lncRNA Glelr modulates microglia inflammatory programs in association with PU.1.

Alcohol impacts an fMRI marker of neural inhibition in humans and rodents.

High-intensity interval training and moderate-intensity continuous training improve hippocampal synaptic plasticity in Alzheimer's disease via differential lactylation.

Mitochondria are multifaceted organelles positioned at the intersection of multiple signaling pathways. Beyond serving as one of the main energy providers in the brain, they play crucial roles in shaping cytosolic calcium signals across both neuronal and glial cell populations, modulating synaptic transmission and plasticity, and regulating neuronal excitability and network activity. The involvement of mitochondrial calcium handling in brain cell physiology has been explored for many years. However, by enabling in vivo cell-specific manipulations, the molecular identification of mitochondrial calcium signaling protein complexes, over the past 2 decades, has tremendously improved our understanding of how mitochondria regulate brain function and behavior.This review synthesizes current knowledge of mitochondrial calcium handling mechanisms and protein complexes in the nervous system, as well as their involvement in brain function, from cellular physiology to behavioral consequences. We discuss pharmacological and genetic evidence for a role of mitochondrial calcium handling in synaptic transmission, neuronal excitability, astrocyte functions, and circuit activity. We underline experimental differences across approaches and models, as well as show how genetic tools have challenged or confirmed earlier pharmacological results. Finally, we examine how recent advances using transgenic models have revealed complex roles for mitochondrial calcium signaling in behavioral responses and opened new research avenues.

Macrophage-mediated refinement of the dural lymphatic regulates social behavior.

The extracellular matrix as a dynamic regulator of brain function and plasticity.

Pig farming faces significant financial losses due to aggressive behavior in individual pigs. Such aggression leads to skin and tail injuries, followed by infections and death. This review summarizes research on genetic and epigenetic mechanisms underlying aggressive behavior in pigs highlighting associations with different SNPs located in intergenic, intronic, and regulatory gene regions. These loci contain a large number of transposable elements (TEs), which occupy 37.9% of the porcine genome and are identified in more than 80% of all protein-coding genes. TEs contribute to cis-, trans-, and epigenetic regulation and serve as important sources for the emergence and evolution of non-coding RNAs. The review discusses the key role of TEs in pig embryogenesis, brain development, and the pathogenesis of neurodegenerative diseases. SNPs associated with aggressive behavior in pigs are likely to affect TE sequences, disrupting their activation and influencing the expression of non-coding RNAs involved in the regulation of brain functions. TEs are highly sensitive genomic sensors for environmental influences, activated by stress, viruses, hormonal fluctuations, and anabolic steroids. TE redistribution and recombination also influence CNV changes associated with aggressive behavior in pigs. TE activation promotes the development of inflammatory processes in the brain, while increased expression of genes involved in immune system function and inflammation has been detected. Differences in the expression of specific genes in the pig and wild boar brain may be due to structural changes in the porcine genome influenced by TEs during breeding, which affects epigenetic features of gene regulation. Increased aggression in certain pig breeds and individual pigs may be related to specific TE redistribution patterns in their genomes. The review suggests strategies for further research on the role of TEs in aggressive behavior and methods to influence them for correcting impaired epigenetic regulation.

The crosstalk between blood-brain barrier and neural cells: bidirectional regulation of brain function and pathology.

White matter, constituting nearly half of the human brain, is increasingly recognized as a dynamic regulator of neural communication, metabolism, and cognition rather than a passive conduit for signal transmission. Recent advances in neuroimaging, molecular biology, and single-cell transcriptomics have revealed that myelin and oligodendrocytes play essential roles in neural plasticity and disease. Here, we synthesize current understanding of white matter organization and myelin function, emphasizing its contributions to conduction efficiency, metabolic support, and network optimization. We further discuss mechanisms of myelin plasticity and highlight its role in learning, adaptation, and repair. Integrating evidence across developmental, immune-mediated, neurodegenerative, and psychiatric disorders, we propose that white matter pathology constitutes a primary driver of brain dysfunction. Finally, we summarize emerging regenerative strategies-including cell and gene therapies, OPC-targeted interventions, and neuromodulation-highlighting translational opportunities for restoring myelin integrity and circuit function. This review reframes white matter as a promising therapeutic frontier.

