Human Brain Research Articles

Detecting biological motion signals in human and monkey superior colliculus: a subcortical-cortical pathway for biological motion perception.

Most vertebrates, including humans, are highly adept at detecting and encoding biological motion, even when it is portrayed by just a few point lights attached to the head and major joints. However, the function of subcortical regions in biological motion perception has been scarcely explored. Here, we investigate the role of the superior colliculus in local biological motion processing. Using high-field (3 T) and ultra-high-field (7 T) functional magnetic resonance imaging, we record the neural responses of the superior colliculus to scrambled point-light walkers (with local kinematics retained) in both humans and male macaque monkeys. Results show that the superior colliculus, especially the superficial layers, selectively responds to local biological motion. Furthermore, dynamic causal modeling analysis reveals a subcortical-cortical functional pathway that transmits local biological motion signals from the superior colliculus via the middle temporal visual complex to the posterior superior temporal sulcus in the human brain. These findings suggest the existence of a cross-species mechanism in the superior colliculus that facilitates the detection of local biological motion at the early stage of the visual processing stream.

The ameliorative potential of platelet-rich plasma and exosome on renal ischemia/reperfusion-induced uremic encephalopathy in rats.

Uremic Encephalopathy results from the elevation of toxins and blood-brain barrier (BBB) disruption. Renal Ischemia/Reperfusion (I/R) injury is the principal cause of acute kidney injury and brain tissue injury. The present study was crafted to estimate the restorative impact of platelet-rich plasma (PRP) and exosome injection before the reperfusion phase on the kidney following renal I/R injury and its influence on brain tissue by tracking the histopathological, biochemical, and Doppler ultrasonography alternations in both kidney and brain tissue. Forty mature male rats were divided into five groups as follows: control, I/R, PRP, exosome, and Exosome + PRP. Renal Doppler ultrasonography was traced for all rats. Serum kidney functions and acetylcholine esterase enzyme (AchE) were evaluated. Both Gamma-aminobutyric acid (GABA) and glutamate were assessed in brain tissues. The oxidative stress (malondialdehyde), anti-oxidative (glutathione and catalase), and pro-inflammatory (Tumor necrosis factor- α and interleukin-6) markers were estimated in renal tissues. Additionally, morphometric histological examination was performed in both renal and brain tissues. Both PRP and exosome-received rats exhibited a significant improvement in both serum kidney functions and AchE compared to I/R rats. There was a 3.39-fold increase in GABA and a 2.27-fold decrease in glutamate levels in the brain tissue of PRP rats compared to the I/R rats. A significant elevation (P ≤ 0.0001) of glutathione and catalase besides a significant reduction in the expression of TNF-α and IL-6 was observed in renal tissue compared to I/R rats. A significant severe reduction (P < 0.0001) in the number of Purkinje cells, pyramidal cells in the cerebellar cortex, and the CA1 region in the hippocampus was observed in I/R rats which was significantly alleviated by both PRP and exosome. Furthermore, there was a significant improvement in Doppler parameters. PRP exerted a significant superior impact on the restoration of kidney functions and repairing uremic-induced damage in brain tissue.

MicroRNAs as Regulators, Biomarkers, and Therapeutic Targets in Autism Spectrum Disorder.

The pathogenesis of autism spectrum disorder (ASD) is complex and is mainly influenced by genetic and environmental factors. Some research has indicated that environmental aspects may interplay with genetic aspects to enhance the risk, and microRNAs (miRNAs) are probably factors in explaining this link between heredity and the environment. MiRNAs are single-stranded noncoding RNAs that can regulate gene expression at the posttranscriptional level. Some research has indicated that miRNAs are closely linked to neurological diseases. Many aberrantly expressed miRNAs have been observed in autism, and these dysregulated miRNAs are expected to be potential biomarkers and provide new strategies for the treatment of this disease. This article reviews the research progress of miRNAs in autism, including their biosynthesis and function. It is found that some miRNAs show aberrant expression patterns in brain tissue and peripheral blood of autistic patients, which may serve as biomarkers of the disease. In addition, the article explores the novel role of exosomes as carriers of miRNAs with the ability to cross the blood-brain barrier and unique expression profiles, offering new possibilities for diagnostic and therapeutic interventions in ASD. The potential of miRNAs in exosomes as diagnostic markers for ASD is specifically highlighted, as well as the prospect of using engineered exosome-encapsulated miRNAs for targeted therapies.

