Frontiers In Cellular Neuroscience[JOURNAL]
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200 papers
Intensive multidisciplinary rehabilitation modulates serum -synuclein and miRNA expression in Parkinson's disease: preliminary results of a randomized study.
Agostini S, Meloni M, Mancuso R … +8 more , Nuzzi R, Ferraro G, Salvatore A, Arcuri P, Castagna A, Navarro J, Saibene FL, Clerici M
Front Cell Neurosci · 2026 · PMID 42290958 · Full text
INTRODUCTION: Parkinson's disease is a progressive neurodegenerative condition, and unfortunately, there are currently no treatments available that can halt or slow down its progression. However, recent research on inten...
INTRODUCTION: Parkinson's disease is a progressive neurodegenerative condition, and unfortunately, there are currently no treatments available that can halt or slow down its progression. However, recent research on intensive and multidisciplinary rehabilitation shows great promise, indicating that vigorous exercise may offer benefits to patients. This study is a randomized, single-blind, controlled, two-arm trial comparing an intensive outpatient multidisciplinary rehabilitation program with a home-based self-administered stretching program in Persons with Parkinson's disease (PwPD). This study aims to assess the effects of an intensive rehabilitation program compared to a home-based self-treatment plan on the serum expression of four molecular biomarkers: brain-derived neurotrophic factor (BDNF), total -synuclein, miR-223-3p, and miR-7-1-5p in PwPD. METHODS: We enrolled seventy PwPD in mild-to-moderate stages (average age: 71.15 ± 16.19 years, disease duration: 7.67 ± 5.61 years; UPDRS: 38.06 ± 13.07). Out of these, 36 participants (19 males and 17 females) were assigned to an outpatient daily intensive multidisciplinary rehabilitation treatment (EXP-PwPD), while 34 (22 males and 12 females) participated in a home-based self-treatment stretching program (CTRL-PwPD). Serum samples were taken at baseline (T0), at the end of the intervention period (T1, 6 weeks after T0), and at T2 (3 months after T1). We measured the protein concentrations (BDNF and -synuclein) and circulating miRNAs (miR-223-3p and miR-7-1-5p) in the serum, and compared results between the groups. RESULTS AND DISCUSSION: The intensive rehabilitation program led to a significant increase in serum BDNF and -synuclein expression. Notably, the rise in serum α-synuclein was dependent on exercise, returning to baseline concentration at T2, while serum BDNF remained significantly elevated even 2 months post-program completion (T2) ( = 0.03). Among the miRNAs studied, miR-7-1-5p reflected the pattern of BDNF, showing a notable increase after intensive rehabilitation ( = 0.05) and persistence at follow-up ( = 0.04). There were no significant changes for miR-223-3p. In conclusion, this study indicates that intensive rehabilitation can modify circulating biomarkers in PD. Our findings indicate that intensive exercise induces a sustained elevation of serum BDNF and miR-7-1-5p, reflecting enhanced neuroplastic and neurotrophic activity. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT05452655.
Copper and cuproptosis-related genes as indictors for the diagnosis of injury time in traumatic brain injury: human cases and animal experiment.
Gu R, Yu X, Tan Y … +4 more , Li G, Suo L, Ding R, Yao H
Front Cell Neurosci · 2026 · PMID 42290957 · Full text
Traumatic brain injury (TBI) is one of the most frequently encountered injuries in forensic practice. Nevertheless, a major technical bottleneck persists: there are no stable, specific indicators available for estimating...
Traumatic brain injury (TBI) is one of the most frequently encountered injuries in forensic practice. Nevertheless, a major technical bottleneck persists: there are no stable, specific indicators available for estimating the injury time of TBI in either clinical or forensic settings, which severely hinders the efficiency and accuracy of relevant case identification. Against this backdrop, the present study centers on the spatiotemporal distribution of copper ions (Cu) and the newly identified cuproptosis pathway, systematically investigating their associations with TBI progression via retrospective detection of human postmortem samples and prospective experiments on mouse TBI models. Preliminary findings revealed that within 30 days after TBI onset in humans, the copper content in the cerebral contusion area rises remarkably in a time-dependent manner, particularly in frozen-preserved cadaver samples. Concurrently, activation of the cuproptosis process was observed in the cerebral contusion region of mouse TBI models. Collectively, these findings may shed new light on the development of potential biomarkers for TBI injury time estimation. In addition, the expression levels of FDX1, DLD and SLC31A1 are applicable for inferring the time of early-stage TBI, while those of LIAS and SLC31A1 can facilitate the determination of injury time in late-stage TBI.
