes onset in female mice. Our data reveal a mechanistic link, bridging adaptive and innate immunity, in the progression and remission of T1D that could potentially be exploited in T1D immunotherapy.

While circuit formation is generally thought to be absent in the adult brain, there is evidence that the adult brain retains a considerable capacity for neuronal wiring. Among other findings, molecular programming by basic helix-loop-helix (bHLH) proteins can reactivate axon growth in adult neurons, allowing the investigation of the mechanisms and potential of adult brain rewiring. Here, we analyzed proteomic and transcriptomic changes during Id2- (a bHLH transcriptional regulator) and Ascl4- (a bHLH transcription factor) induced feedback and feedforward wiring in the hippocampus of adult male and female mice. We find that Id2 and Ascl4 share a molecular cascade through the transcription factor Stat1 and co-regulate a set of proteins that may constitute a core program for adult wiring. Unexpectedly, we also identify shared molecular changes that do not originate directly from the programmed neurons, but from endothelial cells and microglia. Taken together, our results suggest that adult brain wiring is regulated by specific molecular programs and dynamic interactions between the wiring neurons and the circuit environment.Significance statement Contrary to conventional views, axonal wiring and circuit formation is not limited to the developing brain but can also occur in the adult brain. Although this area of research remains largely unexplored in the naive brain, technologies to rewire the adult brain have the potential to help overcome severe limitations imposed by brain disease, injury, or aging. In this study, we investigate the signatures of adult brain wiring induced by molecular cell programming using different factors and reveal common molecular changes to better understand the underlying biological mechanisms.

Aromatase inhibitors are widely used in the treatment of hormone-sensitive breast cancer, but their suppression of estrogen production accelerates bone loss, increases fracture risk, and negatively impacts muscle and fat metabolism. Here, we demonstrate that daily low intensity vibration, serving as a non-drug mimetic for exercise, protects musculoskeletal health in skeletally immature, female mice under complete estrogen deprivation. Subsequent improvements in vertebral bone density are paralleled by greater and leaner skeletal muscle mass and function alongside reduced fat accretion and circulating metabolites. In mature, estrogen deprived mice, vibration enhances weekly bisphosphonate treatment, improving bone density, cortical thickness, and mechanical resistance to fracture. These findings support the proposed hypothesis that low intensity vibration reduces musculoskeletal frailty in estrogen deprived mice, with stronger effects observed in younger cohorts, while in skeletally mature mice combination therapy with anti-resorptive treatment is necessary to suppress cancer-treatment induced musculoskeletal degradation.

Over 25% of active NASA astronauts are women who will be exposed to low daily doses and dose rates of galactic cosmic rays (GCR) in space. We hypothesized that exposing mice to a preliminary simulated GCR mixed heavy ion beam composed of iron, silicon, and titanium ions induces follicle depletion and dose-dependent ovarian tumors. Female mice were exposed to 10, or 20 cGy each of Fe, Si, and Ti ions or sham-irradiation in quick succession within 15 minutes for total doses of 0, 30, or 60 cGy of the three beams. 16 months later, their ovaries were removed. Hyperplasia of the ovarian surface epithelium (OSE) was noted in 13%, 59%, and 22% of the 0, 30, and 60 cGy irradiated mice, respectively. The prevalence of mixed ovarian tumors was 0, 6, and 89%, respectively, in the 0, 30, and 60 cGy groups. Low numbers of Ki67 positive OSE and tumor cells supported a benign tumor phenotype. In a separate study, Si ion irradiation alone at 32 cGy did not induce ovarian tumors in mice; however, the mixed heavy ions at all doses and Si ion irradiation alone reduced the total number of healthy ovarian follicles. Mixed heavy ion exposure reduced lipid peroxidation, fibrosis, inflammation, and lipofuscin accumulation at 60 cGy compared to 0cGy, but elevated inflammation and lipofuscin accumulation at 30 cGy compared to 60 cGy. Preliminary simulated GCR exposure causes ovarian follicle death and tumorigenesis. This study provides insight into space-radiation induced ovarian damage and cancer risk in females.