Potential of ex vivo organotypic slice cultures in neuro-oncology.

Over recent decades, in vitro and in vivo models have significantly advanced brain cancer research; however, each presents distinct challenges for accurately mimicking in situ conditions. In response, organotypic slice cultures have emerged as a promising model recapitulating precisely specific in vivo phenotypes through an ex vivo approach. Ex vivo organotypic brain slice models can integrate biological relevance and patient-specific variability early in drug discovery, thereby aiming for more precise treatment stratification. However, the challenges of obtaining representative fresh brain tissue, ensuring reproducibility, and maintaining essential central nervous system (CNS)-specific conditions reflecting the in situ situation over time have limited the direct application of ex vivo organotypic slice cultures in robust clinical trials. In this review, we explore the benefits and possible limitations of ex vivo organotypic brain slice cultures in neuro-oncological research. Additionally, we share insights from clinical experts in neuro-oncology on how to overcome these current limitations and improve the practical application of organotypic brain slice cultures beyond academic research.

Relationship between regional volume changes and water diffusion in fixed marmoset brains: an in vivo and ex vivo comparison.

Ex vivo studies of the brain are often employed as experimental systems in neuroscience. In general, brains for ex vivo MRI studies are usually fixed with paraformaldehyde to preserve molecular structure and prevent tissue destruction during long-term storage. As a result, fixing brain tissue causes microstructural changes and a decrease in brain volume. Therefore, the purpose of this study was to investigate the regional effect of brain volume and microstructural changes on the restricted diffusion of water molecules in the common marmoset brain using in vivo and ex vivo brains from the same individual. We used 9.4T magnetic resonance imaging and also compared the T2-weighted images and diffusion-weighted imaging (DWI) data between in vivo and ex vivo brains to investigate changes in brain volume and diffusion of water molecules in 12 common marmosets. We compared fractional anisotropy, mean diffusivity, AD (axial diffusivity), and radial diffusivity values in white matter and gray matter between in vivo and ex vivo brains. We observed that AD showed the strongest correlation with regional volume changes in gray matter. The results showed a strong correlation between AD and changes in brain volume. By comparing the in vivo and ex vivo brains of the same individual, we identified significant correlations between the local effects of perfusion fixation on microstructural and volumetric changes of the brain and alterations in the restricted diffusion of water molecules within the brain. These findings provide valuable insights into the complex relationships between tissue fixation, brain structure, and water diffusion properties in the marmoset brain.

Finite element modeling of concentrated impact loads on the masticatory muscles at the head

AbstractNumerical simulation has great potential to provide a more comprehensive understanding of human impact response to injury mechanisms. Finite Element (FE) models are used as a tool to study human injuries in greater detail, for example, the THUMS (Total Human Model Safety of TOYOTA) model, which is widely used as a reliable human model in different fields to predict human injuries such as fractures, internal organ damage, and brain tissue injuries. However, no available FE model can be used to simulate human‐robot collisions based on standards ISO/TS 15066 and the biomechanical characteristics of human soft tissues in vivo. The authors have developed a head model based on the structures (dimensions and anatomy) of the THUMS head model, specifically designed to simulate impact loads on the masticatory muscles. Based on medical imaging (MRI) data, the soft tissues at the location of the masticatory muscles in the THUMS head are transformed from monolayer to multilayer, that is, a composite geometry of skin‐fat‐muscle each with its own material model and parameters. The model was optimized and validated using the experimental data from the Fraunhofer IFF subjects study, which determined biomechanical thresholds for specific body locations in ISO/TS 15066 under dynamic collisions.

