Dead Neurons Research Articles

Nageotte nodules in human DRG reveal neurodegeneration in painful diabetic neuropathy.

Diabetic neuropathy is frequently accompanied by pain and loss of sensation attributed to axonal dieback. We recovered dorsal root ganglia (DRGs) from 90 organ donors, 19 of whom had medical indices for diabetic painful neuropathy (DPN). Nageotte nodules, dead sensory neurons engulfed by non-neuronal cells, were abundant in DPN DRGs and accounted for 25% of all neurons. Peripherin-and Nav1.7-positive dystrophic axons invaded Nageotte nodules, forming small neuroma-like structures. Using histology and spatial sequencing, we demonstrate that Nageotte nodules are mainly composed of satellite glia and non-myelinating Schwann cells that express SPP1 and are intertwined with sprouting sensory axons originating from neighboring neurons. Our findings solve a 100-year mystery of the nature of Nageotte nodules linking these pathological structures to pain and sensory loss in DPN.

Microglial mitochondrial DNA release contributes to neuroinflammation after intracerebral hemorrhage through activating AIM2 inflammasome

Intracerebral hemorrhage (ICH) is a severe disease that often leads to disability and death. Neuroinflammatory response is a key causative factor of early secondary brain injury after ICH. AIM2 is a DNA-sensing protein that recognizes cytosolic double-stranded DNA and take a significant part in neuroinflammation. Mitochondrial DNA participates in the translation of proteins such as the respiratory chain in the mitochondria. Whether mtDNA is involved in forming AIM2 inflammasome after ICH remains unclear. We used mice to construct ICH model in vivo and we used BV2 microglial cells treated with oxyhemoglobin to simulate ICH in vitro. Following lentiviral transfection to overexpress AIM2 antagonist P202, a notable decrease was observed in the levels of AIM2 inflammasome-associated proteins, leading to a reduction in dead neurons surrounding the hematoma and an enhancement in long-term and short-term behavior of neurological deficits. We further explored whether mtDNA took part in the AIM2 activation after ICH. The cytosolic mtDNA level was down-regulated by the mitochondrial division protector Mdivi-1 and up-regulated by transfection of mtDNA into cytoplasm. We found the expression level of AIM2 inflammasome-related proteins and inflammatory cytokines release were regulated by the cytosolic mtDNA level. In conclusion, after ICH, the mtDNA content in the cytoplasm of microglia around the hematoma rises, causing AIM2 inflammation leading to neuronal apoptosis, which leads to neurological deficits in mice. On the other hand, P202 was able to block inflammatory vesicle activation and improve neurological function by preventing the interaction between AIM2 protein and mitochondrial DNA.

Dopaminergic neurons lacking Caspase-3 avoid apoptosis but undergo necrosis after MPTP treatment inducing a Galectin-3-dependent selective microglial phagocytic response

Parkinson’s Disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia nigra pars compacta (SNpc). Apoptosis is thought to play a critical role in the progression of PD, and thus understanding the effects of antiapoptotic strategies is crucial for developing potential therapies. In this study, we developed a unique genetic model to selectively delete Casp3, the gene encoding the apoptotic protein caspase-3, in dopaminergic neurons (TH-C3KO) and investigated its effects in response to a subacute regime of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, which is known to trigger apoptotic loss of SNpc dopaminergic neurons. We found that Casp3 deletion did not protect the dopaminergic system in the long term. Instead, we observed a switch in the cell death pathway from apoptosis in wild-type mice to necrosis in TH-C3KO mice. Notably, we did not find any evidence of necroptosis in our model or in in vitro experiments using primary dopaminergic cultures exposed to 1-methyl-4-phenylpyridinium in the presence of pan-caspase/caspase-8 inhibitors. Furthermore, we detected an exacerbated microglial response in the ventral mesencephalon of TH-C3KO mice in response to MPTP, which mimicked the microglia neurodegenerative phenotype (MGnD). Under these conditions, it was evident the presence of numerous microglial phagocytic cups wrapping around apparently viable dopaminergic cell bodies that were inherently associated with galectin-3 expression. We provide evidence that microglia exhibit phagocytic activity towards both dead and stressed viable dopaminergic neurons through a galectin-3-dependent mechanism. Overall, our findings suggest that inhibiting apoptosis is not a beneficial strategy for treating PD. Instead, targeting galectin-3 and modulating microglial response may be more promising approaches for slowing PD progression.

