Journal of integrative neuroscience最新文献

Background and purpose: Current intrathecal (IT) catheter techniques in rats are problematic due to complex surgical procedures and frequent blockages. This study developed a simpler, faster, and more reliable method for long-term IT catheter placement.

Methods: Fifty adult male Sprague-Dawley rats were randomly divided into three groups: IT group (n = 30), Sham group (n = 10), and Control group (n = 10). We inserted a polytetrafluoroethylene (PTFE) catheter (0.5-mm outer diameter, 0.3-mm inner diameter) into the cauda equina, reaching a depth of 0.5-1 cm via the L5-L6 intervertebral space. Then catheter was tunneled subcutaneously, exiting at the dorsal neck, and held in place with mechanical compression. We assessed safety and efficacy over 12 weeks through behavioral testing, functional evaluations, and immunofluorescence analysis.

Results: Surgery took an average of 7.2 ± 1.8 min, with a 93.3% first-attempt success rate. Remarkably, all catheters remained patent throughout the 12-week study period (100% patency). Behavioral tests showed no changes in pain sensitivity, although rats did experience a temporary reduction in weight gain during the first postoperative week (p < 0.01). Lidocaine testing confirmed proper catheter function, with motor block occurring rapidly (onset: 30 ± 5 s), followed by complete recovery. Lipopolysaccharide doses of 3, 15, and 30 μg demonstrated clear dose-dependent inflammatory responses, confirming accurate drug delivery. Western blot analysis confirmed no chronic inflammation, with interleukin 1 beta (IL-1β), IL-6, and tumor necrosis factor alpha expression in the IT-Saline group comparable with controls (p > 0.05). Immunofluorescence analysis revealed no significant activation of microglia (ionized calcium-binding adaptor molecule 1) or astrocytes (glial fibrillary acidic protein) based on mean fluorescence intensity, with preserved neuronal density (NeuN-positive cells) comparable with controls.

Conclusion: Our L5-L6 approach effectively minimized the risk of spinal cord injury. The choice of PTFE material proved crucial, as it enabled 100% long-term patency, a result not achieved with other materials. Combined with the neck-mounted external design, this technique offers an improved approach for repeated IT drug delivery in rat models, but more studies are needed to confirm its effectiveness in a wider range of pharmacological applications.

Background: Thalamic hemorrhage (TH) is a severe neurological condition, the molecular mechanisms of which are poorly understood, particularly in clinical settings. N-acetyltransferase 10 (NAT10), a regulator of RNA N4-acetylcytidine (ac4C) modification, has been implicated in cell cycle regulation and identified as a potential therapeutic target. This study explored the effects of NAT10 inhibition on TH pathology using a multi-omics approach.

Methods: A mouse model of TH was established via collagenase IV injection. NAT10 activity was detected by dot blot and inhibited using Remodelin. Comprehensive multi-omics analyses, including 16S ribosomal Deoxyribonucleic Acid (16S rDNA) sequencing, metabolomics, and transcriptomics, were used. Behavioral, histological, and molecular evaluations were conducted to evaluate the key genes.

Results: A total of 35 hub genes, 30 hub metabolites, and 28 hub microorganisms associated with NAT10 inhibition were identified. Among them, the xanthine dehydrogenase (XDH) and guanine deaminase (GDA) genes were linked to xanthine, which is a key metabolite implicated in TH pathology. Based on these findings, the xanthine oxidase inhibitor febuxostat was tested, demonstrating significant therapeutic benefits in TH-affected mice. Behavioral, histological, and molecular evaluations confirmed that NAT10 inhibition alleviated TH-induced damage.

Conclusions: This study provides the first comprehensive molecular insights into the therapeutic potential of NAT10 inhibition in TH. Moreover, it identified NAT10 inhibitors and febuxostat as promising candidates for TH management, paving the way for future therapeutic development targeting NAT10 in this condition.

