Cortex Injury Research Articles

Chlorogenic acid alleviates cadmium-induced neuronal injury in chicken cerebral cortex by inhibiting incomplete autophagy mediated by AMPK-ULK1 pathway

Cadmium (Cd) is an environmental pollutant that has neurotoxic properties, which poses serious threats to human health and the development of poultry farming. Chlorogenic acid (CGA) is a dietary polyphenol exhibit various biological activities such as antioxidant, anti-inflammatory, and autophagy regulation. In addition, CGA can penetrate the blood-brain barrier and exert neuroprotective effects. This study explored the mechanism of CGA in alleviating Cd-induced cerebral cortical neuron injury in chickens. The results showed that in vivo, CGA reduced the Cd level and alleviated Cd-induced histopathological and ultrastructural damages in the chicken cerebral cortex. Further research has found that CGA alleviated Cd-induced incomplete autophagy and activation of the AMPK-ULK1 pathway. In vitro, AMPK inhibitors (Compound C) could alleviate Cd-induced incomplete autophagy in chicken cerebral cortical neurons. In addition, CGA alleviated the decreased viability, incomplete autophagy, and activation of the AMPK-ULK1 pathway induced by Cd in chicken cerebral cortical neurons. In summary, CGA can alleviate Cd-induced cerebral cortical neuron injury in chickens, which is related to CGA alleviating Cd-induced incomplete autophagy by inhibiting the AMPK-ULK1 pathway.

Imaging the large-scale and cellular response to focal traumatic brain injury in mouse neocortex.

Traumatic brain injury (TBI) affects neural function at the local injury site and also at distant, connected brain areas. However, the real-time neural dynamics in response to injury and subsequent effects on sensory processing and behaviour are not fully resolved, especially across a range of spatial scales. We used in vivo calcium imaging in awake, head-restrained male and female mice to measure large-scale and cellular resolution neuronal activation, respectively, in response to a mild/moderate TBI induced by focal controlled cortical impact (CCI) injury of the motor cortex (M1). Widefield imaging revealed an immediate CCI-induced activation at the injury site, followed by a massive slow wave of calcium signal activation that travelled across the majority of the dorsal cortex within approximately 30s. Correspondingly, two-photon calcium imaging in the primary somatosensory cortex (S1) found strong activation of neuropil and neuronal populations during the CCI-induced travelling wave. A depression of calcium signals followed the wave, during which we observed the atypical activity of a sparse population of S1 neurons. Longitudinal imaging in the hours and days after CCI revealed increases in the area of whisker-evoked sensory maps at early time points, in parallel to decreases in cortical functional connectivity and behavioural measures. Neural and behavioural changes mostly recovered over hours to days in our M1-TBI model, with a more lasting decrease in the number of active S1 neurons. Our results in unanaesthetized mice describe novel spatial and temporal neural adaptations that occur at cortical sites remote to a focal brain injury.

Impact of intracranial hypertension and cerebral perfusion pressure on spreading depolarization.

Spreading depolarization (SD) develops after stroke and traumatic brain injury and may contribute to secondary brain damage. These diseases are often accompanied by intracranial hypertension, but little is known about the effects of intracranial pressure (ICP) on SD. Here, we study the effect of increased ICP on hemodynamic and metabolic response to SD in rats. SDs were triggered at different ICPs and cerebral perfusion pressures (CPP). The regional cerebral blood flow (rCBF), partial pressure of brain tissue oxygen (PbtO2), cerebral extracellular glucose and lactate concentrations were recorded. Fluoro-Jade staining was used to quantify neuronal injury in cortex. At high ICP (50 mmHg) with low CPP (30 mmHg), rCBF and PbtO2 were monophasically decreased in contrast to a monophasically increased pattern under normal conditions. Neuronal death increased in both hemispheres but much more on the side where SDs were triggered. At high ICP (50 mmHg) with normal CPP (70 mmHg), CBF and metabolism during SD did not differ from baseline, and neuronal death did not increase even on the side of SD induction. These data suggest that maintaining CPP at 70 mmHg, even when the ICP is as high as 50 mmHg, preserves normal blood flow and metabolism during SD events and prevents neuronal degeneration.

