To explore the effect of combined rehabilitation training and transcutaneous vagus nerve electrical stimulation (t-VNS) on promoting central nervous system remodeling and neurological function recovery in stroke patients.

Brain aging is an inevitable process in adulthood, yet there is a lack of objective measures to accurately assess its extent. This study aims to develop brain age prediction model using magnetic resonance imaging (MRI), which includes structural information of gray matter and integrity information of white matter microstructure. Multiparameter MRI was performed on two population cohorts. We collected structural MRI data from T1- and T2-sequences, including gray matter volume, surface area, and thickness in different areas. For diffusion tensor imaging (DTI), we derived four white matter parameters: fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. To achieve reliable brain age prediction based on structure and white matter integrity, we employed LASSO regression. We successfully constructed a brain age prediction model based on multiparameter brain MRI (Mean absolute error of 3.87). Using structural and diffusion metrics, we identified and visualized which brain areas were notably involved in brain aging. Simultaneously, we discovered that lateralization during brain aging is a significant factor in brain aging models. We have successfully developed a brain age estimation model utilizing white matter and gray matter metrics, which exhibits minimal errors and is suitable for adults.

The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) categorizes postpartum depression (PPD) as a subtype of Major Depressive Disorder (MDD) with peripartum onset, generally arising within the initial trimester following delivery. This acute psychiatric condition is characterized by feelings of worthlessness, insomnia, extreme anxiety, or maternal neglect. Intranasal oxytocin (OT) and transcranial magnetic stimulation (TMS) have the potential to address impaired social cognition; nonetheless, their neuronal underpinnings, along with their safety and efficacy, are little comprehended. This study examines the effects of rTMS stimulation with an oxytocin agonist or antagonist in a PPD model. We employed the maternal separation with early weaning (MSEW) strategy for 21 days to attain our objective. Oxytocin acetate (agonist) and atosiban (antagonist) were administered by injection twice daily for three consecutive days following the model according to the established protocol. A single session of rTMS involved the application of high-frequency stimulation (20 Hz) one hour following the final injection. Behavioral testing and brain collection were conducted 12 h post-rTMS. The results indicated that treatment with OT followed by rTMS stimulation decreased neuronal cell death and microglial activation, meanwhile enhancing synaptic plasticity through the upregulation of PSD95, Synapsin I, and Synaptophysin. Simultaneously, both OT therapy and repetitive transcranial magnetic stimulation demonstrated a significant capacity to alter autophagy activity and astrocyte function. Nonetheless, OTA therapy followed by rTMS did not exhibit the same pattern of outcomes. Our findings indicate that the combination of rTMS stimulation and an oxytocin agonist in a PPD model may mitigate depression-like behavior.

Stroke remains a leading cause of disability and mortality worldwide, with mitochondrial dysfunction closely linked to ischemic injury. This study explores the Norad-Pum2-Mff axis as a key regulator of mitochondrial function following ischemia-reperfusion (I/R) injury. Using an oxygen-glucose deprivation/reoxygenation (OGD/R) model, Mff protein levels were significantly elevated post-OGD/R, while mRNA levels remained unchanged, suggesting post-transcriptional regulation. Pumilio2 (Pum2), an RNA-binding protein, was shown to inhibit Mff translation, while Norad, a long non-coding RNA, sequestered Pum2, alleviating this inhibition. We observed decreased Pum2 levels and binding capacity to Mff mRNA, alongside increased Norad levels and binding to Pum2 in neurons after OGD/R. Overexpression of Pum2 in neurons reduced Mff levels, mitigated mitochondrial fragmentation, and alleviated neuronal injury. In a mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R), Pum2 overexpression further improved mitochondrial morphology, reduced infarct volume, and enhanced neurobehavioral recovery. These findings suggest that targeting the Norad-Pum2-Mff axis could provide a promising therapeutic strategy for ischemic stroke by restoring mitochondrial function and reducing neuronal damage.