Nageotte nodules in human DRG reveal neurodegeneration in painful diabetic neuropathy.

Diabetic neuropathy is frequently accompanied by pain and loss of sensation attributed to axonal dieback. We recovered dorsal root ganglia (DRGs) from 90 organ donors, 19 of whom had medical indices for diabetic painful neuropathy (DPN). Nageotte nodules, dead sensory neurons engulfed by non-neuronal cells, were abundant in DPN DRGs and accounted for 25% of all neurons. Peripherin-and Nav1.7-positive dystrophic axons invaded Nageotte nodules, forming small neuroma-like structures. Using histology and spatial sequencing, we demonstrate that Nageotte nodules are mainly composed of satellite glia and non-myelinating Schwann cells that express SPP1 and are intertwined with sprouting sensory axons originating from neighboring neurons. Our findings solve a 100-year mystery of the nature of Nageotte nodules linking these pathological structures to pain and sensory loss in DPN.

Olfactory Ecto-Mesenchymal Stem Cells in Modeling and Treating Alzheimer's Disease.

Alzheimer's disease (AD) is a condition in the brain that is marked by a gradual and ongoing reduction in memory, thought, and the ability to perform simple tasks. AD has a poor prognosis but no cure yet. Therefore, the need for novel models to study its pathogenesis and therapeutic strategies is evident, as the brain poorly recovers after injury and neurodegenerative diseases and can neither replace dead neurons nor reinnervate target structures. Recently, mesenchymal stem cells (MSCs), particularly those from the human olfactory mucous membrane referred to as the olfactory ecto-MSCs (OE-MSCs), have emerged as a potential avenue to explore in modeling AD and developing therapeutics for the disease due to their lifelong regeneration potency and facile accessibility. This review provides a comprehensive summary of the current literature on isolating OE-MSCs and delves into whether they could be reliable models for studying AD pathogenesis. It also explores whether healthy individual-derived OE-MSCs could be therapeutic agents for the disease. Despite being a promising tool in modeling and developing therapies for AD, some significant issues remain, which are also discussed in the review.

The different roles of V-ATPase a subunits in phagocytosis/endocytosis and autophagy