Microglia ameliorate delirium-like phenotypes in a murine model of acute ventilator-induced lung injury

BackgroundDelirium affects 50–85% of patients on mechanical ventilation and is associated with increased mortality, prolonged hospitalization, and a three-fold higher risk of dementia. Microglia, the resident immune cells of the brain, exhibit both neuroprotective and neurotoxic functions; however, their effects in mechanical ventilation-induced acute lung injury (VILI) are unknown. We hypothesize that in a model of short-term VILI, microglia play a neuroprotective role to ameliorate delirium-like phenotypes.MethodsMicroglia depletion (n = 18) was accomplished using an orally administered colony stimulating factor 1 receptor inhibitor, while controls received a vehicle diet (n = 18). We then compared extent of neuronal injury in the frontal cortex and hippocampus using cleaved caspase-3 (CC3) and multiple delirium-like behaviors in microglia depleted and non-microglia depleted male mice (C57BL/6 J aged 4–9 months) following VILI. Delirium-like behaviors were evaluated using the Open Field, Elevated Plus Maze, and Y-maze assays. We subsequently evaluated whether repopulation of microglia (n = 14 repopulation, 14 vehicle) restored the phenotypes.ResultsFrontal/hippocampal neuronal CC3 levels were significantly higher in microglia depleted VILI mice compared to vehicle-treated VILI controls (p < 0.01, p < 0.01, respectively). These structural changes were accompanied by worse delirium-like behaviors in microglia depleted VILI mice compared to vehicle controls. Specifically, microglia depleted VILI mice demonstrated: (1) significantly increased time in the periphery of the Open Field (p = 0.01), (2) significantly increased coefficient of variation (p = 0.02), (3) trend towards reduced time in the open arms of the Elevated Plus Maze (p = 0.09), and (4) significantly decreased spontaneous alternations on Y-maze (p < 0.01). There was a significant inverse correlation between frontal CC3 and percent spontaneous alternations (R2 = 0.51, p < 0.01). Microglia repopulation showed a near-complete return to vehicle levels of delirium like-behaviors.ConclusionsThis study demonstrates that microglia depletion exacerbates structural and functional delirium-like phenotypes after VILI, while subsequent repopulation of microglia restores these phenotypes. These findings suggest a neuroprotective role for microglia in ameliorating neuronal and functional delirium-like phenotypes and call for consideration of interventions that leverage endogenous microglia physiology to mitigate delirium.

Imaging the large-scale and cellular response to focal traumatic brain injury in mouse neocortex.

Traumatic brain injury (TBI) affects neural function at the local injury site and also at distant, connected brain areas. However, the real-time neural dynamics in response to injury and subsequent effects on sensory processing and behavior are not fully resolved, especially across a range of spatial scales. We used in vivo calcium imaging in awake, head-restrained male and female mice to measure large-scale and cellular resolution neuronal activation, respectively, in response to a mild/moderate TBI induced by focal controlled cortical impact (CCI) injury of the motor cortex (M1). Widefield imaging revealed an immediate CCI-induced activation at the injury site, followed by a massive slow wave of calcium signal activation that traveled across the majority of the dorsal cortex within approximately 30 s. Correspondingly, two-photon calcium imaging in primary somatosensory cortex (S1) found strong activation of neuropil and neuronal populations during the CCI-induced traveling wave. A depression of calcium signals followed the wave, during which we observed atypical activity of a sparse population of S1 neurons. Longitudinal imaging in the hours and days after CCI revealed increases in the area of whisker-evoked sensory maps at early time points, in parallel to decreases in cortical functional connectivity and behavioral measures. Neural and behavioral changes mostly recovered over hours to days in our M1-TBI model, with a more lasting decrease in the number of active S1 neurons. Our results in unanesthetized mice describe novel spatial and temporal neural adaptations that occur at cortical sites remote to a focal brain injury.