Cerebrospinal fluid lipid profiles as exploratory biomarkers for pediatric meningitis: a proof-of-concept case series.
Tang F, Li C, Zeng Y … +3 more , Luo W, Xi L, Wang X
Front Cell Neurosci · 2026 · PMID 42290956 · Full text
OBJECTIVES: To investigate the cerebrospinal fluid (CSF) lipid metabolite profiles of pediatric patients with purulent meningitis (PM) or viral meningitis (VM) and to explore their differential diagnostic potential. METH...
OBJECTIVES: To investigate the cerebrospinal fluid (CSF) lipid metabolite profiles of pediatric patients with purulent meningitis (PM) or viral meningitis (VM) and to explore their differential diagnostic potential. METHODS: In this proof-of-concept case series, 13 CSF samples from 10 pediatric patients were analyzed by lipidomics, distributed across four sample-level analytical groups: acute-phase PM (PM_A, = 3) and recovery-phase PM (PM_R, = 3) from 3 PM patients with paired sampling, acute-phase VM (VM_A, = 3) from 3 VM patients, and non-meningitic controls (N, = 4). Lipid separation and detection were performed by UPLC-MS/MS on a Q Exactive high-resolution mass spectrometer, and data were processed using LipidSearch v.4.1. RESULTS: Compared with the N group, the PM_A group displayed exploratory lipid alterations with 30 increased and 45 decreased metabolites, predominantly involving sphingolipid (SPH), dihexosylceramide (Hex2Cer), monohexosylceramide (Hex1Cer), lysophosphatidylcholine (LPC), and acylcarnitine (AcCa) species. Elevated Hex2Cer combined with reduced SPH represented a distinctive exploratory PM_A pattern. Receiver operating characteristic (ROC) analysis identified LPC(20:3) and Hex2Cer(d42:3) as exploratory candidate features for distinguishing PM_A from N (apparent AUC = 0.833 for each marker; leave-one-out jackknife AUC range 0.750-1.000, mean 0.833). Multi-feature composite AUCs were not reported because, at = 7, any composite would be highly susceptible to overfitting. The VM_A group showed limited deviation from N (4 increased, 6 decreased metabolites) but differed from PM_A in 32 increased and 15 decreased metabolites, primarily within SPH, phosphatidylserine (PS), MePC, LPC, and AcCa subclasses. SM(d35:2) emerged as an exploratory candidate distinguishing VM_A from both N and PM_A, but at = 3 vs. 4 the apparent AUC = 1.000 is statistically expected for some of the 344 screened metabolites by chance alone, and the candidate is therefore hypothesis-generating only. CONCLUSION: Cerebrospinal fluid lipidomics revealed disease-stage-specific alterations in pediatric PM and VM. These findings should be regarded as hypothesis-generating in this small proof-of-concept cohort and require validation in larger pediatric studies.
Regulation of NMDA receptor interactions with the actin cytoskeleton in dendritic spine development.
Lloyd J, Litwa K
Front Cell Neurosci · 2026 · PMID 42290955 · Full text
In the central nervous system, the majority of excitatory synapses exist on small actin-enriched structures protruding from dendrites, known as dendritic spines. Actin cytoskeletal rearrangements drive dynamic changes in...
