Molecular Psychiatry最新文献

Long non-coding RNAs (lncRNAs) have emerged as critical regulators of gene expression, particularly in complex neuropsychiatric disorders such as major depressive disorder (MDD). This study investigates the expression of lncRNAs in the dorsolateral prefrontal cortex (dlPFC) of MDD subjects and their potential roles in chromatin remodeling and gene silencing. Following the 8×60 K microarray platform, we profiled the expression of 35,003 lncRNAs in 59 MDD and 41 control subjects, identifying 1625 upregulated and 1439 downregulated lncRNAs in the MDD group. Co-expression network analysis revealed a complex and interconnected lncRNA network in MDD, suggesting intricate regulatory mechanisms. Furthermore, by employing the PIRCh-seq technique, we found that a subset of 60 upregulated lncRNAs in the MDD brain interacts with heterochromatic regions marked by the H3K27me3 modification, thereby silencing gene expression. These lncRNAs were associated with 24 downregulated protein-coding genes linked to neuronal functions, including synaptic vesicle exocytosis and neurotransmitter release. Gene ontology and pathway analyses highlighted disruptions in critical neurobiological functions, with particular emphasis on synaptic and neuronal signaling pathways. Our findings underscore the role of lncRNA-mediated heterochromatization in the pathophysiology of MDD, offering novel insights into the epigenetic regulation of brain function and behavior.

Epidemiologic evidence links follicle-stimulating hormone (FSH), a pituitary glycoprotein that rises during menopause, to memory loss, fat accumulation, and bone loss. We and others have shown that the attenuation of FSH signaling, either genetically or pharmacologically, prevents memory loss, fat accrual, and bone loss in multiple mouse models. Here, we investigated whether the genetic depletion of the FSH receptor (Fshr) affects recognition memory, body composition, and bone mineral density (BMD) in two AD mouse models. We generated male and female 3xTg and APP-KI mice carrying the Fshr^+/+, Fshr^+/-, and Fshr^-/- genotypes. Recognition memory was evaluated using the Novel Object Recognition (NOR) test. Body composition (fat, lean, and total mass) and site-specific bone mineral density (femur, tibia, L3-L5 spine) measurements were made using quantitative nuclear magnetic resonance (qNMR) and dual-energy X-ray absorptiometry (DXA), respectively, at two time points. Given that female Fshr^-/- genotypes are otherwise hypogonadal, they were implanted with 17β-estradiol pellets at 8-12 weeks of age to normalize serum estrogen. At the early time point, the deficit in recognition memory was rescued in female 3xTg;Fshr^-/- and APP-KI;Fshr^-/- mice, but not in male mice. Likewise, female, but not male 3xTg;Fshr^-/- mice showed reduced fat mass at both the early and later time points, but without changes in total body mass. In contrast, in the APP-KI cohort, both female and male Fshr^-/- mice showed reduced fat mass at the early, but not the late time point. DXA revealed that female, but not male APP-KI;Fshr^-/- mice showed progressive increases with time in BMDs in tibiae, femora, and vertebrae, which were either statistically significant or approached significance. This phenotype was not observed on the 3xTg background. These studies constitute the first report for time- and strain-dependent effects of global Fshr depletion in the same mouse, setting the stage for the simultaneous prevention, using a single therapeutic, of three disorders of public health magnitude-Alzheimer's disease, obesity and osteoporosis.

Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental disorders with heterogeneous causes, and are characterized by communication deficits, impaired social interactions, and repetitive behaviors. Despite numerous studies in mouse models focused on pathophysiological circuit mechanisms of ASD in mature animals, little is known regarding ASD onset and its evolution through development. The medial prefrontal cortex (mPFC) is crucial for higher-order cognitive functions and social behavior, thus key to understanding ASD pathology. To explore early developmental disruptions in the mPFC, we used the Shank3 knockout (Shank3^-/-) mouse model. SHANK3 is crucial for glutamatergic synapse maturation, and the Shank3^-/- mouse has been well-characterized for displaying ASD-related behavioral phenotypes. We investigated network, cellular, and synaptic changes within the mPFC and in its projections to the mediodorsal thalamus (MD) at two developmental stages, preweaning (P14) and adulthood (>P55). Our findings reveal early synaptic deficits at P14 both within the mPFC and in its projections to the MD accompanied by alterations in mPFC network activity and reduced excitability of excitatory neurons, overall suggesting hypofunction. Interestingly, behavioral deficits were already detectable by P11, preceding the observation of synaptic changes at P14. By adulthood, these early synaptic and cellular alterations progressed to global dysfunction, characterized by mPFC network hyperfunction and layer 5 pyramidal cell hyperexcitability, accompanied by augmented glutamatergic signaling to MD with enhanced action potential production. These results suggest that early synaptic changes may precede and interact with behavioral deficits, which might lead to compensatory mechanisms that contribute to more pronounced mPFC dysfunction later in development. This study highlights the complex dynamic progression of mPFC deficits in ASD and emphasizes the relevance of early synaptic alterations as potential contributors to later behavioral and cognitive deficits.