Traumatic brain injury (TBI) can lead to chronic neuroinflammation, and neurodegeneration associated with long-term cognitive deficits. Following TBI, the acute neuroinflammatory response involves microglial activation and the release of proinflammatory cytokines and chemokines which induce the recruitment of peripheral immune cells such as monocytes and ultimately T cells. Persistent innate and adaptive immune cell responses can lead to chronic neurodegeneration and functional deficits. Therefore, understanding the dynamic interaction between chronic immune responses and TBI-related pathogenesis and progression of the disease is crucial. We hypothesized that T cells have an essential role in TBI severity and recovery. We used generic T cell deletion mice (TCRβδ) vs Wild-type mice that underwent controlled cortical impact assessing behavioral, histological, and immune system response outcomes at 3 months post-TBI. The absence of T cells reduced neurodegeneration and was associated with improved neurological outcomes 3 months post-injury. Furthermore, the absence of T cells enhanced an anti-inflammatory phenotype in peripheral myeloid cells in the injured brain. Collectively, these data indicate that T cells promote persistent neuropathology and functional impairments chronically after TBI.

For a linking hypothesis in the visual world paradigm to clearly accommodate existing findings and make unambiguous predictions, it needs to be computationally implemented in a fashion that transparently draws the causal connection between the activations of internal representations and the measured output of saccades and reaching movements. Quantitatively implemented linking hypotheses provide an opportunity to not only demonstrate an existence proof of that causal connection but also to test the fidelity of the measuring methods themselves. When a system of interest is measured one way (e.g., ballistic dichotomous outputs) or another way (e.g., smooth graded outputs), the apparent results can differ substantially. What is needed is one linking hypothesis that can produce both types of outputs. The localist attractor network simulation of spoken word recognition demonstrated here recreates eye and mouse movements that capture key findings in the visual world paradigm, and especially relies on one particularly powerful theoretical construct: feedback from the action-perception cycle. Visual feedback from the eye position enhancing the cognitive prominence of the fixated object allows the simulation to fit a wider range of findings, and points to predictions for new experiments. When that feedback is absent, the linking hypothesis simulation no longer fits human data as well. Future experiments, and improvements of this network simulation, are discussed.

Chronic stress profoundly affects the structure and function of the prefrontal cortex (PFC), a brain region critical for executive functions and emotional regulation. This review synthesizes current knowledge on stress-induced PFC plasticity, encompassing structural, functional, and molecular changes. We examine how chronic stress leads to dendritic atrophy, spine loss, and alterations in neuronal connectivity within the PFC, particularly affecting the medial PFC. These structural changes are accompanied by disruptions in neurotransmitter systems, most notably glutamatergic and GABAergic signaling, and alterations in synaptic plasticity mechanisms. At the molecular level, we discuss the intricate interplay between stress hormones, neurotrophic factors, and epigenetic modifications that underlie these changes. The review highlights the significant behavioral and cognitive consequences of stress-induced PFC plasticity, including impairments in working memory, decision-making, and emotional regulation, which may contribute to the development of stress-related psychiatric disorders. We also explore individual differences in stress susceptibility, focusing on sex-specific effects and age-dependent variations in stress responses. The role of estrogens in conferring stress resilience in females and the unique vulnerabilities of the developing and aging PFC are discussed. Finally, we consider potential pharmacological and non-pharmacological interventions that may mitigate or reverse stress-induced changes in the PFC. The review concludes by identifying key areas for future research, including the need for more studies on the reversibility of stress effects and the potential of emerging technologies in unraveling the complexities of PFC plasticity. This comprehensive overview underscores the critical importance of understanding stress-induced PFC plasticity for developing more effective strategies to prevent and treat stress-related mental health disorders.