Amelioration of behavioral and histological impairments in somatosensory cortex injury rats by limbal mesenchymal stem cell transplantation.

Cortical lesions can cause major sensory and motor impairments, representing a significant challenge in neuroscience and clinical medicine. Limbal mesenchymal stem cells (LMSCs), renowned for their remarkable ability to proliferate and distinct characteristics within the corneal epithelium, offer a promising opportunity for regenerative treatments. This study aimed to assess whether the transplantation of LMSCs could improve tactile ability in rats with lesions of the barrel cortex. In this experimental study, we divided 21 rats into three groups: a control group, a lesion group with cortical cold lesion induction but no stem cell treatment, and a group receiving LMSC transplantation following cold lesion induction. We conducted 3-week sensory assessments using a texture discrimination test and an open-field test. We also performed Nissl staining to assess changes on the cellular level. Rats in the LMSC transplantation group demonstrated significant improvements in their ability to discrimination textures during the second and third weeks compared to those in the lesion group. The open-field test results showed an increased exploratory behavior of rats in the LMSC transplantation group by the third week compared to the lesion group. Additionally, Nissl staining revealed cellular alterations in the damaged cortex, with a significant distinction observed between rats in the LMSCs and lesion group. The findings suggest that LMSC transplantation enhances sensory recovery in rats with cortical lesions, particularly their ability to discriminate textures. LMSC transplantation benefits brain tissue reparation after a cold lesion on the somatosensory cortex.

Changes in Noradrenergic Synthesis and Dopamine Beta-Hydroxylase Activity in Response to Oxidative Stress after Iron-induced Brain Injury.

Noradrenaline (NA) levels are altered during the first hours and several days after cortical injury. NA modulates motor functional recovery. The present study investigated whether iron-induced cortical injury modulated noradrenergic synthesis and dopamine beta-hydroxylase (DBH) activity in response to oxidative stress in the brain cortex, pons and cerebellum of the rat. Seventy-eight rats were divided into two groups: (a) the sham group, which received an intracortical injection of a vehicle solution; and (b) the injured group, which received an intracortical injection of ferrous chloride. Motor deficits were evaluated for 20 days post-injury. On the 3rd and 20th days, the rats were euthanized to measure oxidative stress indicators (reactive oxygen species (ROS), reduced glutathione (GSH) and oxidized glutathione (GSSG)) and catecholamines (NA, dopamine (DA)), plus DBH mRNA and protein levels. Our results showed that iron-induced brain cortex injury increased noradrenergic synthesis and DBH activity in the brain cortex, pons and cerebellum at 3 days post-injury, predominantly on the ipsilateral side to the injury, in response to oxidative stress. A compensatory increase in contralateral noradrenergic activity was observed, but without changes in the DBH mRNA and protein levels in the cerebellum and pons. In conclusion, iron-induced cortical injury increased the noradrenergic response in the brain cortex, pons and cerebellum, particularly on the ipsilateral side, accompanied by a compensatory response on the contralateral side. The oxidative stress was countered by antioxidant activity, which favored functional recovery following motor deficits.

Reduced ischemia‐reperfusion oxidative stress injury by melatonin and N‐acetylcysteine in the male rat brain