In the central nervous system, the majority of excitatory synapses exist on small actin-enriched structures protruding from dendrites, known as dendritic spines. Actin cytoskeletal rearrangements drive dynamic changes in spine shape, size, and density depending on developmental stage and synaptic activity. Spines initially emerge from the dendritic shaft as dynamic protrusions known as filipodia-like spines, which serve as precursors to mature dendritic spines. The formation and maturation of dendritic spines facilitate information transfer in neural circuits, underlying cognitive processes, such as learning and memory formation, and altered spine development results in neurodevelopmental disorders. Within dendritic spines, signaling events are regulated by many synaptic receptors such as the ionotropic N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. However, only NMDA receptors are enriched in both immature filopodia-like spine precursors and mature dendritic spines, with AMPA receptors expressed later in development and coinciding with spine maturation. During embryonic development, most NMDA receptors contain GluN2B subunits, in contrast to mature synapses which predominantly contain GluN2A subunits. While many actin regulatory proteins, such as α-actinin-2, interact with NMDA receptor subunits, it remains unclear whether GluN2B vs. GluN2A-containing receptors exhibit differences in their preferential protein interactions that underly dendritic spine development. The following review highlights how preferential interactions between specific GluN2 isoforms and actin cytoskeletal regulators underlie synaptic development by balancing dynamic events of synaptic plasticity with competing events of synaptic strengthening and consolidation. We discuss how alterations in the expression of GluN2 isoforms and/or mutations that disrupt actin interactions contribute to neurological disorders, both developmental and degenerative.
Correction: From Balance to Breakdown: striatal PV interneurons in Huntington's disease and Autism Spectrum Disorder.
Thabault M, Galvan L
Front Cell Neurosci · 2026 · PMID 42282856 · Full text
[This corrects the article DOI: 10.3389/fncel.2026.1717636.].
[This corrects the article DOI: 10.3389/fncel.2026.1717636.].
Editorial: Biomarker discovery and validation in neurological diseases.
Singla S, Vaidya B, Martínez-Palma L … +1 more , Hermann DM
Front Cell Neurosci · 2026 · PMID 42282855 · Full text
Abstract loading — click title to view on PubMed.
Correction: Differential microglial dynamics and neuroinflammation underlying neuropathic pain in the central nervous system: comparative insights from spinal cord injury and compressive myelopathy models.
Kubota A, Nakajima H, Honjoh K … +3 more , Watanabe S, Takahashi A, Matsumine A
Front Cell Neurosci · 2026 · PMID 42273020 · Full text
[This corrects the article DOI: 10.3389/fncel.2026.1769004.].
[This corrects the article DOI: 10.3389/fncel.2026.1769004.].
The kynurenine pathway: an immunometabolic bridge linking systemic inflammation to neuroaxonal vulnerability in multiple sclerosis.
Maldonado-García JL, García-Mena LH, Ferat-Peláez EA … +6 more , Pérez-Sánchez G, Becerril-Villanueva E, Rojas-Mayorquín AE, Girón-Pérez MI, Ortuño-Sahagún D, Pavón L
Front Cell Neurosci · 2026 · PMID 42266250 · Full text
Multiple sclerosis (MS) extends beyond focal autoimmune demyelination, with progressive neurodegeneration and cognitive impairment arising from mechanisms not fully explained by inflammatory lesions alone. We propose the...
Multiple sclerosis (MS) extends beyond focal autoimmune demyelination, with progressive neurodegeneration and cognitive impairment arising from mechanisms not fully explained by inflammatory lesions alone. We propose the kynurenine pathway (KP) as a unifying immunometabolic interface that translates peripheral inflammation into central neuroaxonal vulnerability. Cytokine-driven induction of indoleamine 2,3-dioxygenase accelerates systemic tryptophan catabolism, increasing circulating kynurenine that crosses the blood-brain barrier via L-type amino acid transporter 1 (LAT1). Within the CNS, microglial kynurenine 3-monooxygenase generates the excitotoxic and pro-oxidant metabolites quinolinic acid and 3-hydroxykynurenine, while astrocytic kynurenine aminotransferases produce the neuroprotective antagonist kynurenic acid. This enzymatic dichotomy creates a dynamic amplification loop that intensifies excitotoxicity, oxidative stress, oligodendrocyte injury, and axonal loss. Clinical evidence shows that kynurenine metabolite ratios correlate with plasma neurofilament light chain, cognitive deficits, obesity-related inflammation, and phenotype-specific exercise responsiveness, underscoring KP plasticity as a potential determinant of disease trajectory. By reframing MS through this immunometabolic lens, the KP emerges as both a mechanistic bridge between inflammation and neurodegeneration and a tractable biomarker system with therapeutic potential.
Combination drug therapy reduces iron accumulation and microglia-mediated pathologies in neonatal intraventricular hemorrhage: a biochemical and transcriptomic analysis.
