The TDP-43 protein has a significant relationship to the aetiology of neurodegenerative disorders. Based on its protein structure, protein modification and RNA function, this study analysed its various biological effects and the pathological effects of these biological effects in neurodegenerative diseases. It was found that TDP-43 protein undergoes conformational changes and functional alterations through protein phosphorylation, ubiquitination, SUMOylation, and acetylation, promoting its removal from the nucleus and transforming it from a normal, functional protein to an abnormally aggregated, pathological protein. It is involved in oxidative stress, inflammatory response, autophagy, angiogenesis and other biological effects. Furthermore, investigations have demonstrated that the TDP-43 protein is directly associated with neuronal growth, axon guidance, and synaptic activity, suggesting it may potentially play a significant role in the onset of degenerative neurological conditions. Based on this, the treatment strategy and future research direction are outlined to provide some insights into understanding the pathogenic mechanisms of neurodegenerative disorders and potential treatment approaches.

Tongqiao Huoxue Decoction (TQHXD), a representative Traditional Chinese Medicine (TCM) formula, is known for its effects in revitalizing the brain, opening the orifices, promoting blood circulation, and resolving stasis. It is widely used to treat stroke and related disorders.

Alzheimer's disease (AD) is a multiplex and progressive neurodegenerative disorder commonly recognized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), and dysfunction in the cholinergic and glutamatergic systems. At the early stages of AD, mitochondrion operates as a neuroprotective organelle in both neuronal and glial cells by compensating energy fluctuations. As the disease progresses, mitochondrial function in both neurons and glial cells deteriorates, culminating in impaired cellular metabolism and glial hyperactivation. This time-dependent hyperactivation of microglia and astrocytes sequentially promotes the release of pro-inflammatory cytokines, elevates reactive oxygen species, disrupts calcium homeostasis, and increases oxidative stress. Altogether, these processes drive neuroinflammation, which both influences and is influenced by mitochondrial activity. Additionally, mitochondrial dysfunction across the disease trajectory hampers communication between neurons and glial cells, promoting excitotoxicity in neurons. This review emphasizes the vital role of mitochondrial dynamics in AD pathophysiology across different stages and explores how cell-specific targeting of mitochondrial activity could mitigate neuroinflammation, restore neuronal function, and offer potential treatment benefits. Enhancing mitochondrial function in healthy neurons and glial cells, particularly in microglia as a compensatory mechanism, especially at the early stage of the disease or restoring mitochondrial function of surviving neurons at the later stages, may promote neuroprotection and improve neuron-glia interactions, thus offering a potential strategy for AD treatment.

The rostral part of the nucleus of the solitary tract (rNST) receives gustatory inputs via the facial, glossopharyngeal, and vagus nerves. In addition to these ascending pathways, the rNST receives descending projections from higher brain regions, including the insular cortex (IC). Neurons in the dysgranular and granular IC around the middle cerebral artery (MCA) respond to gustatory stimulation; therefore, descending IC projections to the rNST are thought to regulate gustatory information processing. However, little is known about how IC inputs modulate rNST neuronal activity at the synaptic level, which comprises both glutamatergic and GABAergic neurons. In this study, we examined the synaptic strength of IC → rNST projections in glutamatergic and GABAergic neurons using vesicular GABA transporter-Venus transgenic rats. We first confirmed that the IC subregion around the MCA, a region where gustatory information converges, projects axons to the rNST. Whole-cell patch-clamp recordings revealed that rNST neurons could be classified into three groups: regular-spiking (68.2 %), late-spiking (22.7 %), and burst-spiking (9.1 %). Among glutamatergic neurons, 58.8 % were regular-spiking, 23.5 % were late-spiking, and 17.6 % were burst-spiking, whereas GABAergic neurons were predominantly regular-spiking (77.8 %), with fewer late-spiking (18.5 %) and burst-spiking (3.7 %) neurons. In rats injected with AAV5-CAG-ChR2(H134R)-mCherry into the IC subregion, both glutamatergic and GABAergic rNST neurons exhibited photostimulation-induced monosynaptic excitatory postsynaptic currents with comparable amplitudes and latencies. Paired whole-cell recordings further demonstrated that glutamatergic neurons receive inhibitory inputs from rNST GABAergic neurons with a high failure rate. These findings suggest that IC projections to the rNST primarily enhance excitatory output from the rNST neurons. (250/250 words).

