Isoflurane (Isof), a commonly used pediatric anesthetic, has been linked to neurotoxicity during brain development, resulting in cognitive impairments and neuroinflammation. Androstenediol (ADIOL), a neurosteroid with anti-inflammatory and anti-oxidant activities, exhibits potential in treating neurodegenerative disorders through estrogen receptor β (ERβ) agonism. Thirty-six newborn male albino rats were randomly allocated to four distinct groups: Control, Isof, ADIOL + Isof, and ADIOL + PHTPP (ERβ antagonist) + Isof. Isof neurotoxicity induced by inhalation of 0.75% Isof for 6 h. ADIOL (25 mg/kg/day) and PHTPP were given subcutaneously for two days before Iso exposure. Behavioral tests (Morris water maze, T-maze, open field, and rotarod test) evaluated spatial learning, memory, exploration, motor functions, and biochemical investigations to evaluate oxidative and inflammatory states. Isof exposure significantly reduced spatial learning and memory, with disturbed exploration behavior of neonatal rats with motor incoordination insults. Isof induced oxidative stress with the inflammatory response. ADIOL administration abates these abnormalities, but co-administration with PHTPP averted ADIOL's protective effects, indicating ERβ-mediated processes. ADIOL reduces Isof-induced neurotoxicity via ERB agonist. Its neuroprotective activity suggests a feasible therapeutic approach to reducing anesthetic-induced developmental neurotoxicity.

Goldenhar Syndrome (GS) is a rare congenital craniofacial disorder characterized by asymmetrical facial deformities. It is often underdiagnosed due to the limited availability of clinical data and the absence of automated screening tools. This study establishes a strong foundation for integrating explainable deep learning (DL) models into computerized systems for screening craniofacial anomalies. We employed a publicly available image dataset for the GS detection dataset, comprising 3,550 original and 5,520 augmented craniofacial images, categorized into seven anomaly types. To address the challenges of fine-grained feature localization in rare disorders, we propose YOLO-MvX, a lightweight and adaptive detection model. This model incorporates an OD-Mamba backbone and a Vision Clue Merge (VCM) module to enhance feature fusion and anomaly discrimination. Experiments were conducted with three train/test splits (75/25, 80/20, and 85/15) on both imbalanced and balanced datasets. YOLO-MvX achieved a 96.4% mAP@50, with 94.3% precision and 93.5% recall, outperforming YOLOv9-YOLOv11 by up to 4.3%. Paired t-tests confirmed these improvements as statistically significant [Formula: see text] with large effect sizes. The model showed consistent performance across splits, indicating minimal sensitivity to partitioning, and improved class-wise metrics after balancing, where mean recall increased from 89.5% to 93.3%; mean mAP@50 increased from 92.1% to 95.7%. GradCAM++ provided the most reliable visual explanations (IoU-Heat = 0.87) with enhanced fidelity after balancing. YOLO-MvX also demonstrated efficiency with 4.30M parameters, 10.3 GFLOPs, fast inference speed, and low memory usage. These findings position YOLO-MvX as an efficient and interpretable detector for GS anomaly screening, although external validation under diverse conditions is recommended.