Castro Diaz V, Sunshine M, Hu F … +7 more , Shah S, Huang W, Thompson CI, Wolin MS, Subbian S, LaGamma EF, Vinukonda G
Front Cell Neurosci · 2026 · PMID 42266249 · Full text
This study describes the distribution of non-reactive brain-resident microglia densely populated along the borders of the lateral ventricles and choroid plexus in premature rabbit pups during early forebrain development....
This study describes the distribution of non-reactive brain-resident microglia densely populated along the borders of the lateral ventricles and choroid plexus in premature rabbit pups during early forebrain development. Following intraventricular hemorrhage (IVH) injury, activated microglia expand by proliferation, and migrate deeper into parenchymal regions. During this process, activated microglia exhibit a disproportionate elevation of the proinflammatory microglia phenotype (M1 nomenclature) from the total IBA-1 microglia cell population along with tissue iron accumulation; this shift was reduced by sulforaphane (SFN; Nrf2-antioxidant response element [ARE] activator of anti-inflammatory pathways) plus deferoxamine (DFN; iron chelator) treatment. A separate DFN monotherapy transcriptome analysis identified over expression of pro-inflammatory calcium-binding proteins S100A8 and S100A12 (intracellular damage signals), as well as chemokines CXCL8 and CXCL10 by microglia and other cells, along with upregulated ferroptosis interactive network genes in IVH including: HMOX1, CTSB, FTL, PRM2, LPCAT1, and CDK1. Importantly, the expression of multiple key genes involved in iron metabolism and transport function included: ACSL4, TFRC, SLC7A11 and ABCA4 which were all downregulated in IVH and this trend was reversed after DFN treatment. Taken together, in the developing postnatal brain, the combination treatment of SFN-DFN mitigated M1 infiltration, reduced iron deposition in the tissue and in the CSF, suppressed the magnitude of inflammation and reduced cell death after IVH. Moreover, DFN monotreatment reversed most dysregulated genes in inflammation and iron homeostasis networks, revealing potential molecular targets for additional pharmacologic interventions after IVH. We speculate that reducing the toxic microcellular environment will attenuate injurious inflammatory responses and improve recovery of the trajectory toward normal brain development.
Editorial: Cellular neuropathology of hearing loss.
Levano S, Morley BJ, Zallocchi M
Front Cell Neurosci · 2026 · PMID 42266248 · Full text
Abstract loading — click title to view on PubMed.
Retraction: Administration of tauroursodeoxycholic acid attenuates early brain injury via Akt pathway activation.
Frontiers Editorial Office
Front Cell Neurosci · 2026 · PMID 42253448 · Full text
[This retracts the article DOI: 10.3389/fncel.2017.00193.].
[This retracts the article DOI: 10.3389/fncel.2017.00193.].
Disrupted synapses: prefrontal cortex-reward circuit dysfunction in stress-induced depression-like behaviors.
Mahmud A, Karaman MA
Front Cell Neurosci · 2026 · PMID 42244506 · Full text
Major depressive disorder (MDD) is a multifactorial, circuit-level disorder often triggered by chronic stress, which fundamentally disrupts the neural networks governing reward processing. Central to this pathology is th...
Major depressive disorder (MDD) is a multifactorial, circuit-level disorder often triggered by chronic stress, which fundamentally disrupts the neural networks governing reward processing. Central to this pathology is the prefrontal cortex (PFC), an integration hub exerting top-down executive control over subcortical regions. Here, we synthesize translational and preclinical evidence detailing how chronic stress induces structural, functional, and molecular maladaptations within the PFC and its reward-related downstream projections. By dissecting specific neural pathways-including the PFC's connections to the nucleus accumbens (NAc), ventral tegmental area (VTA), ventral hippocampus (vHIPP), and lateral habenula (LHb)- we map how projection-specific dysregulation drives distinct depressive phenotypes. Furthermore, we examine the cellular mechanisms underlying these circuit alterations, emphasizing the roles of disrupted neuromodulation (dopamine, glutamate, and serotonin), impaired synaptic plasticity, and robust neuroinflammatory cascades. We highlight notable sex-dependent findings where relevant, illustrating how specific transcriptomic, morphological, and circuit-level responses can diverge between males and females. Finally, we discuss the necessity of moving beyond simplistic behavioral dichotomies and integrating multimodal neurobiological approaches. Ultimately, delineating these precise, circuit-specific vulnerabilities provides a critical framework for developing targeted therapeutics for stress-induced affective disorders.
