OBJECTIVE:Alzheimer's disease is a progressive neurological disorder characterized by synaptic injury and loss in its early stage. This study aimed to investigate the effects of treadmill exercise on Alzheimer's disease mice, focusing on the related molecular mechanism of axonal transport. METHOD:In this study, 3-month-old male APP/PS1 mice and C57BL/6J mice were used and divided into four groups ( n = 9). Behavioral performance was evaluated using the Morris water maze, open field test, and tail suspension test. Transmission electron microscopy and ELISA were used to assess the morphology and function of mitochondria and synapses, individually. The colocalization of mitochondria and synapses was analyzed by double-labeling immunofluorescence. Finally, the underlying mechanism of treadmill exercise on Alzheimer's disease mice was evaluated by Western blotting. RESULTS:APP/PS1 mice exhibited significant deficits in spatial learning and memory, accompanied by abnormal ultrastructure and dysfunction in hippocampal mitochondria and synapses. Treadmill exercise could ameliorate cognitive impairments and affective disorders in Alzheimer's disease mice, reduce amyloid-beta levels, improve the morphology and function of mitochondria and synapses, and enhance mitochondrial axonal transport, which might be regulated by the related proteins of kinesins, syntabulin, and dyneins. CONCLUSION:These results suggest that exercise-induced modulation of mitochondrial dynamics can provide neuroprotection and support the development of novel therapeutic strategies for Alzheimer's disease (Video Abstract, SDC 1).
OBJECTIVE:This study aimed to elucidate the neuroprotective mechanism of melatonin (Mel) against hypoxic-ischemic brain damage (HIBD) in neonatal rats, specifically through the thioredoxin-interacting protein (TXNIP)/thioredoxin-1 (Trx-1)/glutathione peroxidase 4 (GPX4) pathway in neuronal ferroptosis, and to concurrently evaluate its therapeutic efficacy using multimodal MRI. METHODS:A neonatal rat HIBD model was established with pre- and postmodeling Mel administration. Neuroprotective effects were dynamically assessed in vivo via multimodal MRI. Hippocampal tissues were analyzed for ferroptosis markers and pathway components. In vitro , PC12 cells underwent oxygen-glucose deprivation (OGD) with or without Mel. TXNIP-overexpressing cells were used to verify the axis's specific role. RESULTS:MRI confirmed that Mel significantly reduced infarct volume and improved cerebral blood flow (all P < 0.05). It preserved neuronal and mitochondrial integrity. Molecularly, Mel restored GPX4/Trx-1 and suppressed acyl-CoA synthetase long-chain family member 4/TXNIP (all P < 0.05). These effects were replicated in OGD-PC12 cells and persisted in TXNIP-overexpressing cells, supporting the involvement of this pathway. CONCLUSION:Mel attenuates acute neonatal HIBD and reduces ferroptosis-associated neuronal injury, potentially involving modulation of the TXNIP/Trx-1/GPX4 pathway. Multimodal MRI may serve as a useful in-vivo tool for evaluating therapeutic responses after neonatal HIBD.
OBJECTIVE:Oligomeric amyloid-β (Aβ) peptide-induced neuronal apoptosis is a key process in Alzheimer's disease pathogenesis. Low-dose N-methyl-D-aspartate (NMDA) has been shown to promote cell survival both in vitro and in vivo, but its effect on Aβ neurotoxicity remains largely unknown. This study aimed to investigate whether low-dose NMDA protects against Aβ-induced neurotoxicity and to elucidate the underlying molecular mechanisms. METHODS:Primary rat cortical neurons were exposed to 10 μM Aβ25-35 to establish a neurotoxicity model. Neuronal apoptosis was assessed by 4',6-diamidino-2-phenylindole staining. The effects of low-dose NMDA (10 μM) on the PI3K-Akt and MLK3-MKK7-JNK3 signaling pathways were examined by immunoprecipitation and Western blotting. The PI3K inhibitor LY294002 was used to verify the role of PI3K signaling in NMDA-mediated regulation of the JNK3 pathway. RESULTS:Low-dose NMDA (10 μM) significantly reduced 10 μM Aβ25-35-induced neuronal apoptosis. Mechanistically, NMDA reversed the Aβ-induced decrease in p-PDK1 and p-Akt levels and concurrently suppressed the activation of the MLK3-MKK7-JNK3 cascade. Moreover, treatment with LY294002 attenuated the inhibitory effect of NMDA on the MLK3-MKK7-JNK3 pathway. CONCLUSION:Low-dose NMDA exerts neuroprotective effects against Aβ-induced neurotoxicity. These effects are mediated by the dual modulation of the pro-survival PI3K-PDK1-Akt pathway and the pro-apoptotic MLK3-MKK7-JNK3 pathway.