To investigate whether cardiac dysfunction predicts further gray matter microstructural integrity and whether this integrity mediates the association with cognitive performance, we conducted a prospective observational cohort study of 73 patients (20 females and 53 males; mean age 54.8 years) from the Leipzig Heart Study. We performed baseline cardiac assessments followed by diffusion-weighted magnetic resonance imaging and cognitive testing after a follow-up of 3.5 years. Participants included patients with established heart failure and matched patients without heart failure presenting with suspected coronary artery disease. We assessed baseline cardiac biomarkers including left ventricular ejection fraction and N-terminal pro-B-type natriuretic peptide. The main outcomes were gray matter microstructural integrity (mean diffusivity) and cognitive performance. Mediation analysis evaluated whether regional mean diffusivity mediated the association between cardiac function and cognition. Across all 73 participants, a lower baseline ejection fraction predicted greater future gray matter mean diffusivity even in patients without clinical heart failure, acting as an early-stage indicator. Conversely, higher natriuretic peptide levels predicted extensive microstructural damage exclusively in the established heart failure group. Notably, increased mean diffusivity in Alzheimer's disease-vulnerable regions (specifically the cingulate and lingual gyri) significantly mediated the association between cardiac health and subsequent memory performance. In conclusion, cardiac dysfunction is associated with a predictable continuum of brain microstructural damage where conventional imaging previously failed. Crucially, this microstructural degradation mediates the link to memory decline, identifying brain microstructural integrity as a high-priority targets for upstream intervention aimed at preserving cognitive health.Significance Statement This study establishes a specific link between cardiac dysfunction and cognitive decline based on microstructural brain alterations. We identify a "heart-brain continuum" where routine cardiac biomarkers predict future brain microstructural damage. Crucially, this microstructural degradation targets Alzheimer's disease-vulnerable regions and acts as the mediator driving memory loss. By validating gray matter mean diffusivity as a sensitive tracker of this progression, our findings underscore that preserving brain microstructural integrity is a critical target in patients with cardiac dysfunction, offering a vital opportunity to intervene upstream before the onset of dementia.

Maternal immune activation (MIA) is associated with increased risk of neurodevelopmental disorders, including schizophrenia. Research demonstrates sex-specific responses to MIA, yet how MIA interacts with intrinsic sex differences during brain development remains unclear. Here, we investigated how poly(I:C)-induced MIA alters metabolic, epigenetic and inhibitory developmental trajectories. Female, but not male, poly(I:C) offspring exhibited an object location memory deficit, implicating the hippocampus as a vulnerable region. Using RNA sequencing of the prenatal hippocampus, we identified a pronounced female-specific transcriptional response to MIA, with enrichment of mitochondrial and chromatin-related pathways. Concurrently, intrinsic sex differences indicated divergent metabolic/mitochondrial maturation, such as increased expression of Ppargc1a (encoding peroxisome proliferator-activated receptor gamma coactivator 1-α) and increased antioxidant activity in females compared to males, consistent with greater metabolic capacity. MIA interacted with these trajectories, producing sex-dependent effects on mitochondrial dynamics which coincided with signatures of a more permissive chromatin state, including reduced histone deacetylase activity, increased histone acetylation and reduced H3K27 methylation. In adulthood, MIA offspring showed altered chloride transporter expression, with a shift toward NKCC1 (a molecular driver of the GABAergic switch) and evidence of promoter-level epigenetic regulation, most evident in females. This coincided with reduced clusters of the scaffolding protein gephyrin in adolescent poly(I:C) females, consistent with altered inhibitory synapse maturation. Together, these findings indicate that sex-specific metabolic programming shapes the neurodevelopmental response to MIA and contributes to the observed sex differences in brain and behavioural response. Understanding typical sex differences in mitochondrial development is critical for predicting vulnerability and informing therapeutic treatment.

Lithium counteracts impulsivity and aggression in affective disorders, two emotion-related facets of inhibitory control. The question arises as to whether lithium affects inhibitory processes in affective and cognitive domains in animals. The effects of lithium were compared with placebo on learning tasks and tests of exploratory activity predominantly in rats and mice. There is evidence from a few studies that lithium facilitates inhibitory processes in regard to perseverative responding in left-right alternation and hole-board learning, premature responding in serial reaction time, delay-discounting impulsivity, and prepulse inhibition, while impeding inhibitory processes in the latent inhibition paradigm as well as tests of exploratory activity as seen in the elevated plus-maze and 2-choice spontaneous alternation. Lithium may lead either to greater or lesser inhibitory control depending on perceived rewards relative to dangers.