Middle cerebral artery occlusion (MCAO) is a model for inducing ischemic stroke in rodents, leading to devastating brain damage. Oxidative stress (OS) plays a crucial role in the pathogenesis of ischemia. In this study, the effect of melatonin and N-acetylcysteine on ischemia-reperfusion-induced oxidative stress injury in the cerebral cortex of male rats was investigated. 30 male Wistar rats were divided into sham, ischemic, NAC, melatonin and NAC + melatonin groups. All groups, except the sham group, underwent MCAO on the left side, and the treatment groups received intraperitoneal injections of either 50 mg/kg N-acetylcysteine (NAC) or 5 mg/kg melatonin or a combination of both 24 and 48 hours later. At 24 and 72 hours after surgery, the animals were examined for sensory and motor activity. The cerebral cortex was dissected after sacrificing the rats, infarct volume estimated and the concentrations of glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA) and nuclear factor erythroid-2 related factor 2 (Nrf2) were analyzed by enzyme-linked immunosorbent assay (ELISA). The results indicate that the NAC + melatonin group exhibited elevated sensory-motor activity and a reduced infarct volume rate in comparison to the ischemic group (p≤ 0.05). Compared to the ischemic group, the NAC + melatonin group showed a significant increase in SOD concentration and a significant decrease in MDA (p≤ 0.05). It can therefore be concluded that the simultaneous administration of NAC and melatonin can reduce the cerebral infarction volume, and improve neurological functions by modulating SOD and MDA.

Activation of adult endogenous neurogenesis by a hyaluronic acid collagen gel containing basic fibroblast growth factor promotes remodeling and functional recovery of the injured cerebral cortex.

JOURNAL/nrgr/04.03/01300535-202510000-00024/figure1/v/2024-11-26T163120Z/r/image-tiff The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury. However, whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions, such as the cortex, remains unknown. In this study, we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury. Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells, as well as their differentiation into mature and functionally integrated neurons. Importantly, these new neurons reconstructed the architecture of cortical layers II to VI, integrated into the existing neural circuitry, and ultimately led to improved brain function. These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries.

Repeated mild traumatic brain injury in the parietal cortex inhibits expressions of NLG-1 and PSD-95 in the medulla oblongata of mice

To assess the effects of repeated mild traumatic brain injury (rmTBI) in the parietal cortex on neuronal morphology and synaptic plasticity in the medulla oblongata of mice. Thirty-two male ICR mice were randomly divided into sham operation group (n=8) and rmTBI group (n=24). The mice in the latter group were subjected to repeated mild impact injury of the parietal cortex by a free-falling object. The mice surviving the injuries were evaluated for neurological deficits using neurological severity scores (NSS), righting reflex test and forced swimming test, and pathological changes of the neuronal cells in the medulla oblongata were observed with HE and Nissl staining. Western blotting and immunofluorescence staining were used to detect the expressions of neuroligin 1(NLG-1) and postsynaptic density protein 95(PSD-95) in the medulla oblongata of the mice that either survived rmTBI or not. None of the mice in the sham-operated group died, while the mortality rate was 41.67% in rmTBI group. The mice surviving rmTBI showed significantly reduced NSS, delayed recovery of righting reflex, increased immobility time in forced swimming test (P < 0.05), and loss of Nissl bodies; swelling and necrosis were observed in a large number of neurons in the medulla oblongata, where the expression levels of NLG-1 and PSD-95 were significantly downregulated (P < 0.05). The mice that did not survive rmTBI showed distorted and swelling nerve fibers and decreased density of neurons in the medulla oblongina with lowered expression levels of NLG-1 and PSD-95 compared with the mice surviving the injuries (P < 0.01). The structural and functional anomalies of the synapses in the medulla oblongata may contribute to death and neurological impairment following rmTBI in mice.

Remazolam affects the phenotype and function of astrocytes to improve traumatic brain injury by regulating the Cx43

PurposeTo explore the mechanism by which Remazolam affects the phenotype and function of astrocytes to improve traumatic brain injury (TBI). MethodsThe oxygen -glucose deprivation/recovery (OGD/R) cell model was constructed to simulate the pathological state of astrocytes in a TBI environment. The viability of astrocytes was measured by CCK-8, and the cytoskeleton changes were observed by Phalloidin- TRITC staining. The expressions of differentiation markers, Cx43 and phosphorylated Cx43 (P-Cx43) of A1/A2 astrocytes were detected by Western blot, and the complement C3 and S100A10 of A1/A2 astrocytes were detected by ELISA. The TBI rat model was established. The water content of brain tissue was measured by dry-wet specific gravity method, the pathological morphology of brain tissue in cortical injury area was observed by HE staining method, ROS was detected by fluorescence quantitative method, Cx43 expression was detected by immunohistochemistry method, and the differentiation markers of A1/A2 astrocytes were detected by immunofluorescence. ResultsIn the TBI environment, astrocytes showed decreased cell viability, blurred skeleton, and increased expression of Cx43. In TBI rats, the water content of brain tissue increased, the brain tissue in the cortex injury area was seriously damaged, ROS and Cx43 expression were significantly increased, and mainly distributed in A2 astrocytes. Remazolam can reverse the above results after the intervention. ConclusionRemazolam affects the phenotype and function of astrocytes to improve TBI via regulating Cx43, and plays a role in protecting the neurological function of TBI rats.