OBJECTIVE:This study aims to characterize brain regional structural alterations across distinct time points in a rat model of trigeminal neuralgia using MRI. METHODS:A rat model of secondary trigeminal neuralgia was established by injecting a talc suspension into the infraorbital foramen. Sixty Sprague-Dawley rats were randomly assigned to six groups, including three experimental groups and three sham groups. This study employed a cross-sectional design. MRI scans were performed on one experimental group and one sham group at 4, 8, and 12 weeks postoperatively. Whole-brain voxel-based morphometry analysis was conducted using the SIGMA and Tohoku rat brain templates, and cross-template validation was performed using both templates. A two-sample t-test was used for intergroup comparisons, whereas analysis of variance was performed for intragroup analyses. RESULTS:Our results demonstrated that, at 12 weeks after trigeminal neuralgia induction, the volumes of the right hippocampus, right primary visual cortex, right temporal association cortex, and left primary somatosensory cortex were significantly lower in experimental rats than those in the sham group. Cross-template validation consistently confirmed the involvement of the right hippocampus and left primary somatosensory cortex. CONCLUSION:Lower volumes in the ipsilateral hippocampus and contralateral primary somatosensory cortex were observed at 12 weeks following trigeminal neuralgia induction when compared with those in the sham group. Comparisons at the 4- and 8-week cross-sectional sampling time points revealed no significant intergroup differences.
BACKGROUND:Triggering receptor expressed on myeloid cells 2 (TREM2) regulates microglial functions in Alzheimer's disease, whereas soluble amyloid precursor protein alpha (sAPPα) has neuroprotective effects. Whether sAPPα directly interacts with TREM2 remains unclear. METHODS:Single-cell RNA sequencing data from wild-type and APP/PS1 mouse cortices and bulk RNA-seq data (GSE18309) were analyzed. Solid-phase binding, pull-down, and co-immunoprecipitation assays were used to examine TREM2-sAPPα binding and map the interacting regions. LPS-stimulated BV-2 cells were used to assess the effects of TREM2 knockdown and sAPPα supplementation on viability, apoptosis, invasion, phagocytosis, cytokine production, and polarization. RESULTS:A TREM2-positive microglial subpopulation was more abundant in the APP/PS1 dataset and showed relatively restrained inflammatory signaling. Cell-cell communication analysis predicted enhanced APP-(TREM2+TYROBP) signaling. Biochemical assays confirmed direct binding between TREM2 and sAPPα. The TREM2 51-71 amino acid region and the APP E1+Ac fragment contributed to this interaction, whereas TREM2 variants Y38C, R47H, R62H, and T66M reduced binding affinity. TREM2 knockdown aggravated LPS-induced loss of viability, apoptosis, inflammatory cytokine production, and M1-like polarization in BV-2 cells. Exogenous sAPPα reversed these changes. CONCLUSION:sAPPα directly binds TREM2 and may limit excessive inflammatory activation of microglia under LPS stimulation. The TREM2-sAPPα interaction may represent a regulatory pathway relevant to Alzheimer's disease.