ABSTRACT Microglia are specialized macrophages responsible for the clearance of dead neurons and pathogens by phagocytosis and degradation. The degradation requires phagosome maturation and acidification provided by the vesicular- or vacuolar-type H+-translocating adenosine triphosphatase (V-ATPase), which is composed of the cytoplasmic V1 domain and the membrane-embedded Vo domain. The V-ATPase a subunit, an integral part of the Vo domain, has four isoforms in mammals. The functions of different isoforms on phagosome maturation in different cells/species remain controversial. Here we show that mutations of both the V-ATPase Atp6v0a1 and Tcirg1b/Atp6v0a3 subunits lead to the accumulation of phagosomes in zebrafish microglia. However, their mechanisms are different. The V-ATPase Atp6v0a1 subunit is mainly distributed in early and late phagosomes. Defects of this subunit lead to a defective transition from early phagosomes to late phagosomes. In contrast, The V-ATPase Tcirg1b/Atp6v0a3 subunit is primarily located on lysosomes and regulates late phagosome-lysosomal fusion. Defective Tcirg1b/Atp6v0a3, but not Atp6v0a1 subunit leads to reduced acidification and impaired macroautophagy/autophagy in microglia. We further showed that ATP6V0A1/a1 and TCIRG1/a3 subunits in mouse macrophages preferentially located in endosomes and lysosomes, respectively. Blocking these subunits disrupted early-to-late endosome transition and endosome-to-lysosome fusion, respectively. Taken together, our results highlight the essential and conserved roles played by different V-ATPase subunits in multiple steps of phagocytosis and endocytosis across various species. Abbrevations: Apoe: apolipoprotein E; ANXA5/annexin V: annexin A5; ATP6V0A1/a1: ATPase H+-transporting V0 subunit a1; ATP6V0A2/a2: ATPase H+-transporting V0 subunit a2; ATP6V0A4/a4: ATPase H+-transporting V0 subunit a4; dpf: days post-fertilization; EEA1: early endosome antigen 1; HOPS: homotypic fusion and protein sorting; LAMP1: lysosomal associated membrane protein 1; Lcp1: lymphocyte cytosolic protein 1 (L-plastin); Map1lc3/Lc3: microtubule-associated protein 1 light chain 3; NR: neutral red; PBS: phosphate-buffered saline; PtdIns: phosphatidylinositol; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol (3,5)-bisphosphate; RAB4: RAB4, member RAS oncogene family; RAB5: RAB5, member RAS oncogene family; RAB7: RAB7, member RAS oncogene family; TCIRG1/Atp6v0a3/a3: T cell immune regulator 1, ATPase H+-transporting V0 subunit a3; V-ATPase: vacuolar-type H+-translocating adenosine triphosphatase; Xla.Tubb2b/NBT: tubulin beta 2B class IIb.

Progressive Feature Extraction with a Greedy Network-growing Algorithm

In this paper, a new information theoretic method called the greedy network-growing algorithm is proposed. The method is called "greedy," because a network with this algorithm grows while absorbing as much information as possible from outside. The method is based upon information theoretic competitive learning and can solve the fundamental problems inherent in competitive learning, such as the dead neurons and inappropriate number of neurons problems. The new model can grow networks by repeatedly maximizing information content and by gradually extracting salient features from input patterns. Because the new model can cope with inappropriate feature detection in the early stage of learning, extracted features should cover most of the input patterns. The new method is applied to political data analysis, medical data analysis, and information science education analysis. Experimental results confirm that the new method can acquire significant information and that more explicit features can be extracted.

Nonintuitive Immunogenicity and Plasticity of Alpha-Synuclein Conformers: A Paradigm for Smart Delivery of Neuro-Immunotherapeutics.

Despite the extensive research successes and continuous developments in modern medicine in terms of diagnosis, prevention, and treatment, the lack of clinically useful disease-modifying drugs or immunotherapeutic agents that can successfully treat or prevent neurodegenerative diseases is an ongoing challenge. To date, only one of the 244 drugs in clinical trials for the treatment of neurodegenerative diseases has been approved in the past decade, indicating a failure rate of 99.6%. In corollary, the approved monoclonal antibody did not demonstrate significant cognitive benefits. Thus, the prevalence of neurodegenerative diseases is increasing rapidly. Therefore, there is an urgent need for creative approaches to identifying and testing biomarkers for better diagnosis, prevention, and disease-modifying strategies for the treatment of neurodegenerative diseases. Overexpression of the endogenous α-synuclein has been identified as the driving force for the formation of the pathogenic α-synuclein (α-Syn) conformers, resulting in neuroinflammation, hypersensitivity, endogenous homeostatic responses, oxidative dysfunction, and degeneration of dopaminergic neurons in Parkinson's disease (PD). However, the conformational plasticity of α-Syn proffers that a certain level of α-Syn is essential for the survival of neurons. Thus, it exerts both neuroprotective and neurotoxic (regulatory) functions on neighboring neuronal cells. Furthermore, the aberrant metastable α-Syn conformers may be subtle and difficult to detect but may trigger cellular and molecular events including immune responses. It is well documented in literature that the misfolded α-Syn and its conformers that are released into the extracellular space from damaged or dead neurons trigger the innate and adaptive immune responses in PD. Thus, in this review, we discuss the nonintuitive plasticity and immunogenicity of the α-Syn conformers in the brain immune cells and their physiological and pathological consequences on the neuroimmune responses including neuroinflammation, homeostatic remodeling, and cell-specific interactions that promote neuroprotection in PD. We also critically reviewed the novel strategies for immunotherapeutic delivery interventions in PD pathogenesis including immunotherapeutic targets and potential nanoparticle-based smart drug delivery systems. It is envisioned that a greater understanding of the nonintuitive immunogenicity of aberrant α-Syn conformers in the brain's microenvironment would provide a platform for identifying valid therapeutic targets and developing smart brain delivery systems for clinically effective disease-modifying immunotherapeutics that can aid in the prevention and treatment of PD in the future.