Cardiovascular modulation in response to movement and gravitational forces can be influenced by vestibular input or peripheral baroreflex mechanisms. Galvanic vestibular stimulation (GVS) is a widely used, noninvasive method for activating neural pathways within the vestibular system, as well as associated pathways such as vestibulo-spinal, oculomotor, and vestibulo-autonomic circuits. Research on vestibulo-autonomic function via GVS has primarily focused on its effects on cardiovascular modulation and sympathetic muscle and nerve activity. However, inconsistencies in GVS application protocols across studies have made it challenging to reach a consensus regarding its effectiveness in modulating the vestibulo-autonomic pathway. Evidence suggests that GVS induces transient autonomic changes by stimulating a neural pathway sensitive to otolith input. This review collates the parameters used in GVS application and examines their effects on autonomic neural pathways by analyzing variations in amplitude, frequency, and electrode montage to understand their impact on autonomic responses, including changes in heart rate (HR), blood pressure (BP), and sympathetic muscle or nerve activity (MSNA). By analyzing stimulation parameters and experimental protocols, we aim to determine their impact on autonomic activation and evaluate their potential for precise autonomic modulation. Finally, based on the evidence generated in populations with neurological disorders and motion sickness, we discuss the potential of GVS as a complementary neuromodulation strategy to treat autonomic dysregulation.

Background: Obstructive sleep apnea (OSA) is associated with widespread higher-order cognitive consequences, including deficits in memory and executive function. However, the specific cognitive architecture and underlying mechanisms that link the disease's pathophysiology to these broad cognitive changes remain poorly understood. This study tested the hypothesis that a selective vulnerability of the working memory (WM) executive control system serves as a central hub, mechanistically mediating the relationship between OSA disease burden and memory retention.

Methods: Thirty male patients with OSA underwent comprehensive polysomnography and neurocognitive assessment. A data-driven Global Severity Index (GSI) was derived from principal component analysis of the most cognitively-relevant physiological metrics. A multi-task paradigm was used to dissociate performance on tasks of WM maintenance capacity from those requiring executive control. Hierarchical linear regression and mediation analyses were performed, controlling for relevant covariates.

Results: A higher GSI was consistently associated with poorer performance across multiple tasks requiring executive control, but not with measures of WM maintenance capacity or attentional control. Critically, the a priori defined mediation model was supported: the relationship between the GSI and memory retention performance was fully mediated by a latent Executive Control Factor (ECF) derived from the executive tasks.

Conclusions: Our findings delineate a specific mechanistic pathway for the cognitive consequences of OSA. The disease's pathophysiological burden is selectively associated with executive control performance, and this vulnerability appears to serve as a core mechanism that accounts for the disorder's downstream impact on memory function. This work identifies executive control as a critical target for mitigating the broader cognitive impact of OSA.

Background: Depression frequently manifests as a secondary affective disorder in individuals who have experienced a stroke. In laboratory rats subjected to stroke, prolonged exposure to chronic stress effectively replicates the physiological impairment and adverse environmental challenges encountered by stroke patients. Nevertheless, the complex mechanisms underlying these phenomena remain unclear.

Methods: To elucidate the mechanisms underlying these impairments, we established a poststroke depression model by combining middle cerebral artery occlusion (MCAO) with 70 minutes of ischemia and chronic unpredictable mild stress (CUMS) exposure. Behavioral assessments, along with analyses of purinergic ligand-gated ion channel 7 receptor (P2X7R) and nucleotide-binding oligomerization domain, leucine-rich repeats, and pyrin domain-containing protein 3 (NLRP3)-associated inflammatory protein levels and peripheral blood inflammatory cytokine levels, were conducted at 1, 2 and 4 weeks post-MCAO, and the results were compared with those of rats subjected to stroke alone.

