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.
The onset and progression of central nervous system (CNS) disorders are frequently associated with aberrant neuronal death. In addition to the classical forms of cell death such as apoptosis and necrosis, neurons can also undergo alternative modes of death, including ferroptosis, cuproptosis, and ammonia-induced cell death, all of which may involve the participation of astrocytes. Neuronal death is an irreversible process and plays a central role in the pathogenesis of numerous CNS diseases. We found that astrocytes exhibit the capacity to regenerate into neurons, a characteristic that may pave the way for novel therapeutic approaches in the treatment of neurological disorders. Astrocytes represent optimal starting cells for reprogramming techniques due to their anatomical proximity to neurons and their shared origin from common progenitor cells—radial glial cells. Reprogramming techniques encompass the conversion of astrocytes into pluripotent neurospheres or their direct in vivo reprogramming into functional neurons, aiming to replace damaged or lost neurons through processes such as transdifferentiation and dedifferentiation. This article examines the interplay between astrocytes and neuronal survival and degeneration in CNS disorders, as well as two reprogramming strategies for converting astrocytes into neurons, with the aim of establishing a scientific foundation for neuronal repair in the treatment of CNS diseases.
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.
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.
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.
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.
To address the unmet need for targeted therapeutic strategies for neonatal hypoxic–ischemic encephalopathy (HIE), we developed a brain-targeting lipid nanoparticle delivery system capable of silencing circular RNA homeodomain-interacting protein kinase 2 (circHIPK2) in astrocytes and investigated its ability to mediate neuroinflammation and improve neurological outcomes.
Dual-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly (ethylene glycol)-neurotropic virus-derived peptide (DSPE-PEG2000-RVG29) peptide/mannose-functionalized lipid nanoparticles loaded with circHIPK2 small interfering RNA (M-R@siC-NPs) were constructed, and their physicochemical properties, stability, and biocompatibility were characterized. Using an in vitro oxygen-glucose deprivation (OGD) model and a neonatal murine hypoxic–ischemic brain damage (HIBD) model, we evaluated the effects of circHIPK2 silencing by the M-R@siC-NPs on the expression of two astrocyte activation markers, glial fibrillary acidic protein (GFAP) and interleukin-1β (IL-1β), via western blotting, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and immunofluorescence staining. Neurobehavioral recovery was assessed through righting reflex, negative geotaxis, and Morris water maze tests.
M-R@siC-NPs exhibited a uniform size distribution (134 nm), good blood–brain barrier penetrability, and astrocyte-targeting specificity. The nanoparticles effectively silenced circHIPK2 while demonstrating excellent colloidal stability and biosafety. In vitro, circHIPK2 knockdown by M-R@siC-NPs markedly suppressed OGD-induced astrocyte activation, reducing GFAP and IL-1β expression (p < 0.01). In HIBD mice, M-R@siC-NPs attenuated hippocampal astrocyte activation and improved motor coordination (shortened righting reflex latency, p < 0.0001) and spatial memory (increased platform crossings in Morris water maze, p < 0.0001).
The RVG29/mannose dual-modified M-R@siC-NPs precisely regulated astrocyte activation and attenuated neuroinflammation, effectively ameliorating brain injury in HIBD mice. This study establishes a novel RNA interference-based therapeutic strategy for targeted neuroinflammatory modulation, providing a promising translational platform for HIE treatment.
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.
Inhibitory control is an important component of cognitive processing that is influenced by multimodal information processing. Recent research has mainly focused on the influence of visual information on inhibitory control, paying less attention to the impact of auditory training, which limits the exploration of the mechanism and practical training of inhibitory control. The influence of music training on inhibitory control has received considerable attention in recent years. To explore the modality-specificity of inhibitory control, this study compares the behavioral and brain electrical activities of different music training experiences through visual and auditory inhibitory control tasks.
This investigation utilized event-related potential (ERP) and time-frequency analysis methodologies to examine the behavioral and neural patterns of thirty participants with musical expertise alongside thirty individuals without such training while completing both visual and auditory Stroop tasks. Further analysis was conducted to examine the modality-specific effect of music training on inhibitory control.