Inhibiting Mitochondrial Damage for Efficient Treatment of Cerebral Ischemia-Reperfusion Injury Through Sequential Targeting Nanomedicine of Neuronal Mitochondria in Affected Brain Tissue.

Oxidative stress, predominantly from neuronal mitochondrial damage and the resultant cytokine storm, is central to cerebral ischemia-reperfusion injury (CIRI). However, delivering drugs to neuronal mitochondria remains challenging due to the blood-brain barrier (BBB), which impedes drug entry into affected brain tissues. This study introduces an innovative tannic acid (TA) and melanin-modified heteropolyacid nanomedicine (MHT), which highly specifically eliminates the neuronal mitochondrial reactive oxygen radicals burst to efficiently reduce neuronal mitochondrial damage through a strategically designed sequential targeting strategy from affected brain tissue to neuronal mitochondria. TA endows MHT with sequential targeting ability by binding to matrix proteins exposed to the damaged BBB and mitochondrial outer membrane proteins of neurons, while melanin significantly enhances the antioxidant capacity of MHT. Consequently, MHT effectively inhibits neuronal apoptosis by protecting mitochondria and reversing the inflammatory immune environment through the deactivation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. MHT demonstrated a strong therapeutic effect on CIRI, with an ultralow dose (2 mgkg-1) proving effective in reversing the condition. This work not only introduces a new avenue to significantly reduce CIRI through sequential targeting therapy but also offers a new paradigm for treating other ischemia-reperfusion injury diseases.

Interdisciplinary and Collaborative Training in Neuroscience: Insights from the Human Brain Project Education Programme.

Neuroscience education is challenged by rapidly evolving technology and the development of interdisciplinary approaches for brain research. The Human Brain Project (HBP) Education Programme aimed to address the need for interdisciplinary expertise in brain research by equipping a new generation of researchers with skills across neuroscience, medicine, and information technology. Over its ten year duration, the programme engaged over 1,300 experts and attracted more than 5,500 participants from various scientific disciplines in its blended learning curriculum, specialised schools and workshops, and events fostering dialogue among early-career researchers. Key principles of the programme's approach included fostering interdisciplinarity, adaptability to the evolving research landscape and infrastructure, and a collaborative environment with a focus on empowering early-career researchers. Following the programme's conclusion, we provide here an analysis and in-depth view across a diverse range of educational formats and events. Our results show that the Education Programme achieved success in its wide geographic reach, the diversity of participants, and the establishment of transversal collaborations. Building on these experiences and achievements, we describe how leveraging digital tools and platforms provides accessible and highly specialised training, which can enhance existing education programmes for the next generation of brain researchers working in decentralised European collaborative spaces. Finally, we present the lessons learnt so that similar initiatives may improve upon our experience and incorporate our suggestions into their own programme.

Tri-culture modeling of neuroinflammation, neurodegeneration, and neuroprotection.

The study of neurodegenerative diseases, such as Alzheimer's disease (AD), has long been a complex and challenging task. One of the major hurdles in understanding these diseases is the difficulty in recapitulating the complex interactions between neurons, astrocytes, and microglia in a laboratory setting. In recent years, researchers have made significant progress in developing triculture models that combine these three cell types, allowing for a more accurate representation of the cellular context of the human brain. This commentary discusses the recent advancements and importance of using tri-culture model systems in clarifying the pathophysiology of AD and discusses the recent article by Kim et al. (2024) published in the Journal of Alzheimer's Disease.

AMFR-mediated Flavivirus NS2A ubiquitination subverts ER-phagy to augment viral pathogenicity.