Mechanisms of COVID-19-associated olfactory dysfunction.

Olfactory dysfunction is one of the most common symptoms of COVID-19. In the first 2 years of the pandemic, it was frequently reported, although its incidence has significantly decreased with the emergence of the Omicron variant, which has since become the dominant viral strain. Nevertheless, many patients continue to suffer from persistent dysosmia and dysgeusia, making COVID-19-associated olfactory dysfunction an ongoing health concern. The proposed pathogenic mechanisms of COVID-19-associated olfactory dysfunction are complex and likely multifactorial. While evidence suggests that infection of sustentacular cells and associated mucosal inflammation may be the culprit of acute, transient smell loss, alterations in other components of the olfactory system (e.g., olfactory receptor neuron dysfunction, olfactory bulb injury and alterations in the olfactory cortex) may lead to persistent, long-term olfactory dysfunction. This review aims to provide a comprehensive summary of the epidemiology, clinical manifestations and current understanding of the pathogenic mechanisms of COVID-19-associated olfactory dysfunction.

Non-severe thermal burn injuries induce long-lasting downregulation of gene expression in cortical excitatory neurons and microglia.

Burn injuries are devastating traumas, often leading to life-long consequences that extend beyond the observable burn scar. In the context of the nervous system, burn injury patients commonly develop chronic neurological disorders and have been suggested to have impaired motor cortex function, but the long-lasting impact on neurons and glia in the brain is unknown. Using a mouse model of non-severe burn injury, excitatory and inhibitory neurons in the primary motor cortex were labelled with fluorescent proteins using adeno-associated viruses (AAVs). A total of 5 weeks following the burn injury, virus labelled excitatory and inhibitory neurons were isolated using fluorescence-activated cell sorting (FACS). In addition, microglia and astrocytes from the remaining cortical tissue caudal to the motor cortex were immunolabelled and isolated with FACS. Whole transcriptome RNA-sequencing was used to identify any long-lasting changes to gene expression in the different cell types. RNA-seq analysis showed changes to the expression of a small number of genes with known functions in excitatory neurons and microglia, but not in inhibitory neurons or astrocytes. Specifically, genes related to GABA-A receptors in excitatory neurons and several cellular functions in microglia were found to be downregulated in burn injured mice. These findings suggest that non-severe burn injuries lead to long lasting transcriptomic changes in the brain, but only in specific cell types. Our findings provide a broad overview of the long-lasting impact of burn injuries on the central nervous system which may help identify potential therapeutic targets to prevent neurological dysfunction in burn patients.

Effect of Naotaifang on microglial polarization and glial scar following cerebral ischemia reperfusion injury