Defining functional states and roles of microglia in neuropsychiatric disorders.
Szydlowska K, Tivanello R, Kaminska B
Front Cell Neurosci · 2026 · PMID 42244505 · Full text
Microglia are myeloid cells of the central nervous system (CNS) that acquire a context-specific phenotype and adjust their functions to microenvironmental cues. They participate in immune signaling, synaptic remodeling,...
Microglia are myeloid cells of the central nervous system (CNS) that acquire a context-specific phenotype and adjust their functions to microenvironmental cues. They participate in immune signaling, synaptic remodeling, and circuit functions, and have emerged as key culprits in neurodevelopmental and psychiatric disorders such as depression, anxiety, autism spectrum disorder (ASD), and schizophrenia. We characterize and discuss different functional state of microglia defined by sc-omics approaches that bring a high resolution to cell functionalities. Subsequently, we review the evidence of microglial states, microglia-driven mechanisms and their impacts on development and progression of neuropsychiatric disorders. In affective mood disorders, chronic stress, glucocorticoid dysregulation, and peripheral inflammation drive microglial nefarious activation. This leads to excessive synaptic pruning, impaired neurotrophic support, glutamate excitotoxicity, and circuit dysfunction in mood-related brain regions, with strong modulation by circadian mechanisms and sex-dependent factors. In ASD, microglia adopt a hybrid activation state characterized by altered inflammatory signaling, dysregulated phagocytosis, and aberrant synaptic pruning, driven by genetic and epigenetic mechanisms, including TREM2, ARID1A, complement components, and calcium-dependent glial signaling, which together disrupt network connectivity and social behavior. In schizophrenia, genetic risk factors related to and , along with inflammatory and metabolic stress, promote excessive microglia-mediated synapse elimination, cytoskeletal and motility deficits, and secondary neuronal metabolic dysfunction, which correlate with cognitive and negative symptoms. These findings strongly position microglia as a hub and key determinants of CNS homeostasis whose context-dependent dysregulation links immune, genetic, and environmental risk factors to synaptic and behavioral pathology. We discuss which microglial signaling pathways are shared and identify promising therapeutic targets across the neuropsychiatric disease spectrum.
Histone demethylase KDM6B promotes postnatal oligodendrocyte maturation and cortical myelination.
Lambries R, Shen Z, Mias GI … +1 more , He J
Front Cell Neurosci · 2026 · PMID 42239646 · Full text
INTRODUCTION: Postnatal cortical myelination requires epigenetic activation of oligodendrocyte gene programs, but the role of histone demethylases remains unclear. METHODS: We conditionally deleted in Emx1 dorsal telen...
INTRODUCTION: Postnatal cortical myelination requires epigenetic activation of oligodendrocyte gene programs, but the role of histone demethylases remains unclear. METHODS: We conditionally deleted in Emx1 dorsal telencephalic progenitors and analyzed oligodendrocyte lineage progression, performed lineage-specific RNA-seq, assessed H3K27me3 occupancy by chromatin immunoprecipitation, and tested functional rescue via induction. RESULTS: deletion delayed cortical myelination and impaired oligodendrocyte maturation without affecting precursor density. Pre-myelinating and mature oligodendrocyte markers were reduced. RNA-seq revealed early suppression of , followed by downregulation of myelin genes. Consistently, H3K27me3 enrichment increased at regulatory regions. induction partially rescued myelination deficits. DISCUSSION: These findings define a KDM6B→ axis that promotes oligodendrocyte maturation and cortical myelination by restricting repressive H3K27me3, providing mechanistic insight into epigenetic control of myelination with relevance to KDM6B-associated neurodevelopmental disorders.
Cellular senescence in brain aging and neurodegeneration: from molecular mechanisms to translational opportunities.
Cantero-Fortiz Y, Butler C, Montalbán X … +1 more , Boada M
Front Cell Neurosci · 2026 · PMID 42239645 · Full text
Aging remains the predominant risk factor for Alzheimer's disease (AD) and other neurodegenerative disorders, yet the mechanisms linking systemic aging to brain dysfunction remain incompletely understood. Cellular senesc...