PURPOSE:This study aimed to investigate diabetic retinopathy-related alterations in spontaneous brain activity using ALFF and to explore whether these alterations show indirect spatial associations with normative molecular, cellular, and neurochemical brain architectures. METHODS:Resting-state functional MRI data were acquired from 46 patients with diabetic retinopathy and 44 healthy controls. The amplitude of low-frequency fluctuation (ALFF) was used to assess regional spontaneous brain activity. ALFF alteration maps were further integrated with cortical gene expression data to perform imaging transcriptomic analysis, functional enrichment, cell-type-specific expression analysis, neurotransmitter map association analysis, and machine learning classification. RESULTS:Compared with healthy controls, patients with diabetic retinopathy showed increased ALFF in the cerebellum VIII region, left inferior temporal gyrus, right hippocampus, and left pallidum, and decreased ALFF in the bilateral middle occipital gyri and left calcarine cortex. Imaging transcriptomic analysis linked ALFF alterations to gene expression patterns enriched in neural development, synaptic structure, cytoskeletal organization, cell adhesion, and immune-inflammatory pathways. Cell-type analysis implicated astrocytes, microglia, oligodendrocyte precursor cells, and oligodendrocytes. Neurotransmitter mapping suggested associations with multiple neurochemical systems. Machine learning models based on ALFF features demonstrated moderate-to-good classification performance, with logistic regression achieving the highest mean area under the receiver operating characteristic curve of 0.854 ± 0.028. CONCLUSION:Patients with diabetic retinopathy showed altered spontaneous brain activity in visual and extra-visual regions. Multimodal analyses provided exploratory biological annotation and preliminary discriminative information for these ALFF alterations, but the transcriptomic and neurotransmitter findings should be interpreted as indirect atlas-based associations requiring further validation.
OBJECTIVE:Acid-sensing ion channel 3 (ASIC3), a proton-gated cation channel predominantly expressed in primary afferent nociceptors, is an acidosis-related pain generator. Previous experiments suggested that ASIC3 is also involved in the generation of itch. However, mechanistic links between ASIC3 and itch, including the expression of ASIC3 in itch-mediating primary sensory neurons, remain unclear. We examined ASIC3 expression in these sensory neurons and then investigated whether mild acid stimulation could induce ASIC3-dependent itch without overt pain in mice. METHODS:Immunohistochemical analyses were performed using ASIC3-FLAG-enhanced green fluorescent protein-FLAG (FEF) expressing mice. Citric acid was applied with a brush to shaved skin of the nape of the neck or cheek in wild-type and ASIC3 knockout (ASIC3 -/- ) mice. Hindlimb scratching and, in the cheek model, forelimb facial wiping were recorded. RESULTS:ASIC3-expressing neurons and plexin C1-positive/tachykinin 1-negative itch-mediating neurons essentially belonged to distinct subpopulations in dorsal root and trigeminal ganglia. Application of 0.2 M citric acid to the nape induced hindlimb scratching directed toward the citric acid-applied area in wild-type mice, and this response was significantly attenuated in ASIC3 -/- mice. Application of 0.5 M citric acid to the cheek induced ASIC3-dependent itch behavior (hindlimb scratching), accompanied by minimal or no pain behavior (forelimb wiping). CONCLUSION:Given the absence of ASIC3 in typical itch-mediating primary sensory neurons, citric acid-induced ASIC3 activation in nociceptive skin afferents primarily involved in pain likely underlies the observed itch behavior. As 0.5 M citric acid likely represents a weak noxious stimulus, weak activation of these pain-mediating afferents can evoke itch, supporting the intensity theory of itch.