The IC87201 (a PSD95/nNOS Inhibitor) Attenuates Post- Stroke Injuries.

N-methyl-D-aspartate receptor-dependent excitotoxicity is one of the most important mechanisms underlying stroke injury and the resulting neuronal death. In the present study, in order to reduce post-stroke brain injury and improve behavioral performance, a new molecule named IC87201, which acts as an inhibitor of PSD95/nNOS interaction in the intracellular signaling pathway of NMDA receptors, was administered. Using the middle cerebral artery occlusion (MCAO) technique, 24 adult male rats were subjected to one hour of cerebral ischemia. Animals were randomly divided into sham, MCAO, MCAO + DXM, and MCAO + IC87201 groups, and in the last two groups, intraperitoneal injection of dextromethorphan hydrobromide monohydrate (DXM), as an NMDA antagonist, and IC87201 was performed after ischemia. Neurobehavioral scores were evaluated for seven days, and on the last two days, the rats' memory performance was appraised using the passive avoidance test. On seventh day, the brain tissue was properly prepared for stereological analysis. Stereological studies of the hippocampus CA1 and CA3 regions revealed that changes in the total and infarcted volumes, total number of neurons, non-neurons, and dead neurons are the consequences of cerebral ischemia. Also, following cerebral ischemia, neurobehavioral and memory function impairments which were assessed by modified neurological severity scores (mNSS) and passive avoidance test, were observed. The aforementioned impairments were recovered after administration of IC87201 significantly and more potently than DXM. Based on our findings, IC87201 successfully attenuated post-ischemia damages. Therefore, this molecule can be considered as a new therapeutic approach in future research.

A novel deep learning technique for medical image analysis using improved optimizer.

Application of Convolutional neural network in spectrum of Medical image analysis are providing benchmark outputs which converges the interest of many researchers to explore it in depth. Latest preprocessing technique Real ESRGAN (Enhanced super resolution generative adversarial network) and GFPGAN (Generative facial prior GAN) are proving their efficacy in providing high resolution dataset. Objective: Optimizer plays a vital role in upgrading the functioning of CNN model. Different optimizers like Gradient descent, Stochastic Gradient descent, Adagrad, Adadelta and Adam etc. are used for classification and segmentation of Medical image but they suffer from slow processing due to their large memory requirement. Stochastic Gradient descent suffers from high variance and is computationally expensive. Dead neuron problem also proves to detrimental to the performance of most of the optimizers. A new optimization technique Gradient Centralization is providing the unparalleled result in terms of generalization and execution time. Method: Our paper explores the next factor which is the employment of new optimization technique, Gradient centralization (GC) to our integrated framework (Model with advanced preprocessing technique). Result and conclusion: Integrated Framework of Real ESRGAN and GFPGAN with Gradient centralization provides an optimal solution for deep learning models in terms of Execution time and Loss factor improvement.