Monoclonal antibodies (mAbs) for Alzheimer's disease (AD) present a fundamental translational challenge, as demonstrated by amyloid-beta (Aβ)-targeting mAbs that successfully employed Fragment crystallizable gamma receptor (FcγR)/Immunoreceptor tyrosine-based activation motif (ITAM)-mediated microglial phagocytosis yet achieved only modest cognitive improvements while introducing significant Amyloid-related imaging abnormalities (ARIA) risk, thereby highlighting inherent single-therapy limitations. Building on these findings, tau-directed antibodies show preclinical promise by targeting pathological seeding and propagation, but face translational challenges including limited extracellular accessibility and variable efficacy across disease stages, necessitating expansion beyond single-target approaches. Consequently, the translational field is advancing toward innovative multi-mechanistic strategies, including synaptic restoration through anti-PrP and neurotrophic receptor agonists that provide functional benefits independent of plaque reduction, neuroinflammation modulation via anti-CD33 and complement inhibitors requiring careful patient selection due to variable outcomes, and emerging anti-TREM2 and anti-APOE4 mAbs enabling precision medicine tailored to individual genetic profiles. Importantly, comparative studies also reveal that combination therapies-especially dual Aβ/tau targeting-demonstrate superior synergistic effectiveness, driving next-generation engineering advances including Fc modifications that reduce ARIA risk, nanobodies/single-chain variable fragments (scFvs) with enhanced blood-brain barrier (BBB) penetration, cell-penetrating formats for intracellular tau access, and pH-sensitive glycoengineering for optimized tissue-specific binding. Ultimately, successful clinical translation depends on integrating biomarker-guided patient selection, optimized dosing strategies, and disease-stage-appropriate timing, with future progress anticipated through bispecific/multispecific antibodies targeting complementary pathways alongside personalized biomarker approaches, collectively providing realistic potential for achieving genuine neuroprotection and meaningful disease modification beyond symptomatic treatment in AD patients.

Astrocytes play important roles in brain pathology. Astrocytes can express inducible nitric oxide synthase (iNOS), which is responsible for the transient production of nitric oxide (NO). Both iNOS and NO have been reported to be actively involved in cocaine addiction. We aimed to investigate if cocaine could directly affect astrocyte iNOS expression. An in vitro astrocyte culture model and an in vivo chronic cocaine mouse model were used. In the in vitro model, astrocytes from human cerebral cortex were treated with cocaine. iNOS expression was measured using solid-phase ELISA and Western blot. Changes in astrocyte morphology were quantified using a Sholl analysis. In the in vivo model, wild type C57BL/6 mice were treated with cocaine for two weeks. Mouse brain tissue, especially in the prefrontal cortex (PFC), was collected. Astrocyte number and iNOS expression were measured. The results demonstrated that cocaine could cause significant morphological changes in astrocytes in vitro. Cocaine could also cause a significant increase in astrocyte iNOS expression in vitro. The in vivo studies showed that chronic cocaine treatment significantly decreased the number of astrocytes in the mouse PFC, resulting in a decreased iNOS expression. In summary, astrocytes could directly respond to cocaine stimulation in vitro and in vivo, and iNOS was involved. Therefore, investigation into the role of astrocytes and iNOS in cocaine addiction may bring insight to new therapeutic targets for cocaine use disorder.

There are individual differences in brain developmental patterns, yet it is unknown to what extent these may be driven by enriched experiences. Moreover, it is not well known whether enriched experiences may result in attenuated or accelerated brain development. Studying the relation between music performance and the brain using a large longitudinal twin study provides a framework for better understanding the genetic and environmental effects on brain development in childhood. The present region-of-interest study tested whether individual differences in sensorimotor synchronization with an auditorily cued finger tapping task are related to individual differences in developmental brain trajectories and if this relation was genetically or environmentally driven. The present study included a longitudinal twin design with up to 3 MRI waves of data (7-14 years old; N = 418, N = 367, N = 228). In line with our preregistered hypotheses, results showed that attenuated patterns of brain development in 27 % of motor and affective ROIs were associated with SMS performance independent of socio-economic status effects. Furthermore, brain-behavior associations were at least partly driven by shared and unique environmental/measurement error effects, in addition to genetic influences. Possibly, attenuated brain development may be indicative of prolonged brain plasticity related to enriched environmental experiences, such as musical training, in addition to predisposing genetic factors.