Objective Previous research suggests that attentional allocation to inclusion cues is associated with subjective amelioration from social exclusion. However, individuals high in avoidant attachment show reduced attention to inclusion cues while still exhibiting subjective amelioration comparable with those low in avoidance. This study examined whether experimentally encouraging attention to inclusion cues enhances attentional processing and subjective amelioration following social exclusion, and whether these effects differ as a function of avoidant attachment. Methods Thirty-six undergraduate students completed a Cyberball task consisting of exclusion and subsequent inclusion sessions under two conditions: an attention-manipulation condition, in which they counted ball receptions, and a natural condition without additional attention instructions. P3b amplitudes elicited by inclusion cues during the inclusion session indexed attentional processing. Subjective amelioration was defined as the reduction in Need-Threat scores from exclusion to inclusion. Results Preregistered analyses of covariance showed that encouraging attention to inclusion cues increased P3b amplitudes ( P = 0.02) and subjective amelioration ( P = 0.04), with no significant moderation by avoidant attachment ( P s > 0.39). However, additional group-based analyses of variance showed that the attention manipulation significantly increased P3b amplitudes in the high-avoidance group ( P = 0.004), but not in the low-avoidance group ( P = 0.55), whereas no corresponding Group × Condition interaction was observed for subjective amelioration ( P = 0.94). Conclusion The present study suggests that encouraging attention to inclusion cues facilitates amelioration from social exclusion without disrupting this process among individuals high in avoidance.
BACKGROUND:Global population aging highlights the need to explore age-related limbic system alterations, which are closely linked to emotion, memory, and cognition. Heterogeneous volume changes of limbic subregions and their memory-related impacts in healthy aging remain poorly understood. METHODS:A total of 315 cognitively normal adults aged 20-89 years were divided into four age cohorts. T1-weighted MRI was applied to quantify volumes of core limbic subregions. Memory and general cognition were evaluated via the Mini-Mental State Examination (MMSE) and Hopkins Verbal Learning (HOP), covering immediate recall, delayed recall, and delayed recognition. Associations between regional brain volumes and memory performance were analyzed. RESULTS:Most regions of the limbic system exhibited a trend of volume reduction across all four age groups. The right anterior basal forebrain atrophied starting from young adulthood, while the fornix, left basal forebrain, and bilateral hypothalamus shrank significantly in late middle-aged and older adults, respectively. Uniquely, the volume of the left septal nucleus exhibits an abnormal increase. MMSE scores declined gradually, with accelerated loss after 65 years. Older adults exhibited lower immediate and delayed recall scores, positively correlated with the volumes of the nucleus accumbens, hypothalamus, fornix, and basal forebrain. No correlation existed between left septal nucleus volume and memory. CONCLUSION:Healthy aging causes heterogeneous limbic structural changes, which are essential for sustaining immediate and delayed memory. This advances understanding of the neural mechanisms underlying normal cognitive aging.
OBJECTIVE:The central neuromedin U receptor 2 (NMUR2) participates in regulating neuronal activity and synaptic transmission. This study aimed to explore the functional role of NMUR2 in climbing fiber-Purkinje cell synaptic transmission in mouse cerebellar slices. METHODS:Climbing fiber-Purkinje cell excitatory postsynaptic currents (EPSCs) and miniature excitatory postsynaptic currents (mEPSCs) were recorded from Purkinje cells using an Axopatch 700B patch-clamp amplifier. Western blot, glutamate sensor fluorescence imaging, and immunohistochemistry were applied to measure phosphorylated protein kinase A (PKA) levels, climbing fiber terminal glutamate release, and NMUR2 expression, respectively. RESULTS:Bath application of the selective NMUR2 agonist CPN-219 reduced the amplitude and area under the curve of climbing fiber-Purkinje cell EPSCs and increased the paired-pulse ratio ( N 2/ N 1). The CPN-219-induced suppression of EPSCs was reversed by an adenylyl cyclase activator and occluded by an AC inhibitor. The CPN-219-mediated inhibitory effect on EPSCs was completely abolished by bath perfusion of the PKA inhibitor, but not by intracellular PKA inhibition. Western blot analysis revealed that CPN-219 decreased phosphorylated PKA levels in cerebellar molecular layer tissue. Furthermore, CPN-219 markedly attenuated Ca 2+ transients and complex spike activity in Purkinje cells, suppressed climbing fiber-evoked glutamate fluorescent signals, and decreased mEPSC frequency, with no significant alteration in mEPSC amplitude. Moreover, immunohistochemical staining showed NMUR2 immunoreactivity distributed throughout the somata and dendritic arbors of Purkinje cells. CONCLUSION:These results indicate that NMUR2 activation suppresses climbing fiber-Purkinje cell synaptic transmission in mouse cerebellar slices predominantly via a mechanism consistent with a presynaptic adenylyl cyclase-PKA signaling cascade.
