Rodent Stroke Research Articles

Experience-driven competition in neural reorganization after stroke.

Behavioural experiences interact with regenerative responses to shape patterns of neural reorganization after stroke. This review is focused on the competitive nature of these behavioural experience effects. Interactions between learning-related plasticity and regenerative reactions have been found to underlie the establishment of new compensatory behaviours and the efficacy of motor rehabilitative training in rodent stroke models. Learning in intact brains depends on competitive and cooperative mechanisms of synaptic plasticity. Synapses are added in response to learning and selectively maintained and strengthened via activity-dependent competition. Long-term memories for experiences that occur closely in time can be weakened or enhanced by competitive or cooperative interactions in the time-dependent process of stabilizing synaptic changes. Rodent stroke model findings suggest that compensatory reliance on the non-paretic hand after stroke can shape and stabilize synaptic reorganization patterns in both hemispheres, to compete with the capacity for experiences of the paretic side to do so. However, the competitive edge of the non-paretic side can be countered by overlapping experiences of the paretic hand, and might even be shifted in a cooperative direction with skilfully coordinated bimanual experience. Advances in the basic understanding of learning-related synaptic competition are helping to inform the basis of experience-dependent variations in stroke outcome.

Single-nucleus RNA sequencing reveals glial cell type-specific responses to ischemic stroke in male rodents

Neuroglia critically shape the brain´s response to ischemic stroke. However, their phenotypic heterogeneity impedes a holistic understanding of the cellular composition of the early ischemic lesion. Here we present a single cell resolution transcriptomics dataset of the brain´s acute response to infarction. Oligodendrocyte lineage cells and astrocytes range among the most transcriptionally perturbed populations and exhibit infarction- and subtype-specific molecular signatures. Specifically, we find infarction restricted proliferating oligodendrocyte precursor cells (OPCs), mature oligodendrocytes and reactive astrocytes, exhibiting transcriptional commonalities in response to ischemic injury. OPCs and reactive astrocytes are involved in a shared immuno-glial cross talk with stroke-specific myeloid cells. Within the perilesional zone, osteopontin positive myeloid cells accumulate in close proximity to CD44+ proliferating OPCs and reactive astrocytes. In vitro, osteopontin increases the migratory capacity of OPCs. Collectively, our study highlights molecular cross talk events which might govern the cellular composition of acutely infarcted brain tissue.

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.

Amide proton transfer MRI at 9.4 T for differentiating tissue acidosis in a rodent model ofischemic stroke.

Differentiating ischemic brain damage is critical for decision making in acute stroke treatment for better outcomes. We examined the sensitivity of amide proton transfer (APT) MRI, a pH-weighted imaging technique, to achieve this differentiation. In a rat stroke model, the ischemic core, oligemia, and the infarct-growth region (IGR) were identified by tracking the progression of the lesions. APT MRI signals were measured alongside ADC, T1, and T2 maps to evaluate their sensitivity in distinguishing ischemic tissues. Additionally, stroke under hyperglycemic conditions was studied. The APT signal in the IGR decreased by about 10% shortly after stroke onset, and further decreased to 35% at 5 h, indicating a progression from mild to severe acidosis as the lesion evolved into infarction. Although ADC, T1, and T2 contrasts can only detect significant differences between the IGR and oligemia for a portion of the stroke duration, APT contrast consistently differentiates between them at all time points. However, the contrast to variation ratio at 1 h is only about 20% of the contrast to variation ratio between the core and normal tissues, indicating limited sensitivity. In the ischemic core, the APT signal decreases to about 45% and 33% of normal tissue level at 1 h for the normoglycemic and hyperglycemic groups, respectively, confirming more severe acidosis under hyperglycemia. The sensitivity of APT MRI is high in detecting severe acidosis of the ischemic core but is much lower in detecting mild acidosis, which may affect the accuracy of differentiation between the IGR and oligemia.

Chronic consequences of ischemic stroke: Profiling brain injury and inflammation in a mouse model with reperfusion.