This study aims to investigate the effect of Naotaifang(NTF) on the proteins associated with microglial polarization and glial scar in the rat model of cerebral ischemia reperfusion injury(CIRI). The CIRI model was established by middle cerebral artery occlusion/reperfusion. The 48 successfully modeled rats were randomized into model 7 d, model 14 d, NTF 7 d, and NTF 14 d groups(n=12). In addition, 12 SD rats were selected as the sham group. The NTF group was administrated with NTF suspension at 27 g·kg~(-1)·d~(-1) by gavage, and the sham, model 7 d, and model 14 d groups were administrated with the same volume of normal saline every day by gavage for 7 and 14 days, respectively. After the intervention, Longa score was evaluated. The infarct volume was measured by 2,3,5-triphenyl-2H-tetrazolium chloride(TTC) staining. Morris water maze and open field tests were carried out to evaluate the spatial learning, memory, cognitive function, and anxiety degree of rats. Hematoxylin-eosin(HE) staining was employed to observe the morphological structure and damage of the brain tissue. The immunofluorescence assay was employed to measure the expression of glial fibrillary acidic protein(GFAP) and glial scar. Western blot was employed to determine the protein levels of GFAP, neurocan, phosphacan, CD206, arginase-1(Arg-1), interleukin(IL)-1β, IL-6, and IL-4. Compared with the sham, model 7 d and model 14 d groups showed cerebral infarction of different degrees, severe pathological injury of cerebral cortex and hippocampus, neurological impairment, reduced spatial learning and memory, cognitive dysfunction, severe anxiety, astrocyte hyperplasia, thickening penumbra glial scar, and up-regulated protein levels of IL-1β, IL-6, GFAP, neurocan, phosphacan, CD206, and Arg-1(P&lt;0.01). Compared with the model group, NTF 7 d and NTF 14 d groups improved spatial learning, memory, and cognitive function, reduced anxiety, improved nerve function, reduced cerebral infarction volume, reduced astrocyte hyperplasia, thinned penumbra glial scar, down-regulated the protein levels of GFAP, neurocan, phosphacan, IL-6, and IL-1β, and up-regulated the protein levels of IL-4, CD206, and Arg-1(P&lt;0.05 or P&lt;0.01). NTF exerts a neuroprotective effect on CIRI by inducing the M2 polarization of microglia, inhibiting inflammatory response, and reducing the formation of glial scar.

Hypercapnia Causes Injury of the Cerebral Cortex and Cognitive Deficits in Newborn Piglets.

In critically ill newborns, exposure to hypercapnia (HC) is common and often accepted in neonatal intensive care units to prevent severe lung injury. However, as a "safe" range of arterial partial pressure of carbon dioxide levels in neonates has not been established, the potential impact of HC on the neurodevelopmental outcomes in these newborns remains a matter of concern. Here, in a newborn Yorkshire piglet model of either sex, we show that acute exposure to HC induced persistent cortical neuronal injury, associated cognitive and learning deficits, and long-term suppression of cortical electroencephalogram frequencies. HC induced a transient energy failure in cortical neurons, a persistent dysregulation of calcium-dependent proapoptotic signaling in the cerebral cortex, and activation of the apoptotic cascade, leading to nuclear deoxyribonucleic acid fragmentation. While neither 1 h of HC nor the rapid normalization of HC was associated with changes in cortical bioenergetics, rapid resuscitation resulted in a delayed onset of synaptosomal membrane lipid peroxidation, suggesting a dissociation between energy failure and the occurrence of synaptosomal lipid peroxidation. Even short durations of HC triggered biochemical responses at the subcellular level of the cortical neurons resulting in altered cortical activity and impaired neurobehavior. The deleterious effects of HC on the developing brain should be carefully considered as crucial elements of clinical decisions in the neonatal intensive care unit.

Adaptation of the layer V supraspinal motor corticofugal projections from the primary (M1) and premotor (PM) cortices after CNS motor disorders in non-human primates: A survey.

Motor commands are transmitted from the motor cortical areas to effectors mostly via the corticospinal (CS) projection. Several subcortical motor nuclei also play an important role in motor control, the subthalamic nucleus, the red nucleus, the reticular nucleus and the superior colliculus. These nuclei are influenced by motor cortical areas via respective corticofugal projections, which undergo complex adaptations after motor trauma (spinal cord/motor cortex injury) or motor disease (Parkinson), both in the absence or presence of putative treatments, as observed in adult macaque monkeys. A dominant effect was a nearly complete suppression of the corticorubral projection density and a strong downregulation of the corticoreticular projection density, with the noticeable exception in the latter case of a considerable increase of projection density following spinal cord injury, even enhanced when an anti-NogoA antibody treatment was administered. The effects were diverse and less prominent on the corticotectal and corticosubthalamic projections. The CS projection may still be the major efferent pathway through which motor adaptations can take place after motor trauma or disease. However, the parallel supraspinal motor corticofugal projections may also participate in connectional adaptations supporting the functional recovery of motor abilities, representing potential targets for future clinical strategies, such as selective electrical neurostimulations.

