Frontiers in Cellular Neuroscience最新文献

Diabetic peripheral neuropathy (DPN), a prevalent and debilitating complication of diabetes, involves complex interactions between peripheral nerve damage and central nervous system (CNS) dysfunction. While traditional research has focused on peripheral and spinal mechanisms, emerging evidence highlights that the brain plays a critical role in the development of painful DPN. This review synthesizes recent advances from neuroimaging, spectroscopy, and preclinical studies to delineate structural, functional, and neurochemical alterations in the central nervous system associated with DPN. Patients exhibit cortical thinning, subcortical atrophy, and disrupted connectivity in sensory, affective, and cognitive networks, accompanied by metabolic imbalances and excitatory-inhibitory neurotransmitter shifts. Preclinical models further implicate maladaptive plasticity, microglial activation, and region-specific astrocytic responses in amplifying central sensitization and pain chronicity. These mechanistic insights underscore the central nervous system as a therapeutic target. Non-invasive neuromodulation techniques, such as repetitive transcranial magnetic stimulation, and brain-directed pharmacological strategies show promising but preliminary benefits in alleviating neuropathic pain. Understanding the interplay between peripheral injury and brain dysfunction in DPN not only broadens the conceptual framework of its pathophysiology but also provides a foundation for developing novel interventions aimed at restoring central network balance and improving patient outcomes.

Introduction: Cognitive impairments associated with schizophrenia (CIAS) include deficits in declarative memory. This is associated with an inability to maintain information in short-term memory when distracted, and increased sensitivity to proactive interference. These CIAS may partly result from decreased expression of parvalbumin (PV) in medial prefrontal cortex (mPFC) interneurons. The sub-chronic phencyclidine (scPCP) rodent is a widely used model for schizophrenia that recapitulates CIAS, including declarative memory, social cognition and mPFC PV deficits. Thus, distraction before the test phase in novel object recognition (NOR) produces robust declarative memory deficits in scPCP rats. Controlling for distraction in the single trial or continuous NOR paradigm (cNOR) protects memory recall, and multi-trial cNOR reveals increased sensitivity to proactive interference for object memory. Here, we sought to expand scPCP model cross-species validity by comparing these NOR/cNOR deficits across scPCP rats and mice. We then aimed to determine whether distraction-dependent deficits are conserved across object and social memory domains in scPCP mice, assessing sociability and social memory using automated mouse tracking to sub-classify social interaction behaviors.

Methods: scPCP mice underwent cNOR testing over 11 trials, and the density of cellular PV expression in putative interneurons (PVIs) in the mPFC was determined. scPCP mice were additionally tested in the Three-Chamber Social Interaction (TCSI) task, investigating social preference and the sensitivity of social memory to distraction. Mouse movement was tracked with a deep-learning tool (DeepLabCut) to classify sniffing and rearing in the TCSI task.

Result: Distraction-dependent NOR deficits were conserved across scPCP rats and mice, while the effects of proactive interference on cNOR testing were species-specific. TCSI testing showed that scPCP mice expressed diminished sociability overall and increased susceptibility to distraction for social memory, particularly for rearing behavior. There was a significant reduction in PVI density in the scPCP mouse mPFC.

Discussion: These results extend the cross-species validity of the scPCP model in rodents. scPCP-induced susceptibility to distraction in mice is broadly comparable to that observed in scPCP rats and is conserved across object and social memory domains. These behavioral effects correlate with scPCP-induced decreases in PV expression in both species, further implicating altered mPFC excitatory-inhibitory balance in CIAS induction.

Introduction: Neuroinflammation triggered by viral infections is increasingly recognized as a driving force in neurodegenerative disease, promoting chronic neuronal injury and cognitive decline. A central mechanism in this process is impaired glutamate clearance due to downregulation of the astrocytic glutamate transporter GLT-1 (EAAT2/SLC1A2), which exacerbates excitotoxicity and neuronal death.

Methods: In this study, we assessed the neuroprotective effects of the β-lactam antibiotic ceftriaxone-a known upregulator of GLT-1-in an in vitro tri-culture model of neurons, microglia, and astrocytes challenged with the viral mimic polyinosinic:polycytidylic acid (Poly I:C).