Studies have shown that exposure to multiple talkers during learning is beneficial in a variety of spoken language tasks, such as learning speech sounds in a second language and learning novel words in a lab context. However, not all studies find the multiple talker benefit. Some studies have found that processing benefits from exposure to multiple talkers depend on factors related to the linguistic profile of the listeners and to the cognitive demands during learning (blocked versus randomized talkers). The current study examines whether scaffolding talker variability (blocked versus randomized) supports word-learning and whether individual differences in language ability, reading ability, and phonological working memory influence word-learning in adults. One hundred and fifty-two listeners were randomly assigned to four conditions: (1) single talker, (2) maximal scaffolding (blocked two-then-two talkers), (3) minimal scaffolding (blocked by four-talkers), and (4) multiple-talker mixed (four-talker randomized). Listeners completed a word-learning task in which they learned to associate nonsense words with novel objects, and were then tested on their ability to name the objects. Our results showed that listeners performed similarly across all talker conditions, with no evidence for a benefit of talker variability. In addition, participants with better language and phonological working memory skills performed better on the word-learning task. These results suggest that blocking and manipulating the presentation of talkers may not support word-learning in adults and that variability benefits may depend on a variety of experimental factors.

Repetitive transcranial magnetic stimulation (rTMS) is acknowledged for its critical role in modulating neuronal excitability and enhancing cognitive function. The dentate gyrus of the hippocampus is closely linked to cognitive processes; however, the precise mechanisms by which changes in its excitability influence cognition are not yet fully understood. This study aimed to elucidate the effects on granule cell excitability and the effects on cognition of high-frequency rTMS in naturally aging mice, as well as to investigate the potential interactions between these two factors. It was observed that 20 Hz high-frequency rTMS attenuated granule cell loss in aged mice, demonstrating both cumulative and real-time effects on neural excitability. Importantly, this intervention significantly ameliorated age-related cognitive decline. The findings suggest that one of the potential mechanisms underlying the amelioration of age-related cognitive decline through high-frequency rTMS may involve the attenuation of granule cell apoptosis and the enhancement of their neural excitability.

Neurodegenerative disorders are characterized by a progressive loss of neurons, causing substantial deficits in motor and cognitive functioning. Bilirubin is a yellow by-product of heme, existing in two primary isoforms namely unconjugated and conjugated, while initially produced unconjugated isomer is lipophilic and cytotoxic in nature. At physiological levels, bilirubin has an important role in brain function by acting as a powerful antioxidant, preventing brain tissues from oxidative damage by eliminating reactive oxygen species (ROS). Additionally, it contributes to immune regulation through microglial activation, cytokine release, complement system interception, fragment crystallization (Fc) receptor modulation, and major histocompatibility complex (MHC II) expression modification, which lower the risk of inflammatory and autoimmune reactions in the central nervous system (CNS). As per the literature, serum bilirubin concentrations are associated with CNS diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, hemorrhagic stroke, traumatic brain injury (TBI), multiple sclerosis (MS), epilepsy, schizophrenia and kernicterus spectrum disorder (KSD), which causes neuronal damage, especially in regions like the basal ganglia and cerebellum, which causes movement abnormalities and cognitive deficits. The aim of this article is to explore the dual role of bilirubin as neuroprotective and neurotoxic, essential for establishing effective therapeutic outcomes for neurodegenerative diseases by looking at its cellular mechanisms and discussing how bilirubin's antioxidant properties can shield neurons and, in some situations, may induce oxidative stress and apoptosis.

Osteoarthritis is associated with a higher risk of developing dementia, though the underlying biological mechanisms have remained unclear. Recent studies suggest that blood phosphorylated tau proteins, particularly Tau-PT217, are sensitive biomarkers capable of detecting cognitive decline in its early stages, making it useful for early diagnosis of Alzheimer's disease and other forms of cognitive impairment.

