Journal of integrative neuroscience最新文献

Neurodegenerative diseases (NDDs) are closely linked to physiological conditions such as oxidative stress, neuroinflammation, neuronal cell death, and proteostatic failure, all of which are associated with cerebral trace-element imbalance. Recent research has highlighted the potential of trace-element-based interventions due to their diverse redox, anti-inflammatory, and pro-survival bioactivities. Leveraging nanotechnology to construct trace-element-based nanotherapeutics capable of crossing the blood-brain barrier, actively targeting neurons, and enabling on-demand payload release has emerged as a promising strategy, transforming empirical supplementation into a precision nanomedicine approach. These nanoplatforms have demonstrated significant effects in disease treatment. However, systematic studies on their application in NDD therapy remain limited. In this review, we provide a comprehensive overview of trace-element-based nanotherapeutics, exploring how trace-metal imbalances contribute to NDD development, nanoparticle construction, and the advantages of trace-element-based nanoparticles. Additionally, we discuss the physiological aspects of trace-element metabolism and inflammation in NDD treatment, offer recommendations for future research, and comprehensively discuss and systematically evaluate the safety of trace-element nanoparticles. In doing so, we provide a resource that will help to guide the design and development of nanotherapeutics for NDDs and assist researchers in this emerging field.

Cardiac arrest (CA) is a leading cause of mortality worldwide, with cerebral injury resulting from hypoxia being its most significant complication. This condition is associated with low survival rates and unfavorable neurological prognosis. Cerebral injury following CA is a major contributor to both mortality and long-term disability. Recently, Targeted Temperature Management (TTM) has garnered considerable attention as a non-pharmacological treatment modality for brain protection, aiming to reduce hypoxia-induced damage and improve neurological outcomes following CA. This work aims to provide a comprehensive review of TTM following CA, focusing on its current status, underlying mechanisms, research advancements, and future prospects for clinical application.

Background: Post-stroke spastic hemiplegia (PSSH) frequently leads to severe motor dysfunction, with its primary pathology being spinal hyperexcitability arising from attenuated descending inhibition. We previously reported that acupuncture alleviated spastic hypertonia induced by middle cerebral artery occlusion (MCAO) via upregulating potassium-chloride cotransporter 2 (KCC2) expression. Cumulative evidence has indicated that N-methyl-D-aspartate receptor (NMDAR) can be a pivotal determinant of spinal excitability via modulating KCC2-mediated neuronal chloride homeostasis. The present study investigated whether acupuncture exerts its therapeutic effects through modulation of NMDAR-mediated activation of protein phosphatase 1 (PP1)/Calpain1-KCC2 pathway.

Methods: Multiple functional assessments, in vivo electrophysiological test, 2,3,5-triphenyl tetrazolium chloride (TTC) staining, immunofluorescence, quantitative real-time PCR (RT-qPCR), and Western blot were used.

Results: In the male MCAO rat model, assessments using the neurological-function score, muscle-tone scale, and footprint analysis demonstrated that acupuncture significantly attenuated spasticity and improved motor performance. H-reflex recordings and immediate early gene c-Fos (c-Fos) immunofluorescence indicated that acupuncture reduced hyperexcitability in spinal ventral horn. These observed effects of acupuncture were associated with its downregulation of N-methyl-D-aspartate receptor 1 (NMDAR1) expression and restoration of both the expression and function of KCC2 in spinal cord. Pharmacological interventions using NMDAR agonist and antagonist demonstrated that acupuncture upregulated KCC2 by inhibiting NMDAR-mediated activation of PP1 and Calpain1.

Conclusion: Acupuncture modulated the NMDAR-PP1/Calpain1-KCC2 pathway in the spinal cord to suppress neuronal hyperexcitability, thereby relieving spasticity and promoting motor function in rats with PSSH.