This review critically appraises seminal studies on emerging mechanisms of gut-brain communication, summarising microbiome-targeted clinical interventions, and highlighting future trajectories for therapeutic development in mental health. The gut microbiome, comprising trillions of microbial cells, exerts major influence over host metabolism, immunity, and neural function. Through the gut–brain axis, a complex network linking neural, immune, and endocrine pathways, microbial communities shape cognition and emotional regulation. Mounting evidence identifies key microbial taxa, metabolites, and molecular pathways governing mental health. Core mediators include short-chain fatty acids, tryptophan–kynurenine metabolites, and bile acid derivatives, which modulate blood–brain barrier integrity, neurotransmission, and systemic inflammation. Dysbiosis-driven endotoxaemia, particularly via lipopolysaccharide signalling, activates neuroinflammatory cascades implicated in depression and anxiety. Precision psychobiotics such as Bifidobacterium longum NCC3001 and Lactobacillus plantarum PS128 show strain-specific efficacy in reducing depressive symptoms in randomised controlled trials. Both animal and human studies highlight bidirectional interplay: psychological stress reshapes gut ecology, while microbial imbalance disrupts mood and cognition. Emerging interventions, including faecal microbiota transplantation and synthetic microbial consortia, show translational promise but remain constrained by ethical and regulatory barriers. This review integrates findings from clinical trials, multi-omics mapping, and computational models to clarify microbiome–brain mechanisms. It outlines prospective directions in psychobiotic design, metabolite biomarkers, and systems-based therapeutics, framing the gut microbiome as a modifiable determinant of neuropsychiatric health. With continued rigorous investigation and integration across disciplines, microbiome research is poised to revolutionise our understanding and management of mental health disorders, ultimately enhancing patient outcomes and quality of life.

Understanding the brain's complexity and developing treatments for its disorders necessitates advanced neural technologies. Magnetic fields can deeply penetrate biological tissues-including bone and air-without significant attenuation, offering a compelling approach for wireless, bidirectional neural interfacing. This review explores the rapidly advancing field of magnetic implantable devices and materials designed for modulation and sensing of the brain. Key modulation strategies include: magnetoelectric (ME) materials that convert magnetic into electric fields for stimulation; magnetothermal (MT) effects, where heating of nanoparticles activates thermosensitive ion channels; and magnetomechanical (MM) approaches that use magnetic forces to gate mechanosensitive channels. Methods for magnetic-based detection encompass: implantable magnetoresistive probes for the reference-free measurement of weak local neural magnetic fields; magnetic resonance needles that enhance metabolic profiling; and magnetoelastic systems where external magnetic fields vibrate magnetic implants to sense biophysical and biochemical conditions. The breadth of these magnetic transduction mechanisms promises future technologies that provide less invasive and more precise methods for understanding and regulating brain function.

Astrocytes are now widely accepted as key regulators of brain function and behavior. Calcium (Ca2+) signals in perisynaptic astrocytic processes (PAPs) enable astrocytes to fine-tune neurotransmission at tripartite synapses. As most PAPs are below the diffraction limit, their content in Ca2+ stores and the contribution of the latter to astrocytic Ca2+ activity is unclear. Here, we reconstruct hippocampal tripartite synapses in 3D from a high-resolution electron microscopy (EM) dataset and find that 75% of PAPs contain some endoplasmic reticulum (ER), a major calcium store in astrocytes. The ER in PAPs displays strikingly diverse shapes and intracellular spatial distributions. To investigate the causal relationship between each of these geometrical properties and the spatiotemporal characteristics of Ca2+ signals, we implemented an algorithm that generates 3D PAP meshes by altering the distribution of the ER independently from ER and cell shape. Reaction-diffusion simulations in these meshes reveal that astrocyte activity is governed by a complex interplay between the location of Ca2+ channels, ER surface-volume ratio, and spatial distribution. In particular, our results suggest that ER-PM contact sites can act as local signal amplifiers if equipped with IP3R clusters but attenuate PAP Ca2+ activity in the absence of clustering. This study sheds new light on the ultrastructural basis of the diverse astrocytic Ca2+ microdomain signals and on the mechanisms that regulate neuron-astrocyte signal transmission at tripartite synapses.