BACKGROUND:Without visual feedback, the central nervous system must rely on the integration of internal models and proprioceptive information. While the dorsolateral prefrontal cortex (DLPFC) is involved in motor control and sensorimotor monitoring, whether it causally influences force steadiness and whether any such influence is dependent on corticospinal excitability remains unclear. OBJECTIVE:This study aimed to investigate whether modulating DLPFC activity using theta burst transcranial stimulation (TBS) influences force steadiness during submaximal contractions performed without visual feedback, and whether this depends on corticospinal excitability. METHODS:Twenty-eight healthy volunteers were randomly assigned to receive either inhibitory continuous TBS (cTBS) or facilitatory intermittent TBS over the left DLPFC. Participants performed a 35% submaximal isometric wrist flexion task without visual feedback. We assessed the submaximal force and its coefficient of variation. Motor evoked potentials (MEPs) and maximal voluntary contraction force were also measured at pre, 15 min, and 30 min poststimulation. RESULTS:Following cTBS, the coefficient of variation of submaximal force significantly decreased at 15 min poststimulation ( P = 0.013), indicating improved force steadiness. This improvement occurred without any significant changes in MEP amplitudes, maximal voluntary contraction force, or the mean level of submaximal force production. CONCLUSION:Transient inhibition of the left DLPFC may enhance force steadiness without visual feedback. This enhancement was not accompanied by detectable changes in resting corticospinal excitability. These results suggest that the DLPFC contributes to the qualitative stability of motor output, possibly by optimizing sensorimotor integration and mitigating maladaptive monitoring of internal feedback under limited-feedback situations.
BACKGROUND:Chronic low back pain (CLBP) is associated with widespread disruptions in intrinsic brain activity; however, the underlying molecular and neurochemical mechanisms remain unclear. This study aimed to elucidate the multiscale biological substrates of alterations in spontaneous neural activity in CLBP using a multimodal framework. METHODS:We enrolled 41 patients with CLBP and 41 matched healthy controls. Resting-state functional MRI was utilized to assess the amplitude of low-frequency fluctuations (ALFFs), a marker of spontaneous brain activity. Regional alterations in ALFF were mapped and correlated with spatial gene expression profiles from the Allen Human Brain Atlas and neurotransmitter receptor density maps derived from PET. RESULTS:Compared with healthy controls, patients with CLBP exhibited increased ALFF in the left cerebellar lobule 10 and decreased ALFF in five cortical regions spanning the visual, default mode, sensorimotor, and frontoparietal networks. Transcriptomic analysis revealed that ALFF-related genes were enriched in pathways associated with synaptic transmission and immune response and were predominantly expressed in excitatory and inhibitory neurons. Spatial correlations further indicated significant alignment between ALFF alterations and the regional distributions of μ-opioid, 5-HT1a serotonin, and CB1 cannabinoid receptors. CONCLUSION:Our findings highlight a multiscale interplay among spontaneous brain activity, gene expression, and neuromodulatory systems in CLBP. Regionally specific alterations in ALFF reflect imbalances between neuronal excitation and neuroimmune regulation, constrained by the spatial architecture of neurotransmitter systems. These results enhance our understanding of the neurobiological basis of chronic pain and suggest potential targets for mechanism-informed interventions.