Stroke is a pervasive and debilitating global health concern, necessitating innovative therapeutic strategies, especially during recovery. While existing literature often focuses on acute interventions, our study addresses the uniqueness of brain tissue during wound healing, emphasizing the chronic phase following the commonly used middle cerebral artery (MCA) occlusion model. Using clinically relevant endpoints in male and female mice such as magnetic resonance imaging (MRI) and plasma neurofilament light (NFL) measurement, along with immunohistochemistry, we describe injury evolution. Our findings document significant alterations in edema, tissue remodeling, and gadolinium leakage through MRI. Plasma NFL concentration remained elevated at 30 days poststroke. Microglia responses are confined to the region adjacent to the injury, rather than continued widespread activation, and boron-dipyrromethene (BODIPY) staining demonstrated the persistent presence of foam cells within the infarct. Additional immunohistochemistry highlighted sustained B and T lymphocyte presence in the poststroke brain. These observations underscore potentially pivotal roles played by chronic inflammation brought on by the lipid-rich brain environment, and chronic blood-brain barrier dysfunction, in the development of secondary neurodegeneration. This study sheds light on the enduring consequences of ischemic stroke in the most used rodent stroke model and provides valuable insights for future research, clinical strategies, and therapeutic development.

The case for neuregulin-1 as a clinical treatment for stroke.

Ischemic stroke is the leading cause of serious long-term disability and the 5th leading cause of death in the United States. Revascularization of the occluded cerebral artery, either by thrombolysis or endovascular thrombectomy, is the only effective, clinically-approved stroke therapy. Several potentially neuroprotective agents, including glutamate antagonists, anti-inflammatory compounds and free radical scavenging agents were shown to be effective neuroprotectants in preclinical animal models of brain ischemia. However, these compounds did not demonstrate efficacy in clinical trials with human patients following stroke. Proposed reasons for the translational failure include an insufficient understanding on the cellular and molecular pathophysiology of ischemic stroke, lack of alignment between preclinical and clinical studies and inappropriate design of clinical trials based on the preclinical findings. Therefore, novel neuroprotective treatments must be developed based on a clearer understanding of the complex spatiotemporal mechanisms of ischemic stroke and with proper clinical trial design based on the preclinical findings from specific animal models of stroke. We and others have demonstrated the clinical potential for neuregulin-1 (NRG-1) in preclinical stroke studies. NRG-1 significantly reduced ischemia-induced neuronal death, neuroinflammation and oxidative stress in rodent stroke models with a therapeutic window of >13 h. Clinically, NRG-1 was shown to be safe in human patients and improved cardiac function in multisite phase II studies for heart failure. This review summarizes previous stroke clinical candidates and provides evidence that NRG-1 represents a novel, safe, neuroprotective strategy that has potential therapeutic value in treating individuals after acute ischemic stroke.

NK1 tachykinin receptor antagonist treatment reduces cerebral edema and intracranial pressure in an ovine model of ischemic stroke

Following ischemic stroke, substance P (SP)-mediated neurogenic inflammation is associated with profound blood-brain barrier (BBB) dysfunction, cerebral edema, and elevated intracranial pressure (ICP). SP elicits its effects by binding the neurokinin 1 tachykinin receptor (NK1-R), with administration of an NK1-R antagonist shown to ameliorate BBB dysfunction and cerebral edema in rodent and permanent ovine stroke models. Given the importance of reperfusion in clinical stroke, this study examined the efficacy of NK1-R antagonist treatment in reducing cerebral edema and ICP in an ovine model of transient middle cerebral artery occlusion (tMCAo). Anesthetized sheep (n = 24) were subject to 2-hours tMCAo and randomized (n = 6/group) to receive early NK1-R treatment (days 1–3 post-stroke), delayed NK1-R treatment (day 5 post-stroke), or saline vehicle. At 6-days post-stroke animals were re-anaesthetized and ICP measured, followed by MRI to evaluate infarction, edema and BBB dysfunction. Following both early and delayed NK1-R antagonist administration, ICP was significantly reduced on day 6 compared to vehicle animals (p < 0.05), accompanied by a reduction in cerebral edema, midline shift and BBB dysfunction (p < 0.05). This study demonstrates that NK1-R antagonist treatment is an effective novel therapy for cerebral edema and elevated ICP following stroke in an ovine model, warranting future clinical evaluation.