The p75 neurotrophin receptor (p75NTR) contributes to the development of Alzheimer's Disease (AD) pathology by enhancing amyloid precursor protein (APP) cleavage and amyloid plaque formation. However, the cell type-specific and temporal roles of p75NTR in AD progression remain unclear. Here, we report that conditional knock-in of functionally impaired p75NTR variants lacking the death domain (ΔDD) or transmembrane Cys259 (C259A) specifically in forebrain excitatory neurons of male and female 5xFAD mice significantly attenuated multiple AD-associated pathologies, including amyloid plaque accumulation, gliosis, neurite dystrophy, as well as learning and memory deficits. Hippocampal amyloid plaque burden was reduced to levels comparable to those found in whole-body knock-in mice. Strikingly, delaying introduction of p75NTR variants until advanced disease stages produced comparable beneficial effects, and rescued behavior performance in cognitively impaired animals. These findings suggest that blunting p75NTR function can have beneficial effects even during symptomatic stages of AD, offering a potential therapeutic approach complementary to passive vaccination.Significance Statement Inactivation of p75NTR has been reported to show various degrees of neuroprotection in Aβ-based mouse models of AD. As p75NTR is expressed in several different cell types in the brain, it has been unclear whether the beneficial effects afforded arose from all cell types or only one. For therapeutic approaches to be viable in AD patients, any form of interference with its activity needs to demonstrate beneficial effects during symptomatic stages of the disease. Here, we show that replacement of native p75NTR with signaling-impaired variants in forebrain excitatory neurons is sufficient to significantly alleviate neuropathological and behavioral outcomes in 5xFAD mice. Moreover, significant amelioration of neuropathology and cognitive deficits were achieved after acute disruption of p75NTR during symptomatic AD stages.

Short-term plasticity occurs at synapses throughout the cerebellum, raising the question of how such plasticity affects cerebellar processing in vivo. To address this issue, we recorded responses of molecular layer interneurons (MLIs), Purkinje cells, neurons of the cerebellar nuclei (CbN), and mossy fibers in the CbN, in awake head-fixed female mice. During short trains of air puffs applied to the whisker pad with intervals from 25 to 200 ms, the first puff generated brief suppressions of spike probability in Purkinje cells and brief elevations in all other cell types, resulting in coincident excitation and disinhibition of CbN cells and large whisker protractions. Later puffs evoked smaller whisks and smaller responses in all cells, with the strongest decrease in the CbN. The reduction resulted from facilitation of EPSCs from parallel fiber axons of granule cells decreasing net inhibition of individual Purkinje cells, and from activation of fewer MLIs reducing inhibition across the Purkinje population. Downstream, the decrease in Purkinje-mediated disinhibition, in conjunction with depression of excitatory mossy fiber-to-CbN pathways, reduced net excitation of CbN cells. Sensory-evoked responses were transient and effectively transmitted synaptically, but movement-related responses were prolonged and progressively cancelled at successive stages of the circuit. Moreover, many MLI, Purkinje, and CbN cells had bilateral receptive fields. In these cells, changing the stimulus location restored responsiveness and increased whisk magnitudes. Thus, several types of cerebellar neurons can report stimulus changes without specifying stimulus parameters, thereby serving as event detectors that can facilitate movement in response to altered sensory inputs.

Abstract Haploinsufficiency of Dyrk1a , which encodes the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), has been causally linked to autism. Here we examined transcriptomic, electrophysiological and behavioral alterations in mice carrying a loss-of-function mutation of Dyrk1a ( Dyrk mut ). We found that genes downregulated in prefrontal cortex (PFC) of male and female Dyrk mut mice were enriched in chemical synaptic transmission and trans-synaptic signaling. In PFC pyramidal neurons of Dyrk mut mice, the frequency of synaptic-driven spontaneous action potentials (sAP) was significantly reduced, and glutamatergic excitatory postsynaptic currents (EPSC) and GABAergic inhibitory postsynaptic currents (IPSC) were markedly diminished. Furthermore, autism-like social preference deficits and elevated anxiety were manifested in Dyrk mut mice of both sexes. A short treatment of Dyrk mut mice with an inhibitor of the epigenetic corepressor lysine-specific histone demethylase 1A (LSD1) led to a significant elevation of sAP frequency, EPSC and IPSC in PFC pyramidal neurons of Dyrk mut mice. Moreover, the LSD1 inhibitor ameliorated social deficits in Dyrk mut mice and reduced anxiety in Dyrk mut males. Therefore, these data have not only revealed synaptic and behavioral deficits in PFC induced by Dyrk1a mutation, but also uncovered the therapeutic potential of LSD1 inhibition in Dyrk1a -deficient conditions.