Results: Depression-like behaviors were induced by CUMS exposure for three weeks. These changes were accompanied by significant increases in the protein levels of interleukin-1β (IL-1β), caspase-1, NLRP3 and Iba-1 in the hippocampus. Additionally, an increase in the fluorescence intensity of Iba-1, P2X7R, and NLRP3 in the Cornu Ammonis 1 (CA1) region was observed, along with dysregulation of plasma IL-6, IL-4, IL-10, and IL-1β levels. Importantly, the interaction of CUMS exposure and time affected behavioral scores and the levels of IL-1β. Notably, intraperitoneal administration of Brilliant blue G reversed depression-like behaviors and reduced the expression of NLRP3, caspase-1, IL-1β and IL-18 in the affected hippocampus.

Conclusions: These findings are consistent with the involvement of P2X7R/NLRP3 signaling in hippocampal impairment and inflammation/immune dysregulation in the context of depression-like behaviors induced by CUMS. In particular, behavioral scores may be affected by the interaction between CUMS exposure and time.

Background: Adding movement sonification to haptic exploration can change the perceptual outcome of a textured surface through multisensory processing. We hypothesized that auditory-evoked emotions influence the appraisal of textured surfaces, with corresponding changes reflected in cortical excitability.

Methods: Twelve participants actively rubbed two different textured surfaces (slippery and rough) either without movement sonification, or with pleasant or disagreeable movement sonification.

Results and discussion: We found that sounds, whether agreeable or disagreeable, did not change the texture appraisal. However, the less pleasant surface was associated with a stronger negative hedonic valence, particularly when paired with disagreeable movement sonification. Time frequency analyses of electroencephalography (EEG) activities revealed a significant reduction in beta-band power [15-25 Hz] within the source-estimated sensorimotor and superior posterior parietal cortices when contrasting both pleasant and unpleasant sounds with the silent touch. This suggests that the primary somatosensory cortices together with the superior parietal regions participated in the audio-tactile binding, with both pleasant and unpleasant sounds. In addition, we observed a significant increase in beta-band power in medial visual areas, specifically when disagreeable movement sonification was paired with tactile exploration. This may reflect a disengagement of visual cortical processing, potentially amplifying auditory-driven emotional responses and intensifying the perceived unpleasantness of the explored surfaces.

Conclusion: Our results offer new insights into the neural mechanisms by which hedonic valence of auditory signals modulates emotional processing, without disrupting the perceptual analysis of texture properties.

Background: Alzheimer's disease (AD) is a severe neurodegenerative disorder that impacts the global impact on the population. Nevertheless, the intricate nature of its pathogenesis has posed significant challenges to drug discovery in this field. This study aimed to verify the therapeutic potential of rubiadin (RB) on AD through both in vivo and in vitro experiments, thereby facilitating translational research for the advancement of AD treatment.

Methods: We investigated the neuroprotective effects of RB on AD using both in vivo and in vitro models. Immunohistochemistry and western blot analysis were employed to evaluate inflammatory factors and the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in Mo/HuAPP695swe (APP)/PS1-dE9 (PS1) mice and N2a cells.

Results: RB enhanced the memory performance of APP/PS1 mice in various tests, including the Morris water maze, step-down and step-through passive avoidance tasks, and novel object recognition. RB reduced the accumulation of Amyloid-beta (Aβ) plaques, as shown by immunohistochemical analysis. It also decreased the expression levels of pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α), while increasing the release of IL-4. Additionally, RB inhibited the NF-κB pathway, as demonstrated by western blot. Moreover, a cell viability test showed that RB protected N2a cells against toxicity caused by Aβ_1-42 through a cell viability test. Western blot analysis revealed that neuroinflammation and the NF-κB pathway were inhibited by RB treatment in Aβ_1-42-induced N2a cells. Accordingly, RB suppressed the nuclear translocation of NF-κB in Aβ_1-42-induced N2a cells.