The severe stresses induce fear memory and mental disorders including anxiety, depression and schizophrenia. Their molecular and cellular mechanisms are expectedly revealed to develop therapeutic strategies. We aim to identify the stress-induced cellular units and neural circuits that are essential for fear memory and schizophrenia in cerebral cortices by behavior tasks, molecular biology, neural tracing and electrophysiology. The social stress by the resident/intruder paradigm leads to the fear memory specific to a resident CD1 mouse and schizophrenia-like behaviors as well as the synapse interconnections among medial prefrontal, auditory and S1Tr cortical neurons in intruder mice. This stress-induced synapse interconnection enables these cortical neurons be recruited as associative memory neurons that are featured by receiving the convergent synapse innervations from the interconnected areas and encoding the stressful signals including the battle sound and the pain signal from trunk-injury area generated in the social stress. The knockdown of dopaminergic receptor-II in the medial prefrontal cortex precludes the recruitment of associative memory neurons and the formation of fear memory and schizophrenia-like behaviors. Eticlopride as a dopaminergic receptor-II antagonist in the medial prefrontal cortex weakens the activities of associative memory neurons and relieves schizophrenia-like behavior. These associative memory neurons recruited by the social stress in the medial prefrontal, auditory and S1Tr cortices through dopaminergic receptors-II are essential for fear memory and schizophrenia.

A deeper understanding of the molecular processes involved in psychological wellbeing in older adults is essential for advancing knowledge of underlying biological mechanisms. Leveraging proteomics data from 3,262 older adults (mean age = 63.5 years, 55% female) of the English Longitudinal Study of Ageing (ELSA), we investigated the cross-sectional and longitudinal associations (before and after protein measurement) between 276 proteins and eudaimonic wellbeing, hedonic wellbeing, life satisfaction, and depressive symptoms, over 20-year span. For positive wellbeing, two proteins (DEFB4A and ECE1) were longitudinally associated with subsequent eudaimonic wellbeing trajectory. We further identified higher concentrations of 7, 8, and 2 proteins were linked to subsequent lower eudaimonic wellbeing, hedonic wellbeing, and life satisfaction, respectively. Sex differences in XCL1 and SLAMF7 were observed, associated with subsequent lower eudaimonic and hedonic wellbeing in males. These findings link human psychological wellbeing to regulation of several biological pathways, particularly involving cytokine regulation, neurotrophic signaling, inflammatory and immune systems.

Gangliosides serve as receptors for proteins, bacteria, and viruses, with sialylation at the termini of their glycan chains playing a crucial role in ligand recognition and endocytosis. The internalization of proteopathic tau aggregates by neurons is integral to the propagation of tau pathology in Alzheimer's disease (AD). However, the influence of gangliosides and their sialylation modifications on the uptake of proteopathic tau aggregates and the subsequent impact on AD pathology remains unclear. This study investigates the roles of the four mammalian sialidases (Neu1-Neu4) in modulating tau aggregation in cellular models. Our findings demonstrate that Neu3 significantly inhibits tau aggregation induced by proteopathic tau derived from the brains of AD patients (AD P-tau). Overexpressing Neu3 or administering ganglioside GM1, which results from Neu3-catalyzed removal of one sialic acid from GD1a, in the mouse model decreases the GD1a/GM1 ratio in mouse brain, effectively blocks the spread of tau pathology and improves recognition in AD P-tau-injected mice. Both Neu3 and GM1 reduce the internalization of tau aggregates, while GD1a enhances tau uptake, showing a positive correlation with the level of internalized tau. Moreover, the internalization of tau mediated by GD1a dependent on low-density lipoprotein receptor-related protein 1 (LRP1) and compensates for heparin-inhibited tau uptake. In vitro assays demonstrate that GD1a exhibits a higher binding avidity for tau filaments than GM1. These findings indicate that GD1a may directly bind to tau aggregates via the sialic acid moiety, facilitating LRP1-mediated tau uptake. This study proposes a novel mechanism for tau internalization and posits that reducing ganglioside sialylation may be a promising strategy for hindering the spread of tau pathology in AD.