Chronic pain and depression exhibit a high comorbidity, are challenging to manage, and their pathophysiology mechanisms are intricated and closely related to the up-regulation of pro-inflammatory response and oxidative stress. Chronic pain and depression often coexist and present significant management challenges. Their underlying pathophysiological mechanisms are complex and closely linked to the up-regulation of pro-inflammatory responses and oxidative stress. α-(Phenylselanyl) acetophenone (PSAP), an organoselenium compound, has shown antioxidant, antidepressant-like and antinociceptive effects in animal models. This study aimed to evaluate the effects of acute PSAP administration in a comorbid pain-depression model induced by intracerebroventricular (i.c.v.) injection of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) in male Swiss mice. TNF-α (0.1 ƒg/5 µL, i.c.v.) was injected 1 h before the behavioral tests, followed by acute PSAP treatment (10 mg/kg, intragastrically [i.g.]) 30 min post-TNF-α injection. TNF-α decreased the latency time to first immobility episode and increased the total immobility time of mice in the forced swimming test (FST), effects prevented by PSAP treatment. PSAP also reversed TNF-α-induced nociceptive responses in mice, assessed by the hot plate test. These behavioral improvements may be attributed, at least in part, to the capacity of PSAP treatment reverse the TNF-α-induced increase on reactive species and lipoperoxidation levels, as well as modulate altered activities of antioxidant enzymes catalase and superoxide dismutase in the cerebral cortex and hippocampus. Furthermore, PSAP decreased circulating corticosterone levels elevated by TNF-α injection. In conclusion, PSAP emerges as a promising candidate for the development of innovative therapeutic strategies to address the comorbidity of pain and depression.

Metabolic dysregulation causes diseases like diabetes and cancer, making PDKs attractive targets. However, a thorough investigation into the unique roles played by the different members of the PDK family, especially PDK3, about memory loss and related diseases like Alzheimer's disease (AD) is still lacking. The current study investigates PF's potential to reduce PDK3-associated toxicity in neurodegenerative illnesses, including AD. The association between PF and PDK3 presents a significant opportunity for medication development and AD therapy approaches. PF efficiently suppresses PDK3 activity, as demonstrated by molecular docking and biophysical characterization, providing an in-depth understanding of their molecular interactions. PF significantly inhibited PDK3 in a concentration-dependent manner with an IC50 value of 4.88 µM. Considering this, the current investigation also explores the biological component of PF, which exhibits potential in treating AD and is primarily associated with neuroprotection. In the present study, a 3-hour pre-treatment of PF was administered at varying concentrations (4, 6, and 8 µM) in response to the 24-hour SCP (2 mM)-mediated toxicity. Based on the results of in silico and biophysical characterization, it is concluded that PF inhibits the PDK3 activity. Additionally, it can enhance cell viability, suppress ROS expression, impede apoptosis, and downregulate TNF-α expression. When combined, these actions help to prevent neuronal death in an in vitro model of SCP. PF strengthens the memory marker, which is confirmed through BDNF expression. This study found that all results were more effective at lower and moderate doses of PF. Our research indicates that PF boosts memory, decelerates the progression of oxidative stress, and could potentially serve as a dose-dependent treatment for AD.

Exercise as a non-pharmacological intervention can exert beneficial effects directly through exosomes crossing the blood-brain barrier and reduce apoptosis after cerebral ischaemia/reperfusion injury (CI/RI). miRNA-124 (miR-124) is present in exosomes and plays an important role in regulating cerebral neurological activity; however, the mechanism of the relationship between exercise and the activity of exosomes and apoptosis after CI/RI remains unclear. Therefore, the present study investigated the effects of exercise preconditioning on CI/RI from the perspective of exosomal miR-124 and apoptosis.

Humans are excellent at modifying our behaviour depending on context. For example, we will change how we explore when losses are possible compared to when losses are not possible. However, it remains unclear what specific cognitive and neural processes are modulated when exploring in different contexts. Here, we had participants learn within two different contexts: in one the participants could lose points while in the other the participants could not. Our goal was to determine how the inclusion of losses impacted human exploratory behaviour (experiment one), and whether we could explain the neural basis of these effects using EEG (experiment two). In experiment one, we found that participants preferred less-variable choices and explored less often when losses were possible. In addition, computational modelling revealed that participants engaged in less random exploration, had a lower rate of learning, and showed lower choice stickiness when losses were possible. In experiment two, we replicated these effects while examining a series of neural signals involved in exploration. During exploration, signals tied to working memory and learning (P3b), attention orienting (P3a) and motivation (late positive potential; an exploratory analysis) were enhanced when losses were possible. These neural differences contribute to why exploratory behaviour is changed by different learning contexts and can be explained by the theoretical claim that losses recruit attention and lead to increased task focus. These results provide insight into the cognitive processes that underlie exploration, and how exploratory behaviour changes across contexts.