Background: Cortical γ-aminobutyric acidergic (GABAergic) neurons are characterized primarily as local inhibitory interneurons that modulate cortical pyramidal neuronal activity. However, emerging evidence has demonstrated that some of them may project to subcortical structures, such as the midline dorsal thalamic nuclei (MDTN), which play a pivotal role in sensory information transmission and emotional regulation. The present study aimed to investigate whether cortical GABAergic neurons project to the MDTN.

Methods: To address this question, this study combined retrograde tracing with immunofluorescent histochemical staining in GAD67-green fluorescence protein (GAD67-GFP) mice.

Results: Cholera toxin B subunit (CTB) retrograde-labeled (CTB⁺), GAD67-GFP-immunoreactive (GAD⁺), and GAD and CTB double-labeled (GAD⁺+CTB⁺) neurons were identified across many cortical regions. CTB⁺ neurons were mainly observed in the motor cortices, cingulate cortex (Cg), prelimbic cortex (PrL), and insular cortex (IC) with sparse distributions in the sensory cortices, orbitofrontal cortex (OFC), piriform cortex (Pir) and claustrum (CL). GAD⁺ neurons were distributed throughout all cortical layers. In the sensory, motor, and granular insular cortices, the highest density was observed in layers II/III or V, with a relatively sparse distribution in layers I and IV. These layers were also widely distributed in other cortical regions such as the OFC, Cg, PrL, and Pir. GAD⁺+CTB⁺ neurons were mainly concentrated in layers V/VI of the motor, sensory, and IC cortices, with sparse distributions in the OFC, PrL, and Cg. These neurons spanned a rostrocaudal range of +2.34 mm to -0.46 mm from the bregma. Quantitative analysis showed that GAD⁺+CTB⁺ neurons accounted for 0.25%-0.55% of GAD⁺ neurons and 2.52%-4.93% of CTB⁺ neurons, respectively.

Conclusions: The present results confirmed the existence of long-range GABAergic projections from the cortex to the MDTN and provide a morphological basis for the functional study of corticothalamic regulation through GABAergic projections.

Exosomes are extracellular vesicles that carry a variety of biomolecules, including nucleic acids, proteins, and lipids, and they play a vital role in intercellular communication. These endogenous carriers offer several advantages over conventional nanocarriers, such as liposomes. These advantages include high biocompatibility, low immunogenicity, and the ability to cross biological barriers such as the blood-brain barrier, making them a promising platform for targeted drug delivery. In this review, we systematically summarize the biological characteristics of exosomes, methods for their isolation and purification, strategies for drug loading (including endogenous and exogenous approaches), and surface engineering techniques (such as genetic engineering and chemical modification) to enhance targeting and therapeutic efficacy, based on a comprehensive PubMed literature search. We particularly focus on the modification of engineered exosomes as drug delivery systems in various clinical contexts, covering multiple diseases including cancer, diabetes, neurological diseases, cardiovascular diseases, and tissue repair. Administration routes include oral, subcutaneous, intranasal, and intravenous delivery. While exosomes have shown promise in preclinical studies, challenges remain in terms of large-scale production, standardized isolation, drug loading efficiency, and safety evaluation. Herein, we aim to provide a theoretical foundation and suggest future directions for developing exosomes as a next-generation drug delivery platform.

The blood-brain barrier (BBB) consists of endothelial cells enmeshed by brain microvessels, surrounding basement membrane, pericytes and astrocyte pedicles. It serves as a natural barrier between the blood and brain tissue and both its structural and functional integrity play a crucial role in protecting the central nervous system (CNS) from harmful substances and maintaining the internal stability of the brain. As an important component of the BBB and a hub in the neurovascular unit that links neurons and the cerebral microvasculature, astrocytes play a key role in providing structural support and dynamic regulation of the BBB. In this review, we describe both the physiological structure and mechanistic functions of the BBB and astrocytes, and explores the role of astrocytes in the development, stabilization, destruction and repair of the BBB. Finally, we outlines the therapeutic potential of targeting these mechanisms for CNS disorders associated with BBB disruption.