Aging remains the predominant risk factor for Alzheimer's disease (AD) and other neurodegenerative disorders, yet the mechanisms linking systemic aging to brain dysfunction remain incompletely understood. Cellular senescence, a state of stable cell-cycle arrest coupled with metabolic and secretory reprogramming, has emerged as a pivotal and context-dependent driver of brain aging. Accumulation of senescent glial cells (astrocytes, microglia, and oligodendrocyte progenitors) and emerging evidence of "neurescence" in post-mitotic neurons contribute to neuroinflammation, impaired proteostasis, and synaptic dysfunction. This review synthesizes molecular, cellular, and translational findings that reframe senescence as an active process shaping brain vulnerability. We discuss SASP-mediated neurotoxicity, crosstalk among senescent glial subtypes, and context-specific pathways (NF-κB, p38 MAPK, mTOR, cGAS-STING) as therapeutic targets. Senomorphic and senolytic strategies, alongside emerging systemic interventions such as therapeutic plasma exchange with albumin replacement, are evaluated for their potential to mitigate senescence burden and restore homeostasis. Integrating evidence from fluid, imaging, and multi-omic biomarkers, we highlight how senescence can now be monitored and stratified across disease stages. Multi-omic and spatial transcriptomic data reveal that central and peripheral senescence signatures only partially overlap, suggesting bidirectional communication across the brain-body axis. This systemic dimension raises key questions about whether modifying peripheral senescence or proteostasis could reshape CNS trajectories. However, key uncertainties remain, particularly regarding the causal role of senescence in human neurodegeneration, the specificity of current biomarkers, and the distinction between adaptive versus maladaptive senescence responses. Notably, direct evidence linking senescent cells to functional alterations in the human brain microenvironment remains limited. This review distinguishes itself from prior literature by integrating a multi-scale brain-body axis perspective, combining molecular, cellular, and systemic evidence to propose senescence as a bidirectional and context-dependent driver of neurodegeneration rather than a purely cell-autonomous process.
Prefrontal long-range somatostatin inhibitory projections modulate fear expression.
Aincy M, El Azraoui A, Chaudun F … +6 more , Kim HR, Zhang CL, Aime M, Girard D, Humeau Y, Herry C
Front Cell Neurosci · 2026 · PMID 42239644 · Full text
Memory extends beyond the simple encoding of learned associations; it also requires the flexible and context-dependent expression of associative memories to appropriately guide behavior. Auditory fear conditioning provid...
Memory extends beyond the simple encoding of learned associations; it also requires the flexible and context-dependent expression of associative memories to appropriately guide behavior. Auditory fear conditioning provides a powerful model to study how neutral cues become threat predictors, relying on coordinated activity across distributed cortical and subcortical circuits. Among these circuits, the medial prefrontal cortex (mPFC) and the periaqueductal gray (PAG) are recognized as key structures involved in both the formation and the expression of fear memories. However, the mechanisms through which these two regions interact to regulate defensive memory expression remain largely unknown. Here, we identify a previously uncharacterized long-range inhibitory projection from somatostatin-expressing (SST) neurons in the mPFC to the ventrolateral PAG (vlPAG) that regulates the temporal maintenance of freezing during fear expression. Through a combination of anatomical tracing and slice electrophysiology, we demonstrate that these SST neurons form direct, monosynaptic GABAergic connections onto vlPAG neurons. Furthermore, optogenetic inhibition of mPFC SST terminals during conditioned stimulus (CS+) presentations markedly shortened the duration of freezing episodes. Together, these results extend the classical view of prefrontal-midbrain communication by revealing that inhibitory mPFC → PAG projections play a pivotal role in shaping the temporal dynamics of fear expression. Within the broader framework of SST neurons plasticity, our findings align with the role of mPFC long-range inhibitory SST projections exerting fine control over cue-specific freezing behavior and the flexible expression of fear-related memories.
Transcriptomic signatures of hippocampal active place avoidance memory maintenance.
Vingan I, Phatarpekar S, Tung VSK … +3 more , Hernández AI, Evgrafov OV, Alarcon JM
Front Cell Neurosci · 2026 · PMID 42232837 · Full text
The gene expression changes associated with memory acquisition, consolidation and reconsolidation-all active epochs in memory formation-have been well characterized in the rodent hippocampus. Less is known, however, of t...