Reactive changes of kisspeptin-producing hypothalamic neuroendocrine cells during hypogonadism and its replacement therapy by the kisspeptin analogue in rats

BACKGROUND: This study is devoted to the morphological substantiation of the model of male hypogonadism and to establishing the effectiveness of its replacement therapy at the level of the central link of the hypothalamic-pituitary-testicular axis using morphological methods. Information about reactive changes in neuroendocrine cells that synthesize the peptide kisspeptin, which regulates the production of gonadoliberin when modeling male and female hypogonadism, has not been described in the literature, which prevents the creation of a micro-morphological basis for the development of models of hypogonadism and the implementation of further preclinical studies of the effectiveness of its replacement therapy. The goal is to carry out a morphological analysis of kisspeptin-producing neuroendocrine cells of the hypothalamus in normal conditions, with experimental hypogonadism and after replacement therapy.
 AIM: To carry out a morphological analysis of kisspeptin-producing neuroendocrine cells of the hypothalamus in normal conditions, with experimental hypogonadism and after replacement therapy.
 MATERIALS AND METHODS: The objects of the study were 3 groups of adult male Wistar rats 6–8 months of age. In animals of the first and second groups, after anesthesia, total ischemia of both testicles was caused by ligating the left and right spermatic cord with the vascular bundle of the testicle for 60 minutes. Rats of the second group, a few minutes after restoration of testicular blood flow, were given replacement therapy by daily administration of a synthetic analogue of kisspeptin KS6 for 7 days. Control animals of the third group were subjected to sham surgery. After 10 days, all animals were sacrificed, their brains were removed and embedded in paraffin. Nissl-stained frontal histological sections of the most massive areas of the kisspeptin-producing nuclei of the hypothalamus-periventricular and arcuate-were examined using the Imagescope program (Electronic Analysis, Russia). The number of cell bodies of viable and dead neurons was counted (under the control of immunohistochemical identification of the caspase-3 antigen), and the area of the body, nucleus and cytoplasm of viable cells was calculated. Statistical processing of the data was carried out using the GraphPad PRISM (USA) program to determine the median, upper and lower quartiles. Differences were considered significant at p 0.01.
 RESULTS: Simulation of acute ischemia caused a significant increase in the number of dead neurons, a slight decrease in the number of viable neurons and a decrease in the area of their cytoplasm in both kisspeptin-producing nuclei. As a result of KS6 replacement therapy, most neuronal cell bodies retained their original phenotype, but the number of dead neurons was high in both experimental groups.
 CONCLUSIONS: Modeling of male hypogonadism using the method of bilateral acute testicular ischemia induces death and partially reversible degenerative changes in kisspeptin-producing neuroendocrine cells of the hypothalamus. Neuropeptide KS6 has a pronounced restorative effect on kisspeptin-producing neurons of the hypothalamus, which is due to its specific activating effect on endocrine cells of all parts of the hypothalamic-pituitary-testicular axis.

Breast Cancer Diagnosis Using YOLO-Based Multiscale Parallel CNN and Flattened Threshold Swish

In the field of biomedical imaging, the use of Convolutional Neural Networks (CNNs) has achieved impressive success. Additionally, the detection and pathological classification of breast masses creates significant challenges. Traditional mammogram screening, conducted by healthcare professionals, is often exhausting, costly, and prone to errors. To address these issues, this research proposes an end-to-end Computer-Aided Diagnosis (CAD) system utilizing the ‘You Only Look Once’ (YOLO) architecture. The proposed framework begins by enhancing digital mammograms using the Contrast Limited Adaptive Histogram Equalization (CLAHE) technique. Then, features are extracted using the proposed CNN, leveraging multiscale parallel feature extraction capabilities while incorporating DenseNet and InceptionNet architectures. To combat the ‘dead neuron’ problem, the CNN architecture utilizes the ‘Flatten Threshold Swish’ (FTS) activation function. Additionally, the YOLO loss function has been enhanced to effectively handle lesion scale variation in mammograms. The proposed framework was thoroughly tested on two publicly available benchmarks: INbreast and CBIS-DDSM. It achieved an accuracy of 98.72% for breast cancer classification on the INbreast dataset and a mean Average Precision (mAP) of 91.15% for breast cancer detection on the CBIS-DDSM. The proposed CNN architecture utilized only 11.33 million parameters for training. These results highlight the proposed framework’s ability to revolutionize vision-based breast cancer diagnosis.