OBJECTIVE:Traumatic brain injury (TBI) constitutes a major inducer of neuroinflammation within the initial 24 h, peak microglial reactivity by day 3 post-injury, and cytokine production through day 7. However, the precise underlying pathophysiology driving immune cell infiltration, inflammatory cascades, and subsequent neuronal damage remains incompletely defined. This study aims to investigate whether C-C motif chemokine ligand 3 (CCL3) plays a functional role in TBI-induced neuroinflammation and associated neuronal injury. METHODS:Datasets of RNA-seq analysis used were: GSE58485 is mice neocortex at 3 days post-TBI, GSE92363 is rat hippocampus at day 1 post-TBI, and GSE59645 is rat hippocampus at day 14 post-TBI. GEO datasets, GSE92363 and GSE59645, sequencing analysis of the normal rat hippocampus were merged to provide a baseline to identify key differentially expressed genes (DEGs). DEGs were used to perform functional annotations through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses, execute gene set enrichment analysis (GSEA), and construct protein-protein interaction (PPI) networks. Microglia HAPI cells and H19-7 cells co-culture system was used to functionally validate microglia-derived neuroinflammatory damage mechanisms on neuronal cells. RESULTS:For screening of DEGs related to TBI, we first performed an integrated analysis of the GSE92363 and GSE59645 datasets. Initial-phase TBI exhibited characteristic immune landscape alterations, marked by significant macrophage and neutrophil infiltration with concurrent M1 macrophage polarization. GSEA further revealed microglial phagocytic pathway dysregulation as the most profoundly perturbed signaling cascade in TBI pathogenesis. Subsequently, we identified CCL3 as a master regulatory hub orchestrating TBI progression with PPI analysis. In HAPI cells, short hairpin RNA-mediated CCL3 knockdown effectively attenuated lipopolysaccharide-induced pro-inflammatory cytokine elevation and suppressed nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome pathway activation. In the HAPI-H19-7 (neuron) co-culture system, CCL3 silencing demonstrated significant neuroprotection by mitigating H19-7 neuronal apoptosis. CONCLUSION:CCL3 functions as a key regulatory chemokine orchestrating NLRP3 inflammasome-mediated microglial activation in post-TBI neuroinflammation. Inhibition of CCL3 may be a promising therapeutic target for ameliorating secondary neuronal injury following TBI.
OBJECTIVE:The functional architecture of the cerebral cortex relies on the coordination between excitatory projection neurons and inhibitory GABAergic interneurons. While intrinsic programs governing their specification are well-characterized, it remains unclear whether the proper development of interneurons is required to maintain the molecular identity of projection neurons. METHODS:We generated double conditional knockout (DCKO) mice lacking the transcription factors Sp8 and Sp9 specifically in the GABAergic lineage using the Dlx5/6-Cre driver. Cortical cytoarchitecture and neuronal identity were assessed via immunohistochemistry at postnatal days 4 (P4) and 11 (P11). RESULTS:Sp8&Sp9-DCKO mice exhibited severe defects in the development and laminar positioning of cortical interneurons, resulting in their abnormal distribution and reduced abundance in the cortex. Despite these inhibitory defects, the general laminar organization, checked by the expression of TBR1, CTIP2, FOXP2, FOXP1, CUX1, and NeuN, remained intact. Strikingly, the expression of BHLHB5, a key regulator of sensory area identity, was specifically downregulated in projection neurons at P11. Crucially, BHLHB5 expression was indistinguishable from controls at P4, indicating that the proper development of cortical interneurons is essential for stabilizing the molecular identity of projection neurons. CONCLUSION:These findings reveal a novel non-cell-autonomous mechanism where proper GABAergic interneuron positioning and development are essential for the maintenance, but not the acquisition, of specific projection neuron molecular identities.