Background/Objectives: Skin photoaging represents a predominant form of extrinsic aging, characterized by structural and functional impairment of the skin barrier. In severe cases, it may precipitate dermatological diseases and even tumors. Given the prevalence and detrimental effects of skin photoaging, strategies for its effective prevention and mitigation have garnered significant research interest. Chrysanthemum morifolium Ramat cv. ‘Hangju’ contains diverse bioactive compounds, including flavonoids, phenylpropanoids, phenolic acids, and polysaccharides, which have been proven to exhibit antioxidant and anti-inflammatory effects. Methods: This study employed a UVB-induced mouse model of skin photoaging to evaluate the potential of dietary supplementation with Chrysanthemum morifolium Ramat cv. ‘Hangju’ flower extract (CME) in vivo. Results: In the photoaged skin of female SKH-1 hairless mice, dietary supplementation with CME significantly increased skin moisture content, reduced wrinkle formation, suppressed epidermal hyperplasia, enhanced collagen density, and suppressed the senescence marker expression and DNA damage marker expression. Analysis of the skin transcriptome suggested that CME could alter gene expression patterns and potentially modulate critical signaling pathways involved in skin homeostasis. Moreover, 16S rRNA sequencing indicated that CME mitigated UVB-induced gut microbiota dysbiosis. Conclusions: These preclinical findings reveal the anti-photoaging property of dietary CME supplementation and point to its potential application as a functional dietary supplement for promoting skin health.

Dense temporal measurements of physiological health, using simple and consistent assays, are essential to characterize biological processes associated with aging and evaluate the effectiveness of interventions on these processes. We measured body weight in 960 genetically diverse female mice, every 7-10 days over the full course of their lifespan. We used a state space model to characterize the trajectories of body weight throughout life and derived novel traits capturing the dynamics of body weight, 10 of which were both heritable and associated with lifespan. Genetic mapping of these body weight-derived traits identified 5 genomic loci, none of which were previously mapped to body weight. We observed that the ability to maintain stable body weight, despite fluctuations in energy intake and expenditure, was positively associated with lifespan in an age-dependent manner and mapped to a genomic locus linked to energy homeostasis. Our results highlight how dense longitudinal measurements of physiological phenotypes offer new insights into the biology of aging.

Neurogenesis in the dentate gyrus of the hippocampus is a conserved and highly regulated process throughout the lifespan. Hippocampal neural stem and progenitor cells (NSPCs) can either transition into an activated proliferative state or remain quiescent. Accumulating data suggests that mitochondrial fatty acid β-oxidation is important in maintaining NSPCs quiescence under normal physiological conditions; however, the contribution of this pathway in NSPCs following brain injury remains unknown. While severe traumatic brain injury (TBI) is characterized by increased NSPCs proliferation in the hippocampus, the extent of this proliferative response after mild TBI, the most prevalent form of TBI, has not been fully delineated. Using closed head injury as a model of mild TBI and a brain-specific knockout mouse of carnitine palmitoyltransferase 2 (CPT2; an obligate gene in mitochondrial fatty acid β-oxidation), we investigated the role of fatty acid oxidation in hippocampal NSPCs proliferation in naïve and injured male and female mice. Our results show that loss of CPT2 in the brain does not affect hippocampal proliferation in naïve mice. Furthermore, mild TBI upregulates proliferation at day 3 post-injury, and is further increased only in male CPT2-deficient mice. Despite the post-injury increase in hippocampal NSPCs proliferation in CPT2B−/− mice, long-term neurogenesis remained unchanged. Together, these data provides a new insight into the metabolic regulation of NSPCs neurogenesis in the hippocampus following mild traumatic brain injury.