The prevalence of Alzheimer's Disease (AD) is projected to triple by 2050, highlighting the need to identify early markers and underlying mechanisms associated with its progression. Olfactory dysfunction has emerged as an early indicator of AD, with its neural basis linked to changes in the medial temporal lobe and associated networks. Cardiovascular risk factors, including metabolic syndrome (MetS) and cerebral small vessel disease (SVD), have been implicated in neurodegenerative processes, yet their impact on olfactory network connectivity remains underexplored. This study aimed to investigate task-based functional connectivity in the olfactory network, medial temporal lobe, and default mode network among cognitively unimpaired individuals with MetS or SVD.

Suicide attempts (SA) and non-suicidal self-injury (NSSI) are critical public health concerns that frequently co-occur in depressed adolescents. However, the neurological mechanisms underlying these behaviors remain poorly understood. This study aimed to identify alterations in brain activity and examine the associations between these changes and clinical symptom severity in depressed adolescents with SA and NSSI. A total of 82 depressed adolescents with NSSI were divided into two groups: those with both SA and NSSI (SA + NSSI, n = 46) and those with NSSI only (n = 36). Static amplitude of low-frequency fluctuation (sALFF) and dynamic ALFF variability (dALFF variability) analyses were conducted to assess local brain activity differences between groups. Regions with abnormal neural activity were used as seeds to investigate static functional connectivity (sFC) and dynamic FC variability (dFC variability) alterations. Correlation analyses as exploratory analysis was subsequently performed. Compared to the NSSI group, the SA + NSSI group exhibited increased sALFF in the left cerebellum, increased dALFF variability in the orbitofrontal cortex and left cerebellum, and increased dFC variability between the orbitofrontal cortex and caudate. The SA + NSSI group also showed decreased sALFF and dALFF variability in the postcentral gyrus (cluster p < 0.05, FDR corrected, two-tailed). Additionally, for the SA + NSSI group, sALFF in the postcentral gyrus was negatively correlated with emotional neglect, while the dFC variability between the orbitofrontal cortex and caudate was positively correlated with internet addiction withdrawal symptoms. These findings provide novel insights into the neurological mechanisms of SA and NSSI, highlighting the potential value of combining static and dynamic functional metrics for clinical differentiation between these behaviors.

Although electrical devices should not be submerged, the brain, despite its electrical implementation, is submerged in an electrolyte solution and has indeed leakage currents as demonstrated by electroencephalograms (EEGs). Ephaptic coupling is a direct electrical neural coupling mediated by leakage currents between adjacent neurons on a microscale, and it affects spike timing. Since EEGs are detectable, meaning that tens of thousands of neurons activate synchronously, their collective leakage currents can extend the coupling over longer distances, hereafter called volume current coupling (VcC). Here, we show neural coupling (NC) = synaptic coupling (SC) + VcC and find a function of VcC. When two people, sensorily isolated but electrically connected at the heads in a skillful way to exchange their volume currents (Vcs) to avoid attenuation, were given separate left-right discrimination tasks, a significant conflict, or a task-irrelevant conditional bias, occurred in the discrimination. No SC existed between the two participants, indicating a behaviorally functional VcC. The Vc propagation path contains neurons of the person producing the Vc, and intra-person VcCs can also occur. In fact, as intra-person effects, an unconditional right-preferential bias emerged when electrically disconnected, but a task-irrelevant conditional right-preferential bias, or priming, emerged when connected. Since the skillful connection intervenes only in VcC, NC = SC + VcC is true also in individual brains and one function of VcC is to generate these biases. Since VcCs are ubiquitous in the brain as electrical crosstalk, it may be better not to study cognitive and behavioral functions in the SC alone.