Relationship between Aspartame-Induced Cerebral Cortex Injury and Oxidative Stress, Inflammation, Mitochondrial Dysfunction, and Apoptosis in Sprague Dawley Rats.

There are emerging concerns about the potential cerebral cortex injury from aspartame due to the accumulation of the various neurotoxic metabolic components in the central nervous system after long-term dietary exposure. The aim of this study was to evaluate the effect of oral aspartame consumption on cerebral cortex injury in the rat brain, and further evaluate the various underlying molecular mechanisms, with a special focus on oxidative stress, inflammation, mitochondrial dysfunction, and apoptosis pathways. Sprague Dawley rats (nineteen, female) were randomly sub-divided into three groups: (i) normal diet with vehicle: control group (five rats), (ii) low dose of aspartame group (LA): seven rats received 30 mg/kg body weight (bw) daily doses of aspartame, (iii) high dose of aspartame group (HA): seven rats received 60 mg/kg bw daily doses of aspartame. After 8 weeks, the LA and HA groups showed lower expression levels of brain-derived neurotrophic factor (BDNF), antioxidant enzyme activity (SOD2, CAT), antioxidant marker (Nrf2), inflammatory response (IκB), mitochondrial biogenesis (Sirt1, PGC1α, Nrf1, TFAM), mitochondrial DNA (mtDNA) copy number, and apoptosis-related proteins (Bax, Caspase-3) expressions. Aspartame administration also elevated oxidative stress levels (Malondialdehyde, MDA), 8-hydroxy-2-deoxy guanosine (8-OHdG), PGE2 and COX-2 expressions, pro-inflammatory cytokines (TNFα, IL6, IL1β), antioxidant marker expression (Keap1), inflammatory responses (iNOS, NFκB), and glial fibrillary acidic protein (GFAP) levels in the cerebral cortex of the rats, thereby contributing to the reduced survival of pyramidal cells and astrocyte glial cells of the cerebral cortex. Therefore, these findings imply that aspartame-induced neurotoxicity in rats' cerebral cortex could be regulated through four mechanisms: inflammation, enhanced oxidant stress, decreased mitochondrial biogenesis, and apoptosis pathways.

Overexpress miR-132 in the Brain Parenchyma by a Non-invasive Way Improves Tissue Repairment and Releases Memory Impairment After Traumatic Brain Injury.

Traumatic brain injury (TBI) is a serious public health problem worldwide, which could lead to an extremely high percentage of mortality and disability. Current treatment strategies mainly concentrate on neuronal protection and reconstruction, among them, exogenous neural stem cell (NSC) transplantation has long been regarded as the most effective curative treatment. However, due to secondary trauma, transplant rejection, and increased incidence of brain malignant tumor, a non-invasive therapy that enhanced endogenous neurogenesis was more suitable for TBI treatment. Our previous work has shown that miR-132 overexpression could improve neuronal differentiation of NSCs in vitro and in vivo. So, we engineered a new kind of AAV vector named AAV-PHP.eB which can transfect brain parenchyma through intravenous injection to overexpress miR-132 in brain after TBI. We found that miR-132 overexpression could reduce impact volume, promote neurogenesis in the dentate gyrus (DG), accelerate neuroblast migrating into the impact cortex, ameliorate microglia-mediated inflammatory reaction, and ultimately restore learning memory function. Our results revealed that AAV-PHP.eB-based miR-132 overexpression could improve endogenous tissue repairment and release clinical symptoms after traumatic brain injury. This work would provide a new therapeutic strategy for TBI treatment and other neurological disorders characterized by markable neuronal loss and memory impairment. miR-132 overexpression accelerates endogenous neurogenesis and releases TBI-induced tissue repairment and memory impairment. Controlled cortical impact onto the cortex would induce serious cortical injury and microglia accumulation in both cortex and hippocampus. Moreover, endogenous neuroblast could migrate around the injury core. miR-132 overexpression could accelerate neuroblast migration toward the injury core and decreased microglia accumulation in the ipsilateral cortex and hippocampus. miR-132 could be a suitable target on neuroprotective therapy after TBI.