Pre-adolescence repeat exposure to sub-anesthetic doses of ketamine induces long-lasting behaviors and cognition impairment in male and female rat adults

In pre-adolescence, repeated anesthesia may be required for therapeutic interventions. Adult cognitive and neurobehavioral problems may result from preadolescent exposure to anesthetics. This study examined the long-term morphological and functional effects of repeated sub-anesthetic doses of ketamine exposure on male and female rat adults during pre-adolescence. Weaned 48 pre-adolescent rats from eight mothers and were randomly divided into four equal groups: control group and the ketamine group of males and females (20 mg/kg daily for 14 days); then animals received care for 20–30 days. Repeated exposure to sub-anesthetic doses of ketamine on cognitive functions was assayed using Social discrimination and novel object tests. Besides, an elevated plus maze and fear conditioning apparatus were utilized to determine exploratory and anxiety-like behavior in adults. Toluidine blue stain was used to evaluate the number of dead neurons in the hippocampus, and the effects of ketamine on synaptic plasticity were compared in the perforant pathway of the CA1 of the hippocampus. Our study indicates that repeated exposure to sub-anesthetic doses of ketamine during pre-adolescence can result in neurobehavioral impairment in male and female rat adulthood but does not affect anxiety-like behavior. We found a significant quantifiable increase in dark neurons. Recorded electrophysiologically, repeat sub-anesthetic doses of ketamine resulted in hampering long-term potentiation and pair pulse in male adult animals. Our results showed that repeated exposure to sub-anesthetic doses of ketamine during pre-adolescence can induce hippocampus and neuroplasticity changes later in adulthood. This study opens up a new line of inquiry into potential adverse outcomes of repeated anesthesia exposure in pre-adolescent rats.

Neural networks from biological to artificial and vice versa

In this paper, we examine how deep learning can be utilized to investigate neural health and the difficulties in interpreting neurological analyses within algorithmic models. The key contribution of this paper is the investigation of the impact of a dead neuron on the performance of artificial neural networks (ANNs). Therefore, we conduct several tests using different training algorithms and activation functions to identify the precise influence of the training process on neighboring neurons and the overall performance of the ANN in such cases. The aim is to assess the potential application of the findings in the biological domain, the expected results may have significant implications for the development of effective treatment strategies for neurological disorders. Successive training phases that incorporate visual and acoustic data derived from past social and familial experiences could be suggested to achieve this goal. Finally, we explore the conceptual analogy between the Adam optimizer and the learning process of the brain by delving into the specifics of both systems while acknowledging their fundamental differences.

Genome‐wide CRISPR knockout screening to identify key regulators of phagocytosis in induced pluripotent stem cell derived microglia

AbstractBackgroundA whole genome knockout CRISPR screen in human induced pluripotent stem cell (hiPSC) derived microglia was undertaken to identify regulators of phagocytosis. The secondary objective was to cross reference these genes to Alzheimer’s Disease genome‐wide association studies to provide potential therapeutic targets for drug development.MethodHiPSC‐derived microglia precursor cells were transduced with the TKOv3 genome‐wide CRISPR/Cas9 knockout library and differentiated for two weeks to microglia in our recently published media. hiPSC‐microglia were then fed dead GFP/mCherry fluorescent labelled SH‐SY5Y neuronal cells as phagocytic meal. Phagocytosis proceeded for 6 hours before washing away non‐phagocytosed SH‐SY5Y, harvesting and fixing the hiPSC‐microglia. hiPSC‐microglia were sorted into high and low levels of phagocytosis by fluorescent activated cell sorting (FACS) for single mCherry‐positive cells as GFP is quenched due to a low pH environment. Genomic DNA was extracted from sorted cell populations and the integrated guide RNA were sequenced by Illumina Novoseq.ResultMicroglia were successfully transduced at a multiplicity of infection at 0.7 to maximize single guide integration. Successful phagocytosis was observed via FACS, with over 60% of hiPSC‐microglia phagocytosing dead neurons after 6 hours. Four populations of varying levels of phagocytosis were harvested and genomic DNA extracted and sequenced.ConclusionWe have developed a pipeline for the first successful genome‐wide CRISPR knockout screening in hiPSC‐microglia and have used this to identify regulators of phagocytosis.