Results and discussion: Poly I:C exposure elicited robust microglial and astrocytic activation and increased levels of TNF-α, IL-6, and IL-10. Concomitantly, we observed significant downregulation of GLT-1, synapse loss, impaired synaptic plasticity, and disrupted amino acid metabolism. A complementary Mendelian randomization analysis of GWAS data revealed that genetically determined alterations in plasma amino acid levels are significantly associated with the risk of five major neurodegenerative disorders, underscoring the role of metabolic dysregulation in disease pathogenesis. Treatment with ceftriaxone effectively reversed the Poly I:C-induced phenotypes: GLT-1 expression, dendritic spine density, and measures of synaptic plasticity were all restored, and abnormalities in amino acid and tricarboxylic acid cycle metabolites normalized. These findings highlight ceftriaxone's multifaceted neuroprotective profile-modulating glutamate homeostasis, preserving synaptic integrity, and rebalancing metabolic pathways-and support its potential as a therapeutic agent to prevent neuronal degeneration in the context of virus-driven neuroinflammation.

Though usually described as isolated models, neurodegenerative diseases exist in a significant proportion of cases as mixed pathologies, particularly in older adults. The presence of co-pathologies may influence phenotypes and progression, and the correct classification in vivo has proven to be challenging, particularly without proper biomarker panels. Recent breakthroughs in biomarkers, enabling earlier detection in Alzheimer's disease and, more recently, in synuclein-related diseases, are promising as a first step toward the wider detection of all other abnormal proteins involved in neurodegenerative diseases. Over the past decade, the growing body of research on TDP-43 pathology has led to considering TDP-43 as a potential major contributor to the neurodegenerative process. TDP-43's normal function is essential for neuronal survival and the regulation of RNA processing and cellular stress response; abnormal TDP-43 protein leads to altered cell function and survival. TDP-43 is notably the neuropathological hallmark of amyotrophic lateral sclerosis (ALS) as well as some form of frontotemporolobar degeneration (FTLD). Tauopathies, divided in primary or secondary tauopathies cover other forms of FTLD including Pick disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) but also non-FTLD diseases like Alzheimer's disease (AD) which can be classified as secondary tauopathy. As the importance of copathology is more and more recognized, TDP-43 is also frequently observed in conjunction with other proteinopathies, possibly with a synergistic or additive effect, although the exact mechanism is still unclear. In Alzheimer's disease, the limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) co-occurrence with Alzheimer's disease neuropathologic changes (ADNC) lead to a more rapid course. Although there are currently no approved and validated biomarkers for its early detection, several promising tools, including neuroimaging and biofluid biomarkers, are under development, offering hope for the earlier detection of TDP-43 pathology in vivo. Accurate identification of the underlying proteinopathies and pathological processes could lead to better diagnosis and classification, more precise selection of clinical trial candidates, and ultimately, disease-specific tailored treatments.

Introduction: Astrocytes are parenchymal cells widely distributed throughout the brain. Beyond their essential functions in healthy tissue, astrocytes exhibit an evolutionarily conserved response to all forms of brain injury, termed astrocytic reactivity. Nevertheless, conceptual understanding of what astrocytic reactivity encompasses and its functional roles remains incomplete and occasionally contentious. Lipopolysaccharide (LPS) is widely used to induce neuroinflammation. In the current study, Histone deacetylase 7 (HDAC7) has been shown to ameliorate LPS-induced neuroinflammation and mitigate astrocytic reactivity.

Methods: We overexpressed HDAC7 using viral vectors and generated primary astrocytes from Hdac7 ^flox/flox mice to achieve astrocyte-specific HDAC7 knockout. Subsequently, we assessed astrocytic reactivity and detected the expression of the Interferon regulatory factor 3 (IRF3)/cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway.

Results: HDAC7 has been implicated in inflammatory regulation, but its role in astrocyte reactivity and the underlying mechanisms remain unclear. Here, we demonstrate that HDAC7 deficiency attenuates LPS-induced astrogliosis by suppressing the cGAS/STING signaling axis. LPS stimulation induced robust upregulation of glial fibrillary acidic protein (GFAP), complement component 3 (C3), and pro-inflammatory cytokines (TNF-α, IL-6) in WT astrocytes, which was significantly blunted in HDAC7 knockout astrocytes. Conversely, lentiviral overexpression of HDAC7 in WT astrocytes exacerbated IRF3/cGAS/STING pathway activation, as validated by Western blot analysis showing upregulated cGAS, STING and IRF3 expression. Pharmacological activation of the STING pathway in astrocytes restored pro-inflammatory cytokine expression and reactive marker levels, indicating pathway dependence.