The gene expression changes associated with memory acquisition, consolidation and reconsolidation-all active epochs in memory formation-have been well characterized in the rodent hippocampus. Less is known, however, of the changes in gene expression during the offline maintenance of memory. In this study, we measured the gene expression changes in the dorsal hippocampus of four mice 3 days after consolidation of an active place avoidance memory. We examined gene expression changes in a putative subset of memory-associated neurons by leveraging the immediate early gene tagging system of the Arc-Cre/flox-eYFP transgenic mouse line. Through spatial transcriptomics we found that memory trained animals exhibited spatially regionalized expression of genes involved in post-synaptic function in CA1, synaptic vesicle transport in CA3, and neuronal differentiation in DG. Surprisingly, these gene expression enrichments were not observed in eYFP mRNA positive spatial spots. To gain granularity into this finding, we carried out single nuclear RNA sequencing, which confirmed enrichment of differentially expressed genes associated with synaptic plasticity and post-synaptic signaling unique to each subregion in trained animals, but not from their eYFP mRNA positive nuclei. Notably, nuclei of hippocampal neurons were largely characterized by their down regulation of genes involved in ATP synthesis and cytoplasmic translation. Our results suggest that two overarching transcriptomic patterns contribute to the functional changes in hippocampal cells during offline memory maintenance: regionally distributed expression of genes linked to synaptic functions (with concomitant sparseness of memory-associated neuronal ensembles) and a reduction of metabolic activity related genes across hippocampal sub-regions.
Early and transient increase in cortical pyramidal cell excitability and delayed alteration of evoked synaptic transmission and t-SNARE proteins content in the hippocampus and neocortex of neonatal and juvenile heterozygous mice.
Pineau L, Brosset-Heckel M, Becq H … +6 more , Pallesi-Pocachard E, Montheil A, Biba-Maazou N, Milh M, Lenck-Santini PP, Aniksztejn L
Front Cell Neurosci · 2026 · PMID 42232836 · Full text
mutations in the gene lead to Munc18.1 haploinsufficiency and are a major cause of neurodevelopmental disorders. Because Munc18.1 is essential for vesicular exocytosis, most electrophysiological investigations have focu...
mutations in the gene lead to Munc18.1 haploinsufficiency and are a major cause of neurodevelopmental disorders. Because Munc18.1 is essential for vesicular exocytosis, most electrophysiological investigations have focused on synaptic transmission and much less on intrinsic neuronal properties. In addition the potential developmental dependence of these effects is unknown. Here, using acute brain slices from neonatal and juvenile heterozygous mice, we examined the intrinsic excitability of CA1 hippocampal and motor cortical layers II/III pyramidal neurons as well as spontaneous and evoked glutamatergic and GABAergic synaptic transmission recorded in these cells. In neonatal mice, Munc18.1 haploinsufficiency leads to a marked increase in intrinsic excitability in both hippocampal and neocortical pyramidal neurons. In juvenile mice, intrinsic properties appear largely normalized, but evoked synaptic transmission is impacted with a higher sensitivity of glutamatergic synapses than of GABAergic synapses to high-frequency electrical stimulation. In contrast, spontaneous synaptic activity mediated by glutamate and GABA receptors remains unchanged at both developmental stages, suggesting that basal synaptic drive is preserved. We also performed western blot analysis and show that Munc18.1 deficiency is associated with a reduction of t-SNARE protein expression in the hippocampus and neocortex of juvenile, but not neonatal mice. Together, these findings indicate that Munc18.1 deficiency induces stage dependent electrophysiological and biochemical alterations. We hypothesize that early changes involve disrupted of certain ion channels function/expression and that the later reduction of t-SNARE proteins in juvenile may play a role in the normalization of neuronal excitability.
Remifentanil self-administration promotes circuit- and sex-specific adaptations within the prefrontal-accumbens pathways.
Kokane SS, Atwell SI, Madayag AC … +5 more , Anderson EM, Demis S, Engelhardt A, Friedrich L, Hearing MC
Front Cell Neurosci · 2026 · PMID 42222059 · Full text
INTRODUCTION: The nucleus accumbens (NAc) and its excitatory input from the medial prefrontal cortex (mPFC) form a critical circuit underlying drug-induced plasticity associated with addiction-related behaviors. However,...