Curcumin mitigates the sleep-deprivation impacts on rat hypothalamic paraventricular nucleus

IntroductionThe paraventricular nucleus of the hypothalamus (PVH) is an important efferent system that relays the circadian rhythm of sleep and stress information to the periphery. Chronic REM sleep deprivation (CSD) is thought to damage this system. We evaluated the effects of CSD after 21 days on the spatial arrangement of PVH in male rats and the anti-apoptotic effects of curcumin on cell loss in sleep-deprived rats. MethodsThe rats received 1 mL of 100 mg/kg/day of curcumin in 3 groups: the CSD (through a modified multiple platform apparatus, 18 h/day), grid-floor control, and cage-control along with the same set of matched groups which received 1 mL PBS. In the grid-floor control group, as a control for CSD, animals were placed on stainless-steel-mesh grids positioned upon the CSD apparatus and then allowed to sustain the chance to sleep. After 21 days, their brains were removed for stereological estimations, Voronoi tessellation, and TUNEL assay. In an unbiased stereological approach, Cavalieri’s principle and an optical disector were used for estimating the volume and total cell number of the PVH, respectively. The Voronoi tessellation was measured using Image J software. ResultsSignificant reductions (P < 0.05) in the PVH volume and cell number, along with an increase in dead neurons, were found in CSD animals. The spatial pattern of two types of PVH neurons (parvocellular and magnocellular) showed random distributions after CSD, whereas curcumin not only increased the volume and neuronal number but also retrieved the spatial distribution to a regular one. ConclusionsCSD decreased the volume and altered the spatial arrangement of the neurons in PVH by increasing apoptosis and decreasing the cell number. However, oral use of curcumin could protect PVH from these changes.

Memristor neurons and their coupling networks based on Edge of Chaos Kernel

Chua's theory of local activity shows that local activity is the origin of complexity, and the complexity can only occur on or near the stable locally active domain, referred to as Edge of Chaos (EOC). Very recently, for the voltage-controlled locally active memristors, a new physical concept dubbed “Edge of Chaos Kernel” (EOCK), which consists of a series combination between a negative resistance and a negative inductance and exhibits the EOC phenomenon of being stable yet potentially unstable, was defined and applied to the Hodgkin-Huxley neural circuit model. When an EOCK is coupled to a passive environment, its stability is disrupted, resulting in the emergence of action potentials, chaos and various complex phenomena. This paper proposes the dual version of the EOCK called as R-C EOCK, which consists of the parallel combination between a negative resistance and a negative capacitance. We show that the actual NbO memristor manufactured by NaMLab essentially belongs to a current-controlled locally active memristor which contains a R-C EOCK and gives the signature of its EOCK and EOC. We construct a second-order neuron based on the NbO memristor when connected in parallel with a passive capacitor, and further prove that only memristors endowed with an EOCK can generate action potential. On this basis, we construct a minimum cellular neural network with only 7 components based on two NbO memristor neurons and a passive coupling resistor, in which neuromorphic behaviors of static and dynamic pattern formation may emerge if and only if the single neuron has an EOCK and is poised on the EOC. The analysis in this paper explains the dynamic mechanism of Smale's paradox, in which two mathematically dead neurons coupled by a passive environment may become alive, under the same or different input current excitation, which are more in line with the actual biological neural networks.