Previous research has shown that cognitive flexibility, the ability to adjust to different rules, is affected by manipulations of orexin and acetylcholine (ACh). Because there are strong neural connections between orexin and ACh, these two neurotransmitter systems may interact to impact cognitive flexibility. In the present experiment, the effects of pharmacological manipulations of orexin-1 and muscarinic-1 receptors in rats were tested on cognitive flexibility. Rats received intraperitoneal injections of VU0453595, a positive allosteric modulator for the M1 subtype of ACh receptors, for seven days prior to a rule switch in a measure of cognitive flexibility. On the day of the rule switch, rats were given the orexin-1 receptor antagonist, SB-334867 or vehicle prior to task performance. As expected, SB-334867 increased the number of trials to criterion during the rule switch. Compared to vehicle, when VU0453595 was administered, orexin-1 receptor blockade increased regressive errors for males and perseverative errors for females. These findings support the hypothesis that there are interactions between the orexin and cholinergic systems affecting cognitive flexibility, but that these interactions affect cognitive flexibility differently for males and females.

Dual decline in gait and memory is associated with a higher risk of dementia. However, little is known about specific brain regions and their association with dual decline. Therefore, this study examined the strength of associations between baseline regional brain volumes and dual decline in gait speed and memory.

Apolipoprotein E (ApoE) plays an important role in cerebral lipid transport. Beyond lipid transport, ApoE also contributes to the maintenance of neuronal integrity. Although DNA damage and dysfunction in the DNA damage response are recognized as early contributors to neuropathology, the connection between ApoE and DNA damage remains poorly understood. In this study, we investigated cells expressing endogenous mouse ApoE (mApoE) in the brain under both normal condition and etoposide-induced DNA damage. Immunohistochemical analysis revealed that mApoE was predominantly expressed in astrocytes and a subset of neurons across various brain regions, with minimal expression in microglia and no detectable expression in oligodendrocytes. Induction of DNA damage through etoposide treatment did not alter the expression level or distribution pattern of mApoE in brain. However, a correlation between neuronal mApoE expression and DNA damage was observed: mApoE-positive neurons were more affected and exhibited a higher number of γH2A.X foci upon etoposide treatment. This observation warrants further investigation to determine whether the increased sensitivity of mApoE-positive neurons to DNA damage is neuroprotective or contributes to neurodegeneration. Our study provides a foundation for understanding the physiological role of mApoE in response to DNA damage and suggests a potential involvement of neuronal mApoE in neurodegeneration.

Aggression, particularly reactive aggression, is a key contributor to violence and public health burdens. The left ventrolateral prefrontal cortex (VLPFC) is central to downregulating and eliciting aggression, and its influence varies with trait hostility, a dispositional tendency toward mistrust and resentment. We aimed to examine whether transcranial direct current stimulation (tDCS) of the left VLPFC alters frustration-induced aggression and whether its impact is moderated by trait hostility. Ninety-nine healthy right-handed men were randomized in a double-blind, sham-controlled trial to receive anodal, cathodal, or sham tDCS while completing an unsolvable number-sequence task. Aggression was quantified using a competitive reaction time task and physiological measurements. Although frustration induction was successful across all groups, no significant group-level differences were observed in aggression or physiological responses. However, trait hostility moderated the effect of stimulation on aggressive behavior: aggression was suppressed among individuals with low hostility but was enhanced among those with high hostility, particularly under cathodal stimulation. These findings suggest that trait hostility critically influences the behavioral impact of tDCS on aggression. Taken together, these findings underscore the dual function of the left VLPFC in anger regulation and highlight the importance of tailoring neuromodulatory interventions to individual hostility levels.

Human faces contain a large amount of information, capturing our attention and inducing physiological engagement. Oculometric (visual exploration) and pupillometric (physiological reactivity) parameters quantified by eye-tracking are potent tools for exploring attraction to human faces from an early age. Autistic people have particularities in visual exploration and physiological reactivity to faces, with reduced time spent on the eyes associated with reduced pupil dilation. To date, no study has assessed the age differences of oculo-pupillometric parameters in response to faces. This study aimed to characterize these parameters in neurotypical (n = 150) and autistic (n = 109) populations (3-34 years old). Visual stimuli were organized along a social saliency gradient, from objects to faces. Oculo-pupillometric responses to faces appear invariant across age in the autistic population, contrary to the neurotypical population that shows an increasing attentional focus on the eye region with age, and a larger pupillary sensitivity to social salient stimuli at an early age. Our results highlight an apparent lack of maturation of face processing in autismspectrum disorder (ASD) at the population level, possibly hiding atypical and complex individual trajectories. However, these findings also point to age windows in which specific parameters could be used as discriminating biomarkers of ASD.