OBJECTIVES:Electroacupuncture, a therapeutic modality integrating electrical stimulation with traditional acupuncture, has emerged as a promising intervention for intracerebral hemorrhage (ICH). This study aimed to elucidate the potential mechanisms underlying electroacupuncture's therapeutic effects in a mouse model of ICH. METHODS:The mice were injected autologous blood into basal ganglia region of brain to establish an ICH model. The study comprised two parts. First, we evaluated the therapeutic efficacy of electroacupuncture at Baihui (GV20) and Dazhui (GV14) points using the ICH model by neurological deficit score, Fluoro-Jade C (FJC) staining, and ELISA. Subsequently, based on the observed therapeutic benefits, we further explored the underlying mechanisms via neurological deficit and adhesive removal score, immunofluorescence staining, immunohistochemical staining, ELISA, and Western blot assays. RESULTS:The first part of the study showed that electroacupuncture treatment alleviated the expression of proinflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β)], neuronal degeneration, and neurological deficits. The second part of the study showed that electroacupuncture treatment upregulated the expression of the α7 nicotinic acetylcholine receptor (α7nAChR), downregulated Janus kinase-2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) phosphorylation, promoted M2 microglia/macrophage polarization, and reduced IL-1β and TNF-α expression, contributing to improved neurobehavioral function. CONCLUSION:Electroacupuncture treatment can alleviate neuroinflammation and improve neurobehavioral function in ICH mice, which might be modulated by the α7nAChR/JAK2/STAT3 pathway, providing a new molecular mechanism of electroacupuncture treatment on ICH.
BACKGROUND:Motor imagery can improve motor performance, but its effects vary among individuals. Hand mental rotation may reflect individual characteristics related to motor imagery processing, including imagery strategies. This study examined whether the reaction time in a hand mental rotation task could explain interindividual differences in motor imagery-induced changes in finger dexterity and spinal motor neuron excitability. METHODS:Participants were classified into 'good' and 'poor' groups according to the reaction times for right- and left-hand mental rotation judgments. Finger dexterity was assessed using the Purdue Pegboard task, and spinal motor neuron excitability during motor imagery was evaluated using F-waves. RESULTS:Grouping based on hand mental rotation reaction time showed no interaction effect on the F/M amplitude ratio. In contrast, grouping based on left-hand mental rotation reaction time revealed greater improvement in finger dexterity in the poor group. Left-hand mental rotation reaction time showed a weak association with backward digit span performance but not with other measures of working memory. CONCLUSION:The hand mental rotation reaction time may reflect differences in motor imagery strategy rather than motor imagery ability and may explain interindividual differences in motor imagery-related improvements in finger dexterity.
OBJECTIVES:Neurofibromatosis type 1 (NF1) is a genetic disorder that affects brain development and increases the risk for neurodevelopmental conditions, including autism spectrum disorder. Given similar behavioral phenotypes and potential shared neurobiological processes in NF1 and autism spectrum disorder, this study evaluates two markers of brain maturation in youth with NF1 and typically developing youth, including auditory white matter and cortical response latency. BASIC METHODS:Participants, aged 8-12 years, completed a multimodal neuroimaging protocol that included MRI with diffusion tensor imaging of the auditory radiation and magnetoencephalography. Analyses included group comparisons on fractional anisotropy measures of white matter and M50 latency responses from magnetoencephalography and the coupling between fractional anisotropy and M50. MAIN RESULTS:Compared to typically developing youth, youth with NF1 did not show maturation in fractional anisotropy or M50 with age and demonstrated shorter M50 auditory response latency. The association between auditory radiation fractional anisotropy and M50 was different in youth with NF1 compared to typically developing youth with youth with NF1 not showing a significant association between fractional anisotropy and M50. CONCLUSION:Maturation of auditory white matter and auditory cortical response latency is disrupted in NF1 and there is a lack of coupling between structure and function. Longitudinal imaging research is needed to further evaluate neurodevelopment and associations between these immaturities and behavior.