INTRODUCTION: The nucleus accumbens (NAc) and its excitatory input from the medial prefrontal cortex (mPFC) form a critical circuit underlying drug-induced plasticity associated with addiction-related behaviors. However, baseline differences in excitatory signaling across NAc subcircuits and sex-specific neuroadaptations following opioid self-administration remain poorly understood. METHODS: Here, we examined synaptic signaling in mPFC-NAc pathways in drug-naïve mice and after abstinence from remifentanil self-administration. RESULTS: Under drug-naïve conditions, AMPA receptor-mediated glutamatergic signaling was generally elevated in D2 medium spiny neurons (MSNs) of both the NAc core and shell across sexes, while females exhibited greater excitatory signaling in D1 MSNs of the NAc core compared with males. Pathway-specific analyses revealed that prelimbic cortex (PL) inputs to NAc core D2 MSNs displayed enhanced calcium-permeable AMPA receptor (CP-AMPAR) signaling and increased presynaptic release relative to D1 MSNs. Following abstinence from remifentanil self-administration, miniature excitatory postsynaptic current analyses showed increased excitatory drive at D1 MSNs and decreased drive at D2 MSNs, largely restricted to the NAc core. At PL-Core D1 MSN synapses, remifentanil reduced AMPA/NMDA ratios, consistent with increased CP-AMPAR incorporation in males and females, while increasing presynaptic signaling exclusively in males. In contrast, PL-Core D2 MSN synapses showed a reduction in presynaptic signaling across sex, while ostensibly weakening postsynaptic signaling selectively in males through reductions in CP-AMPAR signaling. At infralimbic cortex (IL)-shell inputs, a reduction in AMPAR rectification indices at D1 MSN synapses was produced by remifentanil, while release probability was decreased at D2 MSN synapses in males only. DISCUSSION: Together, these findings reveal sex- and pathway-specific synaptic adaptations within mPFC-NAc circuits that may be obscured by global measures of excitatory transmission and identify baseline circuit differences that may shape opioid-induced plasticity.
Microglial state transitions are constrained by developmental and metabolic checkpoints.
El Mesaoudi A, Kim DW
Front Cell Neurosci · 2026 · PMID 42222058 · Full text
Single-cell transcriptomic and epigenomic profiling has revealed extensive microglial heterogeneity across development, homeostasis, and disease. However, one recurring observation remains unexplained. Only subsets of mi...
Single-cell transcriptomic and epigenomic profiling has revealed extensive microglial heterogeneity across development, homeostasis, and disease. However, one recurring observation remains unexplained. Only subsets of microglia adopt expected transcriptional programs in a given context, and transcriptional activation often fails to translate into functional execution. Current frameworks describe microglial states, but they do not explain why individual cells differ in their ability to access, sustain, or complete state transitions. Here, we propose a checkpoint framework for microglial state transitions. In this model, transitions depend on prerequisite conditions that must be met before a response can proceed. We use the term checkpoint in the sense of cell-cycle biology, where progression depends on prior conditions, rather than in the signal-integration sense used for peripheral immune checkpoints. We first consider the peripheral checkpoint model, in which transitions are driven mainly by activating and inhibitory receptor signaling. In that system, continuous hematopoietic renewal buffers many individual cell-level constraints. We then argue that this logic is modified in microglia. Their embryonic origin, lifelong residence in the CNS, and limited replacement capacity make cellular history a more durable determinant of responsiveness. Within this framework, we define three non-redundant classes of checkpoint-like constraints. The first is developmental licensing, which establishes accessible response space through lineage specification, postnatal maturation, and age-dependent stabilization. The second is metabolic and proteostatic capacity, which determines whether cells can meet the energetic and protein-handling demands required for execution. The third is tissue-derived gating, in which neuronal, astrocytic, and extracellular matrix signals set permissive or non-permissive conditions for transition. Together, these constraints help explain why microglial responses are heterogeneous, why transcriptional state and functional output can diverge, and why disease-associated profiles may reflect stalled or incomplete transitions rather than stable functional identities. This framework shifts attention from descriptive states to constrained transitions. It also suggests that therapy should focus on restoring transition competence rather than simply suppressing or inducing specific microglial states.
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