Liver cancer remains a major cause of cancer mortality, and precise CT-based liver tumor segmentation is critical for early diagnosis and personalized treatment. In practice, fully 3D‑supervised training is limited by prohibitive annotation costs and memory and compute demands. Achieving 3D segmentation from purely 2D supervision is attractive yet challenging due to through-plane context loss, inter‑slice inconsistency, weak boundaries, and low contrast and noise. We propose LiT‑WSAG, a 2D‑trained framework that reconstructs voxel‑wise 3D masks. Built upon SAM‑Med2D, it incorporates a wavelet‑guided dual‑scale channel adapter (WDSC‑Adapter) to decouple low- and high-frequency content and enhance multi-scale representations, a lightweight L2.5D neighborhood fusion to recover through‑plane context at near‑2D cost, and adversarial training with a ramped GAN weight ('mean-loss' scheduling) to enforce shape and boundary consistency. Extensive experiments demonstrate significant gains over the baseline across multiple datasets. On the LiTS dataset, LiT‑WSAG achieves slice‑wise and volumetric DSC of 89.74% and 69.27% (+ 8.85 and + 33.64 percentage points over SAM-Med2D); on the WAW‑TACE dataset, the corresponding scores are 96.08% and 82.03%. Furthermore, on the Synapse multi-organ dataset, it attains a state-of-the-art average DSC of 88.23%. These results indicate that LiT‑WSAG delivers robust 3D liver tumor segmentation from 2D supervision, balancing boundary accuracy, noise robustness, and computational efficiency.

Postoperative cognitive dysfunction (POCD) is a common complication of surgery in elderly patients and is characterized primarily by memory impairment; however, the underlying mechanisms remain incompletely understood. By utilizing a laparotomy model in aged mice and the delayed spatial alternation task (DSAT), we found that surgery specifically impaired the memory consolidation process. Importantly, this impairment was accompanied by significant disruption of sharp-wave ripples (SPW-R) in the hippocampal CA1 region. Previous research has indicated that trafficking of GluA2-containing AMPARs at CA3 recurrent synapses is crucial for SPW-R generation. Therefore, we examined postsynaptic AMPARs in the CA3 region after surgery and observed reduced membrane expression of GluA2-containing AMPARs, although the total protein levels and gene transcription remained unchanged. Immunofluorescence and coimmunoprecipitation revealed significantly decreased colocalization and binding of GluA2 with postsynaptic density protein 95 (PSD95), suggesting impaired synaptic GluA2 trafficking. Importantly, immediate postoperative injection of TAT-GluA23Y into the CA3 region to increase GluA2 synaptic expression significantly ameliorated surgery-induced SPW-R disruption and memory consolidation deficits. Conversely, local injection of a GluA2 cross-linking agent into the CA3 region of aged mice to inhibit GluA2 trafficking mimicked the postoperative phenotypes of SPW-R disruption and memory consolidation deficits. These results reveal that surgical trauma induces impaired GluA2 trafficking at hippocampal CA3, leading to CA1 SPW-R disruption and ultimately resulting in memory consolidation deficits. This discovery provides not only a novel molecular and neural circuit explanation for the pathogenesis of POCD but also an experimental foundation for the development of neuroprotective strategies targeting GluA2 trafficking.

Palmitoylation has been implicated in learning and memory processes, yet its precise role and underlying mechanisms remain poorly understood. Here, we report a novel role of palmitoylation in regulating amygdalar synaptic plasticity and fear memory, involving the regulation of palmitate cycling on PSD-95. Using a series of multi-methodological experiments, we demonstrated that conditioned fear learning impairs amygdalar metaplasticity-an effect not observed in the hippocampus. Furthermore, PSD-95 recruits LTP-like mechanisms at lateral amygdala (LA) synapses, and its palmitoylation is critically involved in fear memory expression. Notably, PSD-95 palmitoylation contributes to the occlusion of LA-LTP following fear conditioning. Mechanistically, DHHC2 drives PSD-95 palmitoylation and modulates LA synaptic plasticity following fear conditioning, whereas PICK1 facilitates the activity-dependent trafficking of DHHC2 to PSD-95 at synapses. Collectively, these findings highlight the PICK1-DHHC2-PSD-95 pathway as a critical regulator of learning-dependent metaplasticity in the LA, which occludes further HFS-induced LTP while promoting fear memory expression.