Flaviviruses strategically utilize the endoplasmic reticulum (ER) in their replication cycles. However, the role of ER autophagy (ER-phagy) in viral replication process remains poorly understood. Here, we reveal that prolonged Zika virus (ZIKV) infection results from the degradation of ER-phagy receptor FAM134B, facilitated by viral NS2A protein. Mechanistically, ER-localized NS2A undergoes K48-linked polyubiquitination at lysine (K) 56 by E3 ligase AMFR. Ubiquitinated NS2A binds to FAM134B and AMFR orchestrates the degradation of NS2A-FAM134B complexes. AMFR-catalyzed NS2A ubiquitination not only targets FAM134B degradation but also hinders the FAM134B-AMFR axis. Notably, a recombinant ZIKV mutant (ZIKV-NS2AK56R), lacking ubiquitination and ER-phagy inhibition, exhibits attenuation in ZIKV-induced microcephalic phenotypes in human brain organoids and replicates less efficiently, resulting in weakened pathogenesis in mouse models. In this work, our mechanistic insights propose that flaviviruses manipulate ER-phagy to modulate ER turnover, driving viral infection. Furthermore, AMFR-mediated flavivirus NS2A ubiquitination emerges as a potential determinant of viral pathogenecity.

Exposure to the antiretroviral drug dolutegravir impairs structure and neurogenesis in a forebrain organoid model of human embryonic cortical development

IntroductionFor many therapeutic drugs, including antiretroviral drugs used to treat people living with HIV-1 (PLWH), we have little data on the potential effects on the developing human brain due to limited access to tissue and historical constraints on the inclusion of pregnant populations in clinical trials. Human induced pluripotent stem cells (iPSCs) offer a new avenue to gain insight on how drugs may impact human cell types representative of the developing central nervous system. To prevent vertical transmission of HIV and promote the health of pregnant PLWH, antiretroviral therapy must be initiated and/or maintained throughout pregnancy. However, many antiretroviral drugs are approved for widespread use following clinical testing only in non-pregnant populations and there may be limited information on potential teratogenicity until pregnancy outcomes are evaluated. The integrase strand transfer inhibitor dolutegravir (DTG) is a frontline antiretroviral drug that is effective in viral suppression of HIV but was previously reported to be associated with a slight increase in the risk for neural tube defects in one study, although this has not been replicated in other cohorts.MethodsTo directly investigate the potential impact of DTG on human cortical neurogenesis, we measured the effects of daily drug exposure on the early stages of corticogenesis in a human iPSC-based forebrain organoid model. We quantified organoid size and structure and analyzed gene and protein expression to evaluate the impact of several doses of DTG on organoid development.ResultsWe observed deficits in organoid structure and impaired neurogenesis in DTG-treated organoids compared to vehicle-treated control organoids after 20 or 40 days in culture. Our highest dose of DTG (10 μM) resulted in significantly smaller organoids with a reduced density of neural rosette structures compared to vehicle-treated controls. Mechanistically, RNA-sequencing and immunohistological analysis suggests dysregulated amino acid transport and activation of the integrated stress response in the DTG-treated organoids, and functionally, a small molecule integrated stress response inhibitor (ISRIB) could partially rescue increased expression of proteins related to cell cycle regulation.DiscussionTogether, these results illustrate the potential for human iPSC-based strategies to reveal biological processes during neurogenesis that may be affected by therapeutic drugs and provide complementary data in relevant human cell types to augment preclinical investigations of drug safety during pregnancy.

Organ toxicities associated with diet-induced obesity in rats: Investigation of changes in activities selected enzymes.

Obesity stands out as one of the most significant health problems in the modern world. The prevalence of high-calorie diets (HCDs) globally exacerbates this condition. Throughout history, plants and plant-derived food products have been utilized for medicinal purposes, demonstrating their efficacy in the treatment and prevention of various diseases. Gundelia tournefortii (GT), a plant of interest, is known to possess beneficial properties. Hence, this study aimed to investigate the immunotoxic and neurotoxic effects of two different doses of GT plant extract on the liver, brain, and heart tissues of obese rats. For this purpose, Wistar male rats were divided into four groups: "CG," "HCDG," "HCDGUN1," and "HCDGUN2" At the conclusion of the study, adenosine deaminase (ADA) and myeloperoxidase (MPO) activities, as well as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) biomarkers, were evaluated in the liver, heart, and brain tissues. The study results revealed a statistically significant increase in ADA and MPO activities in the HCDG group compared to the CG group, alongside a significant decrease in the HCDGUN groups compared to the HCDG group. Regarding AChE and BChE activities, a statistically significant decrease was observed in the HCDG group compared to the CG group, whereas an increase was noted in the HCDGUN groups relative to the HCDG group, with the latter approaching values similar to those of the control group. In conclusion, the intake of GT plant extract exhibited positive effects on the immunotoxic and neurotoxic effects induced by HCD in rats with an experimental obesity model, as evidenced by tissue biomarker evaluations.