Prenatal PFHxS Exposure Alters Ovarian Development in Female Adolescent Mice: Transcriptomic, Hormonal, and Structural Evidence of Disrupted Steroidogenesis.

Unbiased, scalable behavioral phenotyping that captures multi-animal interactions in home-cage settings is increasingly needed. Here we present 'IntelliProfiler', a research workflow consisting of data processing scripts that extract locomotor activity and pairwise proximity from a commercially available, previously validated, high-resolution radio frequency identification floor plate. IntelliProfiler is not a standalone system; it operates on data acquired with the Phenovance floor plate and is not yet validated with other hardware configurations. The workflow reconstructs individual trajectories and positions of multiple mice, enabling long-term assessment of locomotor activity and social spacing. In proof-of-concept analyses, male mice placed in a novel cage environment maintained greater inter-animal distances than female mice, an effect that strengthened as group size increased. Aging reduced locomotor activity in a group size-dependent manner and altered proximity patterns. In addition, offspring of aged fathers (a paternal-aging autism spectrum disorder model) exhibited hyperactivity and increased social distance relative to controls, consistent with autism spectrum disorder-related phenotypes and motivating further investigations. Together, these findings demonstrate that IntelliProfiler workflow provides a practical and versatile approach for screening group dynamics and quantifying complex social behaviors in neuroscience research.

The NEGR1 gene has been implicated in several psychiatric disorders, and increased NMDA receptor binding density has been demonstrated in vitro in hippocampal slices from Negr1-deficient mice. In this study, we expanded on these findings by investigating the behavioural response to NMDA receptor antagonism, expression of NMDA receptor subunits, and kynurenine pathway metabolites in a Negr1-deficient mouse model. Male and female wild-type and Negr1-deficient mice received daily injections of MK-801, a non-competitive NMDA receptor antagonist, until behavioural tolerance developed in the open field test (after 9 days in males and 5 days in females). In drug-naive animals, acute MK-801 administration (0.2mg/kg) elicited a stronger motor response in Negr1-deficient males compared to wild-type controls. However, with repeated dosing, Negr1-deficient males exhibited a blunted behavioural response and attenuated progression of rapid behavioural tolerance during every-second-day MK-801 administration, suggesting altered receptor sensitivity. Gene expression analysis revealed sex- and brain region-specific changes in NMDA receptor subunit expression. Additionally, kynurenine pathway metabolites showed genotype- and sex-dependent alterations. These findings suggest that NEGR1 protein modulates NMDA receptor function and tryptophan metabolism in a sex-dependent manner, highlighting the importance of considering both genetic background and sex in models of glutamatergic dysfunction relevant to neuropsychiatric disorders.

Blood-brain barrier (BBB) dysfunction has been associated with vascular dementia (VaD). However, the underlying mechanisms causing BBB dysfunction remain unclear, especially regarding cerebral hypoperfusion. This study aims to investigate the effects of asymmetric hypoperfusion on BBB permeability using a mouse model of VaD. Asymmetric bilateral carotid artery stenosis (ACAS) was induced using ligature rings. BBB integrity was assessed on 3 days post-surgery using Evans blue, IgG and albumin extravasation. A modified tissue processing protocol optimized endogenous markers detection. Regional and sex-based differences in BBB permeability were analyzed. Increased BBB permeability was observed in both corpus callosum and cortical areas, with significantly more severe leakage in the left cortex compared to the right, correlating directly with lower cerebral blood flow on the left side. In contrast, no significant asymmetrical difference in BBB permeability was detected in the corpus callosum. Additionally, male and female mice exhibited similar patterns of BBB permeability. This study provides the first evidence that asymmetrical hypoperfusion significantly impacts regional BBB permeability in a mouse model of VaD. These findings highlight the importance of local hemodynamic changes in driving BBB dysfunction and underscore potential therapeutic targets for preventing or mitigating vascular dementia progression.