Cerebrospinal fluid (CSF) is increasingly recognized as an active regulator of brain function rather than a passive mechanical buffer. Beyond its classical roles in cushioning the brain and removing metabolic waste, CSF participates in a tightly coupled system linking neural activity, vascular dynamics, molecular signaling, and tissue mechanics. Here, we present an integrated theoretical framework that unifies three major conceptual strategies in contemporary CSF research: metabolic clearance, neuromodulatory signaling, and bidirectional coupling between fluid dynamics and neural activity. We argue that these processes form a closed-loop regulatory system in which brain state governs CSF flow, while CSF dynamics reciprocally shape neural function and long-term brain health. Disruptions to this integrated CSF-brain system underlie a wide spectrum of neurological disorders, including Alzheimer's disease, stroke, sleep disorders, and hydrocephalus. By synthesizing evidence across scales and disciplines, this framework provides a coherent conceptual foundation for future experimental, diagnostic, and therapeutic advances targeting CSF physiology.

N6-methyladenosine (m6A) is an abundant post-transcriptional RNA modification that critically regulates brain function. Dysregulation of m6A signaling has been implicated in several neurological diseases, including Alzheimer's disease (AD). However, whether genetic variation associated with the risk of AD is mediated via m6A-dependent gene regulation is currently unknown. Here we investigated the association of m6A with the risk of AD using the summary-data-based Mendelian randomization (SMR) approach. By integrating m6A quantitative trait loci (m6A-QTLs) and genome-wide association study (GWAS) summary data for AD, we identified six nominally significant m6A-AD associations (uncorrected PSMR < 0.05, PHEIDI ≥ 0.01 with ≥5 SNPs), although none remained significant after false discovery rate (FDR) correction. We performed targeted SMR analyses for AD using brain- and blood-based expression QTL summary data, restricting instrumental variables to a set of 18,606 single nucleotide polymorphisms (SNPs) previously identified as m6A-related sites. This analysis identified 75 FDR-significant genes associated with the risk of AD via changes in gene expression (FDR < 0.05, PHEIDI ≥ 0.01 with ≥5 SNPs); however, the instrumental SNPs for these genes showed no enrichment for m6A-QTLs. In summary, we found limited evidence for the direct association of m6A genetic variation with the risk of AD. Larger m6A-QTL datasets will be required to establish whether m6A variation is associated with the risk of AD.

Schizophrenia (SCZ) is a major mental disorder with a high disability rate, and its pathogenesis involves the interaction of multiple factors such as genetics, environment, immunity, and neurodevelopment. Most SCZ patients are complicated with significant sleep disorder (SD), manifested as insomnia, sleep fragmentation, reduction in slow-wave sleep, and circadian rhythm disturbance. This comorbidity not only aggravates the severity of psychiatric symptoms but also significantly impacts treatment adherence and long-term prognosis. In recent years, the role of gut microbiota and its metabolites in mental diseases has received increasing attention. Existing studies have shown that the gut microbiota regulates brain function through the microbiota-gut-brain axis, affects the metabolism of neurotransmitters and immune-inflammatory responses, and thus may play an important role in the occurrence and development of SCZ and SD. However, the specific mechanism is still not clear enough at present, and there are still deficiencies in relevant studies. This article reviews the characteristics of gut microbiota diversity and metabolome related to sleep in SCZ patients, explores the potential mechanism of the role of gut microbiota and its metabolites in SCZ complicated with SD, provides a new microbial-metabolic perspective for understanding the pathogenesis of SD in SCZ patients, and suggests the potential therapeutic value of improving sleep problems in SCZ patients through probiotic intervention or metabolic regulation. These findings not only deepen the understanding of the comorbidity mechanism of mental diseases and SD but also provide a theoretical basis for new intervention strategies based on the gut-brain axis.

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 60upregulated 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.

Pericytes (PCs) are multifunctional mural cells embedded in the basement membrane of microvessels and play essential roles in the development and maintenance of the central nervous system. This review provides a comprehensive synthesis of the current knowledge on PC biology, tracing their trajectory from embryonic origins to specialized functions in the adult brain. During early brain development, PCs are recruited via platelet-derived growth factor B (PDGF-BB)/platelet-derived growth factor receptor beta (PDGFRβ) signaling and contribute to the formation of the blood-brain barrier (BBB), cortical architecture, and vascular stability. Their developmental plasticity is shaped by multiple embryonic origins and dynamic interactions with endothelial and neural precursor cells. In the adult central nervous system, PCs are central to maintaining BBB integrity, regulating cerebral blood flow, and modulating neurovascular coupling. They also participate in immune responses, metabolic waste clearance, and neuroprotection through the secretion of trophic factors and cytokines. Of particular interest is their emerging role in the expression of lipocalin-type prostaglandin D synthase (L-PGDS), which synthesizes prostaglandin D2-a molecule involved in sleep regulation, inflammation, and neurodegeneration. L-PGDS may also act as an amyloid β chaperone, implicating PCs in the pathology of Alzheimer's disease and other neurodegenerative disorders. The regulatory mechanisms of L-PGDS expression involve nuclear factor kappa B and Notch-Hes signaling, as well as potential modulation via brain-derived neurotrophic factor/tropomyosin receptor kinase B/protein kinase C pathway. By integrating developmental, molecular, and pathophysiological perspectives, this review positions PCs as key cellular regulators of brain function and highlights their potential as therapeutic targets in cerebrovascular and neurodegenerative diseases.