Lightweight spiking neural network training based on spike timing dependent backpropagation

Spiking neural networks are energy efficient and biological interpretability, communicating through sparse, asynchronous spikes, which makes them suitable for neuromorphic hardware. However, due to the nature of binary weights and spike trains in time-coded binarized spiking neural networks, their forward propagation may cause neurons to not fire spikes, and their backward propagation has non-differentiable problems. Moreover, the current use of deep and complex network structures generates a large number of redundant parameters. Therefore, we need effective methods to improve energy efficiency without reducing accuracy. We propose a dynamic threshold model that can reduce the number of dead neurons. We combine the backpropagation algorithm and the spike timing dependent plasticity algorithm to avoid the non-differentiable problem. We propose a neuron pruning strategy based on adaptive firing time threshold. This pruning strategy prunes 267 neurons in a network of 600 neurons, reducing the network size and obtaining a more compact network structure. The energy efficiency is improved by 0.55×, while the classification accuracy is lost by 1.1%.

Nasal administration of anti-CD3 monoclonal antibody ameliorates disease in a mouse model of Alzheimer’s disease

Emerging evidence suggests that dysregulation of neuroinflammation, particularly that orchestrated by microglia, plays a significant role in the pathogenesis of Alzheimer's disease (AD). Danger signals including dead neurons, dystrophic axons, phosphorylated tau, and amyloid plaques alter the functional phenotype of microglia from a homeostatic (M0) to a neurodegenerative or disease-associated phenotype, which in turn drives neuroinflammation and promotes disease. Thus, therapies that target microglia activation constitute a unique approach for treating AD. Here, we report that nasally administered anti-CD3 monoclonal antibody in the 3xTg AD mouse model reduced microglial activation and improved cognition independent of amyloid beta deposition. In addition, gene expression analysis demonstrated decreased oxidative stress, increased axogenesis and synaptic organization, and metabolic changes in the hippocampus and cortex of nasal anti-CD3 treated animals. The beneficial effect of nasal anti-CD3 was associated with the accumulation of T cells in the brain where they were in close contact with microglial cells. Taken together, our findings identify nasal anti-CD3 as a unique form of immunotherapy to treat Alzheimer's disease independent of amyloid beta targeting.

Omarigliptin inhibits brain cell ferroptosis after intracerebral hemorrhage

Intracerebral hemorrhage (ICH) is a disastrous disease without effective treatment. An extensive body of evidence indicate that neuronal ferroptosis is a key contributor to neurological disfunctions after ICH. Omarigliptin, also known as MK3102, is an anti-diabetic drug that inhibits dipeptidyl peptidase (DPP4). Recently, MK3102 is reported to exhibit anti-ferroptosis and anti-oxidative effects in different pathological conditions. However, the anti-ferroptosis ability of MK3102 in ICH injury is unknown. Hemin was administrated to model ICH injury in cultured primary cortical neurons, and collagenase VII was used to induce ICH in C57BL/6 mice. MK3102 was administered after ICH. Cell Counting Kit-8 (CCK-8) was applied to detect cell viability. Neurological functions were assessed through the Focal deficits neurological scores and corner test. HE and TUNEL staining was applied to evaluate brain damage areas and cell death, respectively. Ferroptosis was evaluated in cultured neurons by fluorescent probe DCFH-DA, FerroOrange, Liperfluo and immunofluorescence of GPX4, AIFM2 and FACL4. Perls staining was performed to visualize Fe3+ deposition. Ferroptosis-related proteins in mouse brain were measured by immunohistochemistry and western blotting. MK3102 reduced the neurotoxicity of hemin in cultured primary cortical neurons. It improved neurological functions associated with a decrease in the number of dead neurons and the area of brain damage after ICH in mice. Moreover, MK3102 prominently upregulated glucagon-like peptide-1 receptor (GLP-1R) levels after ICH. In addition, the elevation of iron content, lipid peroxidation and FACL4 after ICH; and reduction of GPX4 and AIFM2; were mitigated by MK3102 in vitro and in vivo. The neuroprotective effect of MK3102 may be related to anti-ferroptosis by regulating GLP-1R after ICH injury.