Tufm lactylation regulates neuronal apoptosis by modulating mitophagy in traumatic brain injury.

Lactates accumulation following traumatic brain injury (TBI) is detrimental. However, whether lactylation is triggered and involved in the deterioration of TBI remains unknown. Here, we first report that Tufm lactylation pathway induces neuronal apoptosis in TBI. Lactylation is found significantly increased in brain tissues from patients with TBI and mice with controlled cortical impact (CCI), and in neuronal injury cell models. Tufm, a key factor in mitophagy, is screened and identified to be mostly lactylated. Tufm is detected to be lactylated at K286 and the lactylation inhibits the interaction of Tufm and Tomm40 on mitochondria. The mitochondrial distribution of Tufm is then inhibited. Consequently, Tufm-mediated mitophagy is suppressed while mitochondria-induced neuronal apoptosis is increased. In contrast, the knockin of a lactylation-deficient TufmK286R mutant in mice rescues the mitochondrial distribution of Tufm and Tufm-mediated mitophagy, and improves functional outcome after CCI. Likewise, mild hypothermia, as a critical therapeutic method in neuroprotection, helps in downregulating Tufm lactylation, increasing Tufm-mediated mitophagy, mitigating neuronal apoptosis, and eventually ameliorating the outcome of TBI. A novel molecular mechanism in neuronal apoptosis, TBI-initiated Tufm lactylation suppressing mitophagy, is thus revealed.

Distinct brain and neurocognitive transformations after bariatric surgery: a pilot study

BackgroundObese patients have worse outcomes after surgery and are at increased risk for perioperative neurocognitive disorders (PND). Our aim was to detail the cognitive trajectories of patients undergoing bariatric surgery (BS) and map distinct structural brain changes using magnetic resonance imaging (MRI) to better understand the association between the vulnerable brain, surgery, and the arc of PND.MethodsProspective pilot study with longitudinal comprehensive cognitive assessments and MRI were performed on obese patients scheduled for BS. We analyzed baseline cognitive function and high-resolution T1-/T2-weighted brain images on 19 obese patients [age, 54 (9) years, BMI, 40 (36, 42) kg m−2] and compared with 50 healthy control subjects [age, 52 (6) years; BMI, 25 (24, 27) kg m−2]. Patients were evaluated within five days of BS (baseline), immediately after (within 48h), and follow up at six months.ResultsAt baseline, obese patients had significant brain tissue changes seen in MRI and decreased cognitive scores compared to controls (MoCA 26 vs 28, P = 0.017). Surgery induced further gray matter volume and brain tissue changes along with reduced cognitive scores within the immediate postoperative period (MoCA 26 vs 24, P &amp;lt; 0.001). At six months, we observed reversal of brain alterations for most patients and a concomitant rebound of cognitive scores to patient’s baseline status.ConclusionsBariatric surgery resulted in worsening of preexisting brain structural integrity and lower cognitive function for obese patients compared to baseline. These distinct brain lesions are consistent with specific domains of cognition. Most of these changes reverted to patient’s baseline condition within six months after surgery.

Pulmonary Flora-Derived Lipopolysaccharide Mediates Lung-Brain Axis through Activating Microglia Involved in Polystyrene Microplastic-Induced Cognitive Dysfunction.