Selenium and zinc elements have been proven to participate in immune regulation and infertility improvement. Their potential has been confirmed in in prostatitis and reproductive performance modulation. In this study, first the composition of selenium- and zinc-enriched duck embryo egg (SZDE) powder was analyzed, especially trace elements and oligopeptides. Secondly, acute toxicity was evaluated. A prostatitis rat model was constructed to explore the SZDE anti-inflammation effects. Levels of selenium and zinc elements were much higher in SZDE than in normal eggs. SZDE showed no toxicity in male or female mice according to behavior and pathological parameters. Significant downregulated pro-inflammatory cytokines and increased androgens levels (P < 0.05) were found after the SZDE intervention. Prostatitis was significantly improved via inhibition of the MAPK/p38 pathway following SZDE treatment (P < 0.05). Overall, these findings demonstrated the security and prostatitis regulation effect of SZDE, indicating that it might serve as a new dietary strategy for prostate health. © 2025 Society of Chemical Industry.

Tackling the interplay between the brain and kidneys: CYP2C19 mice as a preclinical tool for studying cognitive impairment in kidney disease?

To investigate the therapeutic effects and mechanisms of curcumin (Cur) in adenomyosis (AM). A mouse uterine AM model was established by exposing ICR neonatal mice to tamoxifen (TAM). Female neonatal mice (day 1, n=24) were numbered and randomly divided into control, model (TAM 1 mg/kg per day, day 2 to 5), low- and high-doses Cur groups (TAM 1 mg/kg per day, day 2 to 5; Cur 50 and 200 mg/kg per day, respectively, week 13 to 15), by a random number table, with 6 mice in each group. The effect of Cur was assessed by a hot-plate test on mice and uterine sections for hematoxylin and eosin (HE), Masson staining, and immunohistochemistry staining of E-cadherin, N-cadherin, matrix metalloproteinases (MMP) 9 and MMP 11. Ishikawa (IK) cell phenotypic transformation was induced by transforming growth factor beta 1 (TGF-β1), and the mRNA and protein expressions of E-cadherin, N-cadherin, MMP 9, MMP 11 and p-Smad3/Smad3 were detected by quantitative real-time PCR and Western blot after Cur treatment. In vivo study results showed that Cur significantly improved pain tolerance (P<0.01). The degrees of lesion fibrosis and invasion of ectopic glands in model mice were significantly higher than those in control mice, and the degrees were significantly reduced after high-dose Cur treatment (P<0.01). High-dose Cur reversed the decrease of E-cadherin and the increase of the levels of N-cadherin, MMP 9 and MMP11 by inhibiting the production of TGF-β1 in the uterine tissue (P<0.01). In vitro study, Cur increased the protein expression of E-cadherin and reduced the protein expressions of N-cadherin, MMP 9 and MMP 11 (P<0.01). Cur effectively inhibited the phosphorylation of p-Smad3/Smad3 in IK cells induced by TGF-β1 (P<0.01). Cur effectively alleviates AM and inhibits fibroblast differentiation and epithelial-mesenchymal transition by TGF-β1/Smad3 pathway, which provides a new approach for treating AM by non-hormonal drugs.

Anticoagulation/ antiplatelet treatment could potentially reduce the metastatic process, however, consistent evidence is lacking. Here we explored an in vivo model of experimental metastasis of murine B16 melanoma to observe tumor cell extravasation under therapy with aspirin or enoxaparin. Three treatment groups by 5 C57BL/6 female mice were injected with B16/F10 cells in the retro orbital sinus. After two weeks necropsy was performed. In the group treated with enoxaparin, a marked reduction in the number of metastatic foci in the lungs, with 6-193 metastases and 0.04-2.3% affected lung area were observed. The control group had 561-1000 metastatic lesions and 13-21% affected area. In the aspirin-treated group, there was a reduction in the number of metastatic lesions (386 - 640) and area (6.4-19%). Both aspirin and enoxaparin treatment affect the progression of metastases in mice, with enoxaparin being the most effective.