Discussion: Our results delineate a novel HDAC7/IRF3/cGAS/STING signaling axis that governs astrocyte reactivity. This discovery provides a crucial cellular neurophysiological mechanism by which astrocytes integrate inflammatory signals and subsequently modulate the central nervous system microenvironment. Targeting HDAC7, therefore, represents a therapeutic strategy to mitigate neuroinflammation by specifically correcting this aberrant cell-physiological state of astrocytes, ultimately preserving neural circuit function.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with unknown etiology. Currently, the role of post-transcriptional mechanisms in ASD remains unclear. microRNAs (miRNAs) are small non-coding regulatory RNAs that mediate mRNA destabilization and/or translational repression. To investigate the potential role of miRNAs in ASD, we performed miRNA expression profiling in the hippocampus of the BTBR ASD mouse model and age-matched C57BL/6 J mice. Alongside, we analyzed the BTBR hippocampal transcriptomic profile to identify differentially expressed transcripts (DETs). By integrating differentially expressed miRNA (DEmiRNA) and DET lists, we discovered mRNA transcripts that are putative targets of BTBR DEmiRNAs and exhibit an anti-correlated differential expression in the BTBR hippocampus. These interactions suggest potential regulatory networks related to gene transcription regulation, and synaptic structure and function relevant for ASD. These include miR-200 family members, miR-200a-3p, miR-200b-3p, miR-200c-3p, and miR-429, and the experimentally validated target, the transcription factor Zeb2. Moreover, we identified a set of non-canonical interactions characterized by extensive pairing between BTBR DEmiRNAs and DETs, potentially triggering target-directed miRNA degradation (TDMD). Our findings support a role for miRNA dysregulation in the pathophysiology of ASD.

Exposure to traumatic stress can lead to psychopathology, including post-traumatic stress disorder (PTSD), but may also cause inflammation and cardiovascular dysfunction. Clinical evidence suggests that exposure to traumatic stress, independent of psychopathology development, may be sufficient to induce pathophysiological sequelae, but this has not been thoroughly investigated. Using a novel model of repeated social defeat stress (RSDS) that allows for both sexes, we explored links between the behavioral and physiological consequences of this paradigm. RSDS was sufficiently able to elevate systemic inflammation in both male and female mice, with no observed sex differences. RSDS also induced a heightened blood pressure sensitization response to low dose exogenous angiotensin II (AngII), suggesting the model was also sufficient in generating cardiovascular pathology. Interestingly, the RSDS-induced sensitization to AngII was completely abrogated in mice lacking T-lymphocytes (i.e., Rag2^-/- mice). Of note, Rag2^-/- mice demonstrated similar pro-social and anxiety-like behavior to wild-type mice, inferring that (1) differences in these behavioral outcomes do not explain the loss of RSDS-induced AngII sensitization in Rag2^-/- mice and (2) T-lymphocytes do not appear to impact these specific RSDS-induced behaviors. Indeed, intra-animal correlations demonstrate a tight association between the inflammatory and cardiovascular consequences post-RSDS, but no associations between these parameters with behavior. Together, our data suggest that exposure to traumatic stress, independent of psychopathology, is sufficient to induce pathophysiology. These findings have significant clinical implications, specifically for individuals who have experienced traumatic stress without the development of psychopathology, as this overlooked population may have similar risks of developing somatic diseases.

Early-life stress (ELS) and enrichment often have opposing effects on long-term cognitive abilities. Deprivation, such as institutionalized care during early childhood neurodevelopmental periods, results in lifelong working memory and recall deficits. In contrast, enrichment facilitates new learning and slows cognitive decline due to aging and neurodegenerative diseases. Similarly, in rodent models, enrichment facilitates learning whereas ELS induces prominent spatial memory deficits. Environmental enrichment (EE) and ELS can cause opposing changes in hippocampal structure (e.g., shifts in synaptic density) that largely depend on experimental conditions. However, it remains untested whether EE can rescue the behavioral disruptions caused by ELS and how this would impact the hippocampus at advanced ages. To address this, we conducted a longitudinal study on ELS mice, extensively training them on a cognitive enrichment track (ET) or an exercise alone control track (CT). After this, the mice underwent repeated memory testing followed by brain extraction for anatomical analysis of their hippocampus. We found that ET reversed spatial memory deficits at 6, 13, and 20 months and reduced the number of dentate gyrus (DG) to CA3 synapses. Surprisingly, this reduction occurred at excitatory MF synapses surrounding CA3 somas in the stratum pyramidale-a layer not typically associated with MF terminals. Collectively, these findings suggest that cognitive enrichment during early adulthood may reverse ELS-induced spatial memory deficits by adjusting synaptic connectivity between the DG and CA3.