Microplastics (MPs) have been detected in the atmospheric and the human respiratory system, indicating that the respiratory tract is a significant exposure route for MPs. However, the effect of inhaled MPs on cognitive function has not been adequately studied. Here, a C57BL/6 J mouse model of inhalation exposure to polystyrene MPs (PS-MPs, 5 µm, 60 d) is established by intratracheal instillation. Interestingly, in vivo fluorescence imaging and transmission electron microscopy reveal that PS-MPs do not accumulate in the brain. However, behavioral experiments shows that cognitive function of mice is impaired, accompanied by histopathological damage of lung and brain tissue. Transcriptomic studies in hippocampal and lung tissue have demonstrated key neuroplasticity factors as well as cognitive deficits linked to lung injury, respectively. Mechanistically, the lung-brain axis plays a central role in PS-MPs-induced neurological damage, as demonstrated by pulmonary flora transplantation, lipopolysaccharide (LPS) intervention, and cell co-culture experiments. Together, inhalation of PS-MPs reduces cognitive function by altering the composition of pulmonary flora to produce more LPS and promoting M1 polarization of microglia, which provides new insights into the mechanism of nerve damage caused by inhaled MPs and also sheds new light on the prevention of neurotoxicity of environmental pollutants.

Advancements in Nanowire-Based Devices for Neuromorphic Computing: A Review.

Neuromorphic computing, inspired by the highly interconnected and energy-efficient way the human brain processes information, has emerged as a promising technology for post-Moore's law era. This emerging technology can emulate the structures and the functions of the human brain and is expected to overcome the fundamental limitation of the current von Neumann computing architecture. Neuromorphic devices stand out as the key components of future electronic systems, exhibiting potential in shaping the landscape of neuromorphic computing. Especially, nanowire (NW)-based neuromorphic devices, with their advantages of high integration, high-speed computing, and low power consumption, have recently emerged as candidates for neuromorphic computing technology. Here, a critical overview of the current development and relevant research in the field of NW-based neuromorphic devices are provided. Neuromorphic devices based on different NW materials are comprehensively discussed, including Ag NW-based, organic NW-based, metal oxide NW-based, and semiconductor NW-based devices. Finally, as a foresight perspective, the potentials and the challenges of these NW-based neuromorphic devices for use as future brain-like electronics are discussed.

Network medicine informed multiomics integration identifies drug targets and repurposable medicines for Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. We developed a network medicine methodology via integrating human brain multi-omics data to prioritize drug targets and repurposable treatments for ALS. We leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on human brain expression quantitative trait loci (QTL) (eQTL), protein QTL (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL). Using a network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in known ALS pathobiological pathways. Applying network proximity analysis of predicted ALS-associated genes and drug-target networks under the human protein-protein interactome (PPI) model, we identified potential repurposable drugs (i.e., Diazoxide and Gefitinib) for ALS. Subsequent validation established preclinical evidence for top-prioritized drugs. In summary, we presented a network-based multi-omics framework to identify drug targets and repurposable treatments for ALS and other neurodegenerative disease if broadly applied.

T1-weighted MRI texture analysis in amyotrophic lateral sclerosis patients stratified by the D50 progression model

Abstract Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, presents challenges in predicting individual disease trajectories due to its heterogeneous nature. This study explores the application of texture analysis on T1-weighted MRI in patients with ALS, stratified by the D50 disease progression model. The D50 model, which offers a more nuanced representation of disease progression than traditional linear metrics, calculates the sigmoidal curve of functional decline and provides independent quantifications of disease aggressiveness and accumulation. In this research, a representative cohort of 116 patients with ALS were studied using the D50 model and texture analysis on MRI images. Texture analysis, a technique used for quantifying voxel intensity patterns in MRI images, was employed to discern alterations in brain tissue associated with ALS. This study examined alterations of the texture feature autocorrelation across subgroups of patients based on disease accumulation, aggressiveness, and the first site of onset, as well as in direct regressions with accumulation/aggressiveness. The findings revealed distinct patterns of the texture-derived autocorrelation in gray and white matter, increase in bilateral corticospinal tract, right hippocampus, and left temporal pole as well as widespread decrease within motor and extra-motor brain regions, of patients stratified based on their disease accumulation. Autocorrelation alterations in grey and white matter, in clusters within the left cingulate gyrus white matter, brainstem, left cerebellar tonsil gray matter, and right inferior fronto-occipital fasciculus, were also negatively associated with disease accumulation in regression analyses. Otherwise, disease aggressiveness correlated with only two small clusters, within the right superior temporal gyrus and right posterior division of the cingulate gyrus white matter. The findings suggest that texture analysis could serve as a potential biomarker for disease stage in ALS, with potential for quick assessment based on using T1-weighted images.