Conclusions: Our results provide experimental evidence supporting the preclinical research and future clinical applications of RB, thereby facilitating the development of new drugs for AD clinical therapy.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with strong genetic and environmental components. Despite progress made over the past decades, no effective therapies targeting the core symptoms of ASD are currently available. More research is required to explore the underlying mechanisms of ASD and discover potential therapeutic targets. Chromodomain helicase DNA-binding protein 8 (CHD8) is one of the most significant high-confidence ASD risk genes identified to date. However, the precise roles and mechanisms of CHD8 in neurodevelopment and behaviors remain incompletely understood. Zebrafish represent an emerging model organism for ASD research. While several zebrafish models with Chd8 disruption have been established, behavioral consequences have not been thoroughly characterized.

Methods: Leveraging the high survival rate of homozygous Chd8 mutant males, we comprehensively assessed their behaviors.

Results: The mutants exhibited social deficits across multiple assays, including shoaling, social interaction and three-chamber social preference test. Additionally, anxiety-like behavior, locomotor coordination deficits, and macrocephaly were observed. These phenotypes closely resemble the symptoms in patients carrying disruptive CHD8 mutations.

Conclusions: Our findings establish this Chd8 mutant zebrafish line as a robust model for investigating ASD pathological mechanisms and screening for potential therapies.

Background: Electroacupuncture pretreatment (EA-pre) has been shown to help reduce myocardial ischemia-reperfusion injury (MIRI), but the underlying mechanism remains unclear. Our previous studies indicated that EA activates the cerebellar cortex, specifically the Crus Ⅰ. However, whether activation of the Crus Ⅰ contributes to the attenuation of MIRI induced by EA-pre remains unclear. This study investigated the possible relationship between EA-induced relief of MIRI and the activation of Crus Ⅰ.

Methods: Electrocardiogram recording, echocardiography, and cardiac histology staining were used to assess the heart's functional status. In vivo electrophysiological recordings, Fos-targeted recombination in active populations (Fos-TRAP) gene-labeling technology and chemogenetic viral modulation were used to explore the effects of Crus Ⅰ activation in EA-pre on MIRI.

Results: In vivo electrophysiological recordings demonstrated that Crus Ⅰ plays a crucial role in EA-pre by modulating sympathetic activity to alleviate MIRI. Subsequent Fos-TRAP studies showed that EA stimulation primarily induces changes in the neuronal activity of Crus Ⅰ Purkinje cells (Crus Ⅰ^PC). Chemogenetic viral manipulations further verified that EA-pre suppresses PC activity in MIRI.

Conclusion: EA-pre mitigated cardiac sympathetic nerve dysfunction during MIRI by regulating Crus Ⅰ^PC activity.

Background: This study aimed to explore the potential relationship between resting-state brain network attributes and adolescent major depressive disorder (MDD), with a focus on understanding how resting-state electroencephalogram (EEG) network features correlate with Hamilton Depression Rating Scale (HAMD) scores, and to identify potential physiological biomarkers for predicting HAMD scores in adolescents with MDD.

Methods: Adolescent MDD presents unique neurodevelopmental challenges, yet the neurophysiological correlates of symptom severity remain poorly characterized. This study investigated resting-state EEG network topology and its relationship with HAMD scores in adolescent MDD, aiming to identify potential neural biomarkers for depression severity.

Results: MDD patients exhibited significantly enhanced frontal-parietal connectivity compared with healthy controls (HC) (p < 0.05, false discovery rate (FDR)-corrected). HAMD scores correlated positively with coefficient (Clu) (r = 0.401), global efficiency (Ge) (r = 0.408), and local efficiency (Le) (r = 0.402), while showing a negative correlation with characteristic path length (Cpl) (r = -0.408; all PFDR < 0.05). The regression model achieved strong prediction accuracy (R² = 0.38, p < 0.001; root mean square error (RMSE) = 2.83), and network features distinguished MDD from HC with 94% classification accuracy.

Conclusion: These preliminary findings deepen our understanding of adolescents with MDD and suggest that resting-state brain network attributes in the alpha band may serve as a potential physiological biomarker for predicting HAMD scores.