OBJECTIVE:Metabotropic glycine receptors (mGlyRs) have been identified in the prefrontal cortex and nucleus accumbens, but their function in the hippocampus remains unreported. This study aimed to probe functional mGlyR signaling in the hippocampus. METHODS:We pharmacologically isolated conditions favoring mGlyR activation and performed gramicidin-perforated whole-cell recordings from CA3 pyramidal cells in rat organotypic hippocampal slice cultures. Intrinsic electrophysiological properties were compared before and after bath application of glycine. To assess G protein dependence, we examined responses after pretreatments with N-ethylmaleimide (NEM), a broad G protein blocker, and pertussis toxin (PTX), a Gi/o-selective inhibitor. RESULTS:Under control conditions, we observed changes indicating enhanced neuronal excitability, including an increase in the number of action potentials fired and a reduction in the amplitude of the medium after hyperpolarization. Moreover, in the presence of either NEM or PTX, the changes observed in the control group were abolished. CONCLUSION:These results indicate that there are functional mGlyRs in the hippocampus and that they mediate their effects via Gi/o signaling.
BACKGROUND:Alzheimer's disease is a neurodegenerative disorder, in which ferroptosis contributes to its pathogenesis and progression. This study explored the precise mechanisms of ferroptosis in the pathological development of Alzheimer's disease. METHODS:Amyloid beta 1-42 oligomer-treated SH-SY5Y cells were used to simulate Alzheimer's disease in vitro. Ferroptosis was evaluated by detecting the levels of reactive oxygen species (ROS), malonaldehyde, glutathione, Fe2+, and ferroptosis-related proteins. Cell viability was assessed by a Cell Counting Kit-8 assay. Total RNA N6-methyladenosine (m6A) levels were detected using an RNA methylation quantification kit, and peroxiredoxin 6 (PRDX6) m6A levels were analyzed by m6A RNA immunoprecipitation. The binding of methyltransferase-like 14 (METTL14) to PRDX6 was investigated by a dual-luciferase reporter assay. RESULTS:METTL14 levels were decreased in the serum of Alzheimer's disease patients and in an in-vitro model of Alzheimer's disease, and serum levels correlated with the degree of cognitive impairment. METTL14 overexpression significantly inhibited amyloid beta 1-42 oligomer-induced ferroptosis and cytotoxicity in SH-SY5Y cells. Mechanistically, METTL14-mediated m6A modification increased PRDX6 mRNA stability, which inactivated the ROS-apoptosis signal-regulating kinase 1/p38 pathway. Rescue experiments demonstrated that PRDX6 overexpression reversed sh-METTL14-induced ferroptosis and neurotoxicity. CONCLUSION:METTL14 suppressed neuronal ferroptosis to delay Alzheimer's disease progression through m6A modification of PRDX6 to inactivate the ROS-apoptosis signal-regulating kinase 1/p38 pathway. Our observations provide a potential therapeutic strategy for Alzheimer's disease.
OBJECTIVES:The primary visual cortex (V1) is tuned to several visual features, including orientation and spatial frequency, that are organized into overlapping functional maps. Local neurons sharing tuning properties tend to connect more strongly, but how these features lead to distal functional connectivity in V1 remains unclear. METHODS:We recorded multiunit activity from layers II/III of cat V1 using electrode pairs separated by 410 µm and assessed functional connectivity using shift-corrected cross-correlograms. Visual stimuli were positioned to largely overlap the receptive fields of neurons at both recording sites. Functional connectivity was compared during orientation-constant and spatial frequency-constant stimulus conditions. RESULTS:Neurons in the same ensemble exhibited significantly more and stronger distal functional connections during the spatial frequency-constant condition than during the orientation-constant condition. This effect persisted at the population level, indicating that distal connectivity is selectively recruited depending on the stimulus feature rather than anatomical proximity or differential stimulus drive. CONCLUSION:These findings demonstrate that functional connectivity in V1 is stimulus-dependent, with spatial frequency processing preferentially engaging distributed cortical interactions. Such feature-dependent distal connectivity may support integration across spatial scales and reflect the flexible organization of early visual cortical networks.
