ABSTRACT The apolipoprotein E ε4 allele (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD) and confers disproportionate risk in women, particularly after reproductive senescence. The brain changes preceding overt neurodegeneration in APOE4 carriers remain incompletely characterized. We conducted neuroimaging and behavioral studies in aged (18‐month) female APOE4 humanized knock‐in rats and APOE3 controls. Regional brain volumes across 197 areas were quantified by voxel‐based morphometry (VBM); white and gray matter microstructure by diffusion tensor imaging (DTI), yielding fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Spatial memory was assessed with the Barnes maze and motor coordination with the beam walk. APOE4 rats showed significantly larger regional brain volumes than APOE3 controls. DTI revealed increased FA in the thalamus, brainstem, and white matter tracts, and reduced FA in the sensorimotor cortex. Across most regions elevated FA was accompanied by reduced ADC, an inverse relationship consistent with cytotoxic edema. Behaviorally, APOE4 rats were significantly impaired on the Barnes maze. Aged female APOE4 knock‐in rats exhibit a preclinical AD phenotype: widespread volumetric enlargement across white matter, sensorimotor, and limbic circuits, with microstructural alterations (elevated FA in brainstem, thalamus, and white matter; reduced FA in sensorimotor cortex). This mirrors the imaging and cognitive profile of cognitively normal human APOE4 carriers in preclinical AD and validates the model as a translationally relevant platform for investigating early APOE4‐driven pathophysiology and testing preventive interventions.
ABSTRACT Serotonin transporter (SERT) variation is linked to depression risk after stress, conferring an increased risk to SERT‐linked polymorphic region (5‐HTTLPR) short‐allele carriers, who show heightened sensitivity to cumulative stress and childhood maltreatment. To elucidate the neurobiological mechanisms underlying SERT × early‐life adversity interactions, animal models capturing this genetic vulnerability are of translational relevance. We evaluated four maternal separation (MS) paradigms to determine how different forms of early‐life stress influence adult behavior in female SERT‐deficient rats, given the higher prevalence of depression in women and the limited translational value of male‐only preclinical findings. We applied several behavioral tests to wildtype (SERT +/+ ), heterozygous (SERT +/− ), and homozygous (SERT −/− ) knockout females exposed to MS: predictable 3 h/day (MS180) or 6 h/day (MS360), unpredictable 3 h/day (MSU180), or unpredictable 3 h/day plus unpredictable maternal stress (MSUS180). Controls were 15‐min handled. SERT −/− females exhibited higher anxiety‐like responses, passive stress coping, and increased social exploration. MS180 and MS360 induced some anxiety‐like behaviors, while MS360 increased hedonic responding. Females responded differently to MS depending on their SERT genotype. First, some anxious behaviors of SERT −/− females were attenuated when exposed to unpredictable MS (MSU180 and MSUS180). Second, MSU180 reduced object recognition in SERT −/− females, while enhancing it in SERT +/− females. Third, SERT +/− females exhibited less passive stress coping when exposed to MS360 than all other groups. Neither predictable nor unpredictable MS exposure increased vulnerability to depressive‐related behaviors in SERT‐deficient females. Variations in SERT expression may confer some beneficial effects in response to MS, depending on the specific genotype and behavioral domain evaluated.
ABSTRACT Based on post‐mortem studies, a long‐standing hypothesis on the biological bases of specific reading disabilities (RD) has been that alterations in neuronal migration alter language neural circuits. However, there are questions concerning the original studies (small sample size, comorbidities). Further, this idea has not been strongly supported by current genetic studies. In this study, we test altered neural cell phenotypes using cells derived from two pairs of siblings strongly discordant for reading—probands with severe RD and their strong‐reader siblings. We observed significant differences in neurosphere outgrowth between the neural precursor cells (NPCs) from the probands compared to their strong‐reader siblings. Transcriptome analyses of adherent NPCs and neurons derived from the NPCs identified genes differentially expressed between the probands and siblings, including genes previously identified in neurodevelopmental disorders. Of note was the overexpression of the hormone IGF1 and the transcription factor OTX2 , responsible for the opening and closing of critical windows in development and predicted to be involved in critical windows for language acquisition. Our results support altered transcriptome and cellular phenotypes in RD neural cells and suggest possible molecular mechanisms underlying the changes.
Alzheimer's disease (AD), a neurodegenerative condition marked by amyloid-beta plaques and tau protein neurofibrillary tangles, progresses against a backdrop of essential biological processes. Manganese, an indispensable trace element for vital functions including energy metabolism and antioxidant defense, is integral to neurological health. Its precise metabolic role throughout the course of AD pathogenesis is not fully elucidated. Four essential manganese metabolism-related genes were identified as diagnostic markers through a multi-omic framework. This approach integrated Weighted Gene Co-Expression Network Analysis with machine learning ensembles (Least Absolute Shrinkage and Selection Operator/Random Forest/Extreme Gradient Boosting), followed by rigorous testing in an independent dataset. Beyond identification, we utilized CIBERSORT and ssGSEA to characterize immune infiltration and leveraged GSEA/GO/KEGG for pathway elucidation. Finally, AD patients were stratified into molecular subgroups based on these hub genes, and their underlying regulatory networks involving miRNAs and transcription factors were reconstructed. An integrated bioinformatics framework identified 12 differentially expressed genes related to manganese metabolism in AD. Machine-learning-based feature selection further pinpointed four key diagnostic biomarkers (TSPO, PTBP1, GLO1, and ACACB) with high discriminative power (AUC: 0.831-0.905). Immune infiltration analysis revealed substantial immune remodeling in AD, including an elevation of naïve B cells. Moreover, AD samples were classified into two molecular subtypes displaying distinct immune and metabolic characteristics, and regulatory miRNA/TF interaction networks were constructed for the core genes. Our results shed new light on the molecular mechanisms underlying AD and support future efforts toward early diagnosis and personalized therapeutic interventions based on molecular subtypes.
Glucocorticoid signalling plays a central role in the processing of traumatic memories and contributes to adaptive and pathological responses to stress, with dysregulation frequently reported in trauma-related conditions such as post-traumatic stress disorder (PTSD). A key stage in trauma memory formation is the early consolidation window, during which aversive experiences are stabilised into long-term memory through protein synthesis and activity-dependent gene expression. To investigate how glucocorticoid levels during trauma exposure shape this process, we examined the behavioural and molecular consequences of acute and chronic corticosterone elevation, the rodent analogue of cortisol. Adult male mice received either repeated corticosterone injections for 5 days prior to fear conditioning (FC) or vehicle injections for 5 days followed by a single corticosterone injection immediately before FC. Two hours after FC, we quantified expression of genes encoding mineralocorticoid receptors (Nr3c2, MR), glucocorticoid receptors (Nr3c1, GR), and FK506-binding protein 5 (Fkbp5) in the amygdala, hippocampus, and anterior cingulate cortex (ACC). Trauma memory was assessed 24 h later by measuring freezing and exploratory behaviour to conditioned cues in separate experimental cohorts. Chronic corticosterone exposure was associated with attenuated conditioning-related behavioural responses, whereas acute corticosterone did not alter these responses. These effects were accompanied by region-specific alterations in glucocorticoid-signalling gene expression, most notably coordinated regulation of hippocampal and ACC Nr3c2 following FC. We propose that this regional Nr3c2 transcriptional signature represents an early molecular adaptation to prolonged glucocorticoid exposure that may alter hippocampal-prefrontal communication during trauma-memory formation.