Alzheimer's Disease (AD) is an age-dependent neurodegenerative disorder and represents the most common type of dementia, increasing in incidence at an alarming rate in the aging population. The hallmarks of the disease are amyloid plaque accumulation, microglia and astrocyte activation, and loss of presynaptic structure leading to cognitive decline. Recently, oligodendrocyte (OL) and myelin abnormalities have emerged as important contributors to the pathogenesis of AD. In normal brain homeostatic conditions, OL maintain neuronal health through myelin axon interactions and by supplying neurotrophic and metabolic support. How strengthening OL function may support neuronal health in AD neurodegeneration remains to be fully characterized and represents a gap in knowledge and a missed therapeutic opportunity. This study sought to examine how myelin and OL may improve neuronal deficits associated with AD. We have generated a novel mouse model (AD/cKO) by crossing the AppNL-G-F mouse, an established AD model, which carries three human AD mutations in the mouse App gene, with the FusOLcKO whose OL depleted of Fus (Fused in Sarcoma) produce thicker myelin associated with greater cholesterol biosynthesis. We evaluated spatial memory function with standardized cognitive testing. We evaluated microglia density and state, astrocytic activation and toxic phenotype, myelin density, cholesterol content, amyloid plaque burden, presynaptic structures, and neuronal hypoxic and oxidative damage in the hippocampus and cortex. We characterized the transcriptome of AD/cKO hippocampal OL compared to AD by using single-cell transcriptomic studies. Spatial working memory was fully preserved in the aged AD/cKO mouse relative to the AD mouse. This outcome was associated with reduced neuronal oxidative damage, preserved presynaptic structures at the amyloid plaque niches, and a shift in microglia state at the niches in both hippocampus and cortex. In contrast, amyloid plaque burden and microglia density were decreased in the hippocampus but not in cortex, uncoupling the neuronal and microglia effects from the amyloid burden. Fus dependent myelin increase was present in both hippocampus and cortex. Single-cell transcriptomics of AD/cKO hippocampal OL revealed upregulation of energy metabolism and antioxidant genes, suggesting a role of OL enhanced energy metabolism in mediating protection of neurons and affecting microglia state in AD pathology. This work provides new insight into how oligodendrocytes may protect neurons in AD, communicate with other glial cellular players, and point to potential targets for disease intervention aimed at slowing AD progression.

Clinical and epidemiological data support the link between viral encephalitis and neurodegeneration but its causal mechanism remains mostly unknown. Zika virus (ZIKV) is an emerging, neurotropic flavivirus susceptible to induce cognitive impairments in infected adults. In this work we have analyzed the capacity of ZIKV to induce the accumulation of pathological phosphorylated Tau protein (pTau), a major driver of neurodegenerative disorders such as Alzheimer's disease, throughout the infection of adult immunocompetent mice. The capacity of ZIKV to induce pTau in vivo, was analyzed in the long term in three Collaborative Cross mouse strains displaying different responses to ZIKV. The establishment and propagation of pTau was quantified up to 60 days post-infection (dpi) in correlation with the level and localization of neuronal viral infection and of microglia activation using immunofluorescence, immunohistochemistry, wide field and confocal microscopy and gene expression analysis. Strength, coordination, memory and social behavior were evaluated before and following the establishment and progression of pTau. The role of microglia on ZIKV-induced pTau was investigated by partially depleting microglial cells using PLX3397 (PLX). ZIKV infection induced a significant accumulation of pTau starting at 15 that persisted at least until 60 dpi. At 15 dpi, pTau was observed in ZIKV-infected neurons in the CA2 and CA1 regions of the hippocampus and in non-infected cortical neurons in association with neuroinflammation and social behavior alterations. At 30 dpi, pTau progressed independently of infection and inflammation, positively correlated to PLX-susceptible Apoe gene expression in association with short-term memory defects. These results shed light on how brain viral infections, which are a major concern for public health, drive pTau accumulation and propagation in link with memory impairment and social behavior alterations laying the groundwork for potential new therapeutic treatments.