Dynamics of functional impairments during focal transient ischemia in three-dimensional cortical space

Ischemic injury in the cerebral cortex results in decreased electrical activity across all frequency bands and the emergence of abnormal electrophysiological patterns, including spreading depolarization (SD) and negative ultraslow potential (NUP) [1, 2]. Despite this, the specific dynamics of these changes in electrical activity within the three-dimensional cortical space during ischemia remain incompletely described and poorly understood. To simultaneously investigate changes in electrical activity across the layers of the cerebral cortex and in the horizontal cortical space, we used two linear 16-channel silicone probes (Neuronexus, USA) in combination with a flexible transparent 60-channel matrix of subdural electrodes (MIPT, Russia) and intrinsic optical signal imaging (IOS, 665 nm, transillumination mode) during focal ischemia induced by intracortical injection of the potent vasoconstrictor endothelin-1 (ET-1, 1 μL, 1 μM). These experiments were carried out in head-restrained rats under urethane anesthesia (1.5 g/kg). Formation of the ischemic lesion following ET-1 administration was correlated with clusters of SDs that demonstrated considerable variability in their propagation patterns within both vertical and horizontal planes. The initial SDs originated from the injection site of ET-1 and diffused across all cortical layers. Subsequently, the initiation point of the ensuing SDs gradually shifted towards the deeper layers while the electrical activity showed inadequate recovery between SDs within the injection site. SDs originating in the surrounding cortex did not invade the area near the injection point. Instead, they tended to spread around, often compartmentalizing in the superficial layers of the cortex. Some SDs were observed deep in the cortex, while others were detected on the surface via superficial electrodes and IOS, without leaving typical intracortical electrode traces. Electrographic activity was significantly depressed, especially in the superficial layers around the injection site, three hours after ET-1 administration. However, it returned to pre-ET-1 levels at the remote site, with a spatial gradient observed in subdural electrodes. Functional impairments corresponded to the histological lesion observed in coronal brain sections. Recently discovered NUPs were initiated by SD and were most prominent in the electrodes closest to the ET-1 injection site. These NUPs reached their maximal amplitude at one hour and subsided three hours after ET-1 injection. Our research indicates intricate dynamics in the creation of an ischemic focal point. The data gathered suggest that the emergence of cerebral harm during focal ischemia is associated with the growth of a focus extending both horizontally and vertically across cortical dimensions. This growth is fueled by the generation of SDs within the ischemic penumbra.

Early-Stage Application of Agomir-137 Promotes Locomotor Recovery in a Mouse Model of Motor Cortex Injury.

Traumatic brain injury (TBI) is a significant risk factor for neurodegenerative disorders, and patients often experience varying degrees of motor impairment. MiR-137, a broadly conserved and brain-enriched miRNA, is a key regulator in neural development and in various neurological diseases. Following TBI, the expression of miR-137 is dramatically downregulated. However, whether miR-137 is a therapeutic target for TBI still remains unknown. Here, for the first time, we demonstrate that intranasal administration of miR-137 agomir (a mimic) in the early stage (0-7 days) of TBI effectively inhibits glial scar formation and improves neuronal survival, while early-stage administration of miR-137 antagomir (an inhibitor) deteriorates motor impairment. This study elucidates the therapeutic potential of miR-137 mimics in improving locomotor recovery following motor cortex injury.