Effective methods for establishing an aged animal model of diabetes and glycemic fluctuation have rarely been investigated. The aim of the study was to explore the feasibility of inducing glycemic fluctuation in aged Sprague-Dawley rats and to evaluate the corresponding changes in cognitive function.

Whisker deprivation at different stages of early development results in varied behavioral outcomes. However, there is a notable lack of systematic studies evaluating the specific effects of whisker deprivation from postnatal day 0 (P0) to P14 on adolescent behavioral performance in mice. To investigate these effects, C57BL/6J mice underwent whisker deprivation from P0 to P14 and were subsequently assessed at 5 weeks of age using a battery of tests: motor skills were evaluated using open field test; emotional behavior was evaluated using a series of anxiety- and depression-related behavioral tests; cognitive function was examined via novel location and object recognition tests; and social interactions were analyzed using three-chamber social interaction test. Results show that early-life whisker deprivation impairs social discrimination, as evidenced by reduced interaction preference for novel mice, while not impacting general motor abilities, cognitive performance in novel object and location recognition, or anxiety- and depression-related behaviors during adolescence. The treatment effects were consistent across sexes, with no significant differences observed between control and experimental groups within each sex. These findings contribute to a comprehensive understanding of the behavioral impacts during adolescence resulting from early-life whisker deprivation and provide valuable criteria for selecting appropriate whisker deprivation models in future research.

Disruption of the glymphatic system plays a vital role in pathogenesis of neurodegeneration in normal tension glaucoma (NTG). We evaluated the impairment of glymphatic system of NTG patients by diffusion tensor image analysis along the perivascular space (DTI-ALPS), and explored the correlation between the ALPS index and dysfunction of visual cortices in resting state. DTI-ALPS was applied to 37 normal controls (NCs) and 37 NTG patients. Multidirectional diffusivity maps and fractional anisotropy (FA) maps were reconstructed to calculate ALPS index. The Amplitude of low-frequency fluctuation (ALFF) in visual cortices (V1-V5) were calculated using resting-state fMRI. Clinical data and ALPS indexes were compared between the groups. Lateralization of ALPS indexes and differences in visual field of two eyes were analyzed. Subsequently, regression analyses between ALPS indexes and mean deviation (MD) values of bilateral eyes and ALFF of visual cortices were performed. The bilateral ALPS indexes of NTG patients decreased significantly. In NCs and NTG patients, ALPS indexes in right hemisphere were lower than that in left hemisphere. The right ALPS indexes of NTG patients were positively correlated with the MD values of the left eyes. In NTG patients, decreased ALFF was detected in right V1 and bilateral V2-5, and the left ALPS indexes were positively correlated with ALFF in bilateral V1, V2, V5, and right V3V area. The ALPS index decreased in NTG patients, correlated with visual defects and ALFF, indicating impairment of the glymphatic system and the potential to be a biomarker in the future.

Ageing is a major risk factor for neurodegenerative diseases like Alzheimer's disease (AD). Microglia, as the principal innate immune cells within the brain, exert homeostatic and active immunological defense functions throughout human lifespan. The age-related dysfunction of microglia is currently recognized as a pivotal trigger for brain diseases associated with aging. In AD, microglia exhibit alterations in gene expression, cellular morphology, and functional behavior. By focusing on the immunomodulatory functions of factors secreted by senescent microglia, such as cytokines, chemokines, complement factors, and reactive oxygen species (ROS), we explore the diverse detrimental effects of microglia in aging and AD pathogenesis, including Aβ accumulation, Tau deposition, synaptic dysfunction, and neuroinflammation. These collectively contribute to hastening the progression of. In this review, we highlight the key role of senescent microglia in the pathological processes of AD. Then we propose that targeting senescent microglia holds great promise for therapeutic interventions in neurodegenerative diseases.