Neuroblastoma (NB) is a common pediatric solid tumor with poor prognosis, in which macrophage polarization is increasingly recognized as a key driver of progression. However, the roles of RNA-binding proteins such as DEAD-box helicase 3 X-linked (DDX3X) and interleukin enhancer-binding factor 3 (ILF3) in this process remain unclear. This study aims to explore the role of the DDX3X-ILF3 axis in modulating macrophage polarization and promoting the malignant progression of NB. ILF3 expression was analyzed by RT-qPCR and Western blotting. Lentiviral-mediated knockdown of ILF3 or DDX3X was performed, followed by evaluation of cell viability, proliferation, invasion, and migration, respectively. In a Transwell co-culture system, the expression of polarization markers was examined by Western blotting, and the secretion of inflammatory cytokines was measured by enzyme-linked immunosorbent assay. Actinomycin D treatment combined with RT-qPCR was used to assess ILF3 mRNA stability. RIP-qPCR was employed to explore the interaction of DDX3X with ILF3 mRNA. NB xenograft and metastasis mouse model (lung, liver, and kidney) was established to evaluate the regulatory effects of the DDX3X inhibitor RK-33 and ILF3 overexpression on NB growth and metastasis. ILF3 expression was significantly upregulated in NB cells. Knockdown of ILF3 or DDX3X suppressed NB cell viability, proliferation, invasion, and migration, while promoting M1 macrophage polarization accompanied by increased secretion of inflammatory cytokines. Silencing DDX3X reduced ILF3 mRNA stability and protein expression, whereas ILF3 overexpression negated the suppressive impacts of DDX3X knockdown on malignant behaviors and polarization status. In vivo, DDX3X inhibitor, RK-33, markedly inhibited NB tumor growth and metastasis and enhanced M1 macrophage polarization, which was partially reversed by ILF3 overexpression. DDX3X promotes NB progression by stabilizing ILF3 mRNA, thereby facilitating M2 macrophage polarization.

Alzheimer's disease (AD) is characterized by cognitive decline and neuronal loss, with cellular senescence emerging as a key driver. The insulin-like growth factor-1 receptor (IGF1R) pathway is implicated in aging and AD pathology. IGF2 mRNA binding protein 2 (IGF2BP2) can stabilize IGF1R mRNA, but its role in AD-associated neuronal senescence remains unclear.

According to Levelt's language production model, to name an object, speakers must first conceptualize and lexicalize the object before it can be named. Conceptualization is conducted through the semantic network, with concepts activating lexical items at the lemma level, i.e., lexicalization. So far, research has focused on the roles of semantic categories (i.e., semantic category interference) and single semantic features (i.e., semantic feature interference) but less so on the number of overlapping features. To investigate the role of the number of overlapping features in language production, we conducted a picture-word interference study in Mandarin Chinese, varying the semantic category and shape congruency whilst controlling for classifier congruency. We also recorded behavioural and electrophysiological responses. We observed a main effect of semantic category that was stronger than a main effect of shape (i.e., a semantic feature). That is, the reduction in naming accuracies, the increase in naming latencies, and the increase in ERP amplitudes between 275 - 575 ms post-stimulus onset (N400 effect) for congruent vs. incongruent conditions were larger for semantic category than for shape. In addition, we found an interaction effect between semantic category and the semantic feature 'shape' regarding naming accuracies and also at the electrophysiological level. We conclude that, with increasing feature overlap between word pairs, there may be more spreading of activation between such pairs in word production.

Immune checkpoint inhibitor-induced colitis (CICs) represents a state of systemic immune activation and is paradoxically associated with superior anti-tumor responses. This study has been designed to explore gene signatures derived from CICs that could identify the key immunological drivers, and predict sensitivity of immunotherapy in immunologically cold tumors e.g. glioma.

Vascular dementia (VaD) is one of the most common subtypes of dementia after Alzheimer's disease. Investigating body fluid metabolites is critical for understanding VaD pathophysiology and identifying potential therapeutic targets. This study employs Mendelian randomization (MR) analysis to explore the causal relationship between body fluid metabolites and VaD.

This study aimed to investigate the sensorimotor network (SMN) alterations in chronic insomnia disorder (CID) following treatment with Suanzaoren decoction (SZRD) or estazolam, and to explore their associations with clinical variables and genetic variations.