Although adenosine was identified in the brain many decades ago, our understanding of when, where, and how it functions has expanded rapidly in recent years, driven in part by innovative technological advances. Adenosine is now increasingly recognized as a key neuromodulator that dynamically regulates brain circuits important for sleep/wakefulness, movement, cognition, and homeostasis. In addition, growing attention has been directed toward the molecular mechanisms governing adenosine production and its downstream signaling pathways, both of which hold great promise as therapeutic targets for neuropsychiatric disorders and neurodegenerative diseases. This review highlights recent progress in detecting adenosine, unraveling its signaling pathways in vitro and in vivo, and understanding how it regulates brain function under physiological and pathological conditions.

The two-way communication between intestinal microbiota and the central nervous system (the microbiota-gut-brain axis) is involved in the regulation of brain function, neurodevelopment, and aging. The microbiota-gut-brain axis dysfunction may be a predisposition factor for Parkinson's disease (PD), Alzheimer's disease (AD), Autism spectrum disorder (ASD), and other neurological diseases. However, it is not clear whether gut microbiota dysfunction contributes to neuropsychiatric disorders. Changes in the gut microbiota may modulate or modify the effects of environmental factors on neuropsychiatric disorders. Factors that impact neuropsychiatric disorders also influence the gut microbiota, including diet patterns, exercise, stress and functional gastrointestinal disorders. These factors change microbiome composition and function, along with the metabolism and immune responses that cause neuropsychiatric disorders. In this review, we summarized epidemiological and laboratory evidence for the influence of the gut microbiota, metabolism and environmental factors on neuropsychiatric disorders incidence and outcomes. Furthermore, the role of gut microbiota in the two-way interaction between the gut and the brain was also reviewed, including the vagus nerve, microbial metabolism, and immuno-inflammatory responses. We also considered the therapeutic strategies that target gut microbiota in the treatment of neuropsychiatric disorders, including prebiotics, probiotics, Fecal microbiota transplant (FMT), and antibiotics. Based on these data, possible strategies for microbiota-targeted intervention could improve people's lives and prevent neuropsychiatric disorders in the future.

Long non-coding RNAs (lncRNAs) are emerging as key regulators of brain function, but their contribution to microglial aging and neurodegenerative disease remains largely unknown. Because only 1.5% of the human genome encodes proteins, whereas the vast majority of transcripts belong to the largely unexplored non-coding RNAome, elucidating the functions of non-coding RNAs provides an unprecedented opportunity to expand the space for therapeutic discovery. We recently identified the glia-enriched lncRNA 3222401L13Rik as upregulated in the aging mouse hippocampus. Here, we investigated its function in microglia and its human homolog ENSG00000272070. We found that 3222401L13Rik is expressed in both astrocytes and microglia and increases with age. Knockdown of 3222401L13Rik in primary microglia led to enhanced expression of pro-inflammatory cytokines, including TNFα, and increased phagocytic activity. RNA-sequencing revealed widespread transcriptional changes enriched for TNF and complement signaling pathways. The human homolog ENSG00000272070 showed conserved functions in iPSC-derived microglia, where its loss similarly promoted inflammatory gene expression and phagocytosis. Mechanistically, 3222401L13Rik interacts with the microglial transcription factor PU.1, and its depletion overlapped with PU.1-driven transcriptional programs. Consistent with these findings, ENSG00000272070 expression was significantly reduced in postmortem Alzheimer’s disease (AD) brains, and AD-associated genes were enriched among 3222401L13Rik-regulated targets. Together, our results identify 3222401L13Rik/ENSG00000272070 as a conserved, aging-associated lncRNA that modulates microglial inflammatory states through interaction with PU.1. This work links glial lncRNA regulation to AD-related neuroinflammation and suggests 3222401L13Rik as a potential molecular target to fine-tune microglial activity in neurodegenerative diseases.