Electroacupuncture alleviated post-stroke cognitive impairment via the mTOR/NLRP3-mediated autophagy-inflammatory pathway

BackgroundPost-stroke cognitive impairment (PSCI) severely reduces quality of life of patients with stroke. This study aimed to assess the effects of electroacupuncture (EA) on PSCI and the role of the mTOR/NLRP3-mediated autophagy-inflammatory pathway in this process.MethodsThe rat focal cerebral ischemia model was established using middle cerebral artery occlusion (MCAO). Following successful induction of the model, EA was applied to the bilateral Fengchi, Fengfu, and Dazhui acupoints, and brain tissue samples were collected on day 15. Cognitive function was assessed using the Morris water maze test. Cerebral infarct volume was quantified by Triphenyltetrazolium chloride (TTC) staining. Hematoxylin–eosin and TUNEL staining were performed to evaluate pathological changes and apoptosis rates. Apoptosis-, inflammation-, and autophagy-related biomarkers were measured, and autophagosomes were visualized using transmission electron microscopy.ResultsMCAO rats exhibited slower weight gain, reduced mobility, increased infarct size, pathological damage, and apoptosis, confirming successful establishment of the MCAO rat model. Following EA treatment, MCAO rats displayed faster weight gain, improved mobility, and shorter escape latency. EA also reduced the area of cerebral infarction and alleviated pathological damage and apoptosis in MCAO rats. Furthermore, EA downregulated IL-1β, IL-18, NLRP3, and LC3 II/LC3 I expression and upregulated p62, mTOR, and Beclin-1 expression in MCAO rats. EA treatment also decreased the number of autophagosomes in these rats.ConclusionsEA effectively mitigates post-stroke cognitive impairment by reducing apoptosis, inflammation, and autophagy through the regulation of the mTOR/NLRP3-mediated autophagy-inflammatory pathway, offering valuable therapeutic insights for stroke rehabilitation.

PEGylated Multimeric RNA Nanoparticles for siRNA Delivery in Traumatic Brain Injury.

Traumatic brain injury (TBI) impacts millions of people globally, however currently there are no approved therapeutics that address long-term brain health. In order to create a technology that is relevant for siRNA delivery in TBI after systemic administration, sub-100nm nanoparticles with rolling circle transcription (RCT) are synthesized and isolated in order improve payload delivery into the injured brain. Unlike conventional RCT-based RNA particles, in this method, sub-100nm RNA nanoparticles (RNPs) are isolated. To enhance RNP pharmacokinetics, RNPs are synthesized with modified bases in order to graft polyethylene glycol (PEG) to the RNPs. PEGylated RNPs (PEG-RNPs) do not significantly impact their knockdown activity in vitro and lead to longer blood half-life after systemic administration and greater accumulation into the injured brain in a mouse model of TBI. In order to demonstrate RNA interference (RNAi) activity of RNPs, knockdown of the inflammatory cytokine TNF-α in injured brain tissue after systemic administration of RNPs in a mouse model of TBI is demonstrated. In summary, small sub-100nm multimeric RNA nanoparticles are synthesized and isolated that can be modified using accessible chemistry in order to create a technology suitable for systemic RNAi therapy for TBI.