Background: Asymptomatic carotid stenosis (ACS) and asymptomatic intracranial atherosclerotic stenosis (aICAS) present ongoing treatment challenges. These conditions can lead to cognitive impairment through cerebral hypoperfusion and silent cerebral embolism. However, it is unclear whether they result in the same degree of cognitive dysfunction. Furthermore, the neurological mechanisms behind these dysfunctions are still not well understood. This study used cognitive neuro-electrophysiological techniques to examine differences in cognitive impairment caused by ACS and aICAS.

Methods: A total of 22 patients with ACS and 15 patients with aICAS were enrolled, all with at least 70% unilateral severe stenosis. The control group (CG) consisted of 23 patients who were matched with the ACS and aICAS groups for age, gender and vascular risk factors. All participants conducted the flanker task, and their behavioral and neuroelectric data were also collected. Cognitive impairment of the hypoperfused hemisphere was compared with the normally perfused hemisphere.

Results: At the level of behavioral performance, the ACS group presented longer reaction times (RTs) for both flanker types. At the level of event-related potentials, patients in both the ACS and aICAS groups showed decreased N2 amplitudes in the parietal region of the hypoperfused hemisphere. They also showed reduced P300 amplitudes in the anterior frontal regions of both the hypoperfused and normally perfused hemispheres. Patients in the ACS group exhibited longer P300 latencies in the bilateral anterior frontal regions. In addition, both groups showed an increase in P300 amplitude in the central parietal region of the hypoperfused hemisphere. Notably, the aICAS group showed stronger compensatory capacity.

Conclusions: ACS and aICAS patients exhibit different cognitive dysfunctions, with ACS patients presenting with more severe dysfunction of executive control. aICAS patients present with stronger compensatory capacity.

Background: Disorders of consciousness (DoCs) following traumatic brain injury (TBI), or cerebrovascular disease (CVD) are difficult to prognose, as reliable biomarkers are lacking. Resting-state functional magnetic resonance imaging (fMRI) amplitude of low-frequency amplitude (ALFF) may capture etiology-specific neural activity, but its prognostic value for spinal cord stimulation (SCS) outcomes remains unknown. In this study we therefore investigated etiology-specific ALFF patterns in TBI- and CVD-induced DoCs and evaluated their prognostic value for recovery after SCS.

Methods: Resting-state fMRI data from patients with TBI (n = 16) and CVD (n = 15), and healthy controls (n = 12), were analyzed. Whole-brain ALFF differences were also compared between the groups. Correlations between ALFF and 6-month post-SCS Coma Recovery Scale-Revised (CRS-R) score improvements were assessed. Logistic regression was used to identify consciousness recovery markers.

Results: Compared with healthy controls, patients with TBI demonstrated a significant increase in ALFF within the bilateral insula, thalamus, and brainstem (p < 0.05), suggesting compensatory neural hyperactivity potentially involving glutamatergic pathways. Patients with CVD exhibited elevated ALFF in the contralateral sensorimotor cortex (p < 0.05), indicating ipsilateral neural reorganization. Notably, the thalamic ALFF were strongly correlated with consciousness recovery, as measured by improvements in CRS-R score at 6 months in both the TBI (r= 0.64, p = 0.0071) and CVD (r = 0.59, p = 0.02) groups. Furthermore, logistic regression analysis identified increased ALFF in the anterior cingulate cortex-thalamic loop (odds ratio [OR] = 3.21, p < 0.05) as a potential cross-etiology biomarker for recovery following SCS.

Conclusions: ALFF reveal distinct neuroplasticity mechanisms, including compensatory activation in TBI and ipsilateral reorganization in CVD. Elevated anterior cingulate cortex (ACC)-thalamic ALFF are a key cross-etiology biomarker for consciousness recovery to guide SCS target selection.