The results showed no significant group differences in behavioral performance or traditional ERP components (N450 and sustained potential (SP)) in either modality. Time-frequency analysis revealed no significant differences in theta power in the visual modality. However, in the auditory modality, the music training group exhibited significantly lower beta power, suggesting that music training may more efficiently recruit neural resources when resolving auditory conflict.
These findings indicate that inhibitory control exhibits modality specificity across both visual and auditory modalities. Specifically, music training mainly improves auditory conflict resolution, suggesting its impact on inhibitory control is limited to specific sensory modalities.
The spinal dorsal horn (SDH) plays a crucial role in nociceptive processing. However, the temporal dynamics of neuronal excitability across different laminae during inflammatory pain remain incompletely understood.
Complete Freund’s adjuvant (CFA) was injected into the left hindpaw to induce inflammatory pain. Spontaneous pain behaviors were evaluated using CatWalk gait analysis and weight-bearing tests, while mechanical hypersensitivity was assessed using von Frey filaments. Neuronal activation patterns were mapped using c-Fos (a protein product of the c-Fos immediate-early gene) immunolabeling across superficial and deeper laminae of the SDH. Spontaneous and mechanically-evoked neuronal discharges were recorded in vivo using multi-electrode arrays.
Spontaneous pain behaviors were most pronounced during the first 3 days post CFA injection, with mechanical hypersensitivity persisting through day 7. A marked increase in c-Fos-positive neurons was observed specifically in superficial laminae on day 1, with no significant changes detected in the deeper laminae. Spontaneous and mechanically-evoked firing rates of SDH neurons increased significantly during days 1–5 post CFA injection. Importantly, wide dynamic range (WDR) neurons exhibited the greatest increase in evoked discharge frequency, while low-threshold mechanoreceptor (LTM) neurons showed the greatest proportional increase amongst neuronal subtypes. Furthermore, both WDR and LTM neurons shifted towards a more superficial distribution.
Peripheral inflammatory pain induced distinct alterations in SDH neurons, characterized by an early increase in neuronal activities, followed by changes in the spatial distribution and proportion of WDR and LTM neurons.
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.
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.
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.
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.
Quercetin is a naturally occurring flavonoid widely distributed in plants that exhibits various biological activities, including anti-inflammatory, antioxidant, and neuroprotective effects. It exhibits a potential role in sleep regulation and homeostasis; however, its specific effects on sleep-wake cycles and underlying mechanisms remain unelucidated.
To systematically investigate the regulatory role of quercetin in sleep architecture and homeostatic recovery, polysomnography (PSG) was used to monitor sleep parameters in mice under normal circadian rhythms and acute sleep deprivation (ASD). Immunofluorescence staining was performed to assess the expression of cellular proto-oncogene protein Fos (c-Fos) and microglial activation in sleep-related brain regions, including the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), bed nucleus of the stria terminalis (BNST), paraventricular thalamic nucleus (PVT), hippocampal dentate gyrus (DG), basolateral amygdala (BLA), and periaqueductal gray (PAG).
Under normal circadian conditions, high-dose quercetin promoted non-rapid eye movement (NREM) sleep in mice. In ASD models, quercetin enhanced NREM sleep rebound during the early recovery phase. It sustained higher levels of wakefulness during the subsequent light phase, exhibiting its dual role in accelerating homeostatic recovery while balancing circadian arousal. Immunofluorescence analyses showed that quercetin markedly suppressed c-Fos expression in the mPFC, BLA, and PVT under sleep-deprived conditions. Additionally, it inhibited microglial activation in the mPFC and NAc.
These results mechanistically associate the sleep-regulatory effects of quercetin with its dual inhibition of neuronal hyperactivity in sleep-associated brain regions and neuroinflammatory responses. Altogether, this study identifies quercetin as a novel natural modulator of sleep homeostasis, underscoring its therapeutic potential for sleep disorders via anti-excitatory and anti-inflammatory mechanisms.
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.
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.
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.
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.
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.
To address this question, this study combined retrograde tracing with immunofluorescent histochemical staining in GAD67-green fluorescence protein (GAD67-GFP) mice.
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.
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.
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.