Hi1a Improves Sensorimotor Deficit following Endothelin-1-Induced Stroke in Rats but Does Not Improve Functional Outcomes following Filament-Induced Stroke in Mice.

Activation of acid-sensing ion channel 1a (ASIC1a) plays a major role in mediating acidosis-induced neuronal injury following a stroke. Therefore, the inhibition of ASIC1a is a potential therapeutic avenue for the treatment of stroke. Venom-peptide Hi1a, a selective and highly potent ASIC1a inhibitor, reduces the infarct size and functional deficits when injected into the brain after stroke in rodents. However, its efficacy when administered using a clinically relevant route of administration remains to be established. Therefore, the current investigation aims to examine the efficacy of systemically administered Hi1a, using two different models of stroke in different species. Mice were subjected to the filament model of middle cerebral artery occlusion (MCAO) and treated with Hi1a systemically using either a single- or multiple-dosing regimen. 24 h poststroke, mice underwent functional testing, and the brain infarct size was assessed. Rats were subjected to endothelin-1 (ET-1)-induced MCAO and treated with Hi1a intravenously 2 h poststroke. Rats underwent functional tests prior to and for 3 days poststroke, when infarct volume was assessed. Mice receiving Hi1a did not show any improvements in functional outcomes, despite a trend toward reduced infarct size. This trend for reduced infarct size in mice was consistent regardless of the dosing regimen. There was also a trend toward lower infarct size in rats treated with Hi1a. More specifically, Hi1a reduced the amount of damage occurring within the somatosensory cortex, which was associated with an improved sensorimotor function in Hi1a-treated rats. Thus, this study suggests that Hi1a or more brain-permeable ASIC1a inhibitors are a potential stroke treatment.

The role of dorsolateral striatum in the effects of deep cerebellar stimulation-mediated motor recovery following ischemic stroke in rodents

Despite great advances in acute care and rehabilitation, stroke remains the leading cause of motor impairment in the industrialized world. We have developed a deep brain stimulation (DBS)-based approach for post-stroke rehabilitation that has shown reproducible effects in rodent models and has been recently translated to humans. Mechanisms underlying the rehabilitative effects of this novel therapy have been largely focused on the ipsilesional cortex, including cortical reorganization, synaptogenesis, neurogenesis and greater expression of markers of long-term potentiation. The role of subcortical structures on its therapeutic benefits, particularly the striatum, remain unclear. In this study, we compared the motor rehabilitative effects of deep cerebellar stimulation in two rodent models of cerebral ischemia: a) cortical ischemia; and b) combined striatal and cortical ischemia. All animals underwent the same procedures, including implantation of the electrodes and tethered connections for stimulation. Both experimental groups received four weeks of continuous lateral cerebellar nucleus (LCN) DBS and each was paired with a no stimulation, sham, group. Fine motor function was indexed using the pasta matrix task. Brain tissue was harvested for histology and immunohistochemical analyses. In the cortical-only ischemia, the average pasta matrix performance of both sham and stimulated groups reduced from 19 to 24 pieces to 7—8 pieces following the stroke induction. At the end of the four-week treatment, the performance of stimulated group was significantly greater than that of sham group (14 pieces vs 7 pieces, p < 0.0001). Similarly, in the combined cortical and striatal ischemia, the performance of both sham and stimulated groups reduced from 29 to 30 pieces to 7–11 pieces following the stroke induction. However, at the end of the four-week treatment, the performance of stimulated group was not significantly greater than that of sham group (15 pieces vs 11 pieces, p = 0.452). In the post-mortem analysis, the number of cells expressing CaMKIIα at the perilesional cortical and striatum of the LCN DBS treated animals receiving cortical-only stroke elevated but not those receiving cortical+striatal stroke. The current findings suggested that the observed, LCN DBS-enhanced motor recovery and perilesional plasticity may involve striatal mechanisms.

Low-intensity focused ultrasound stimulation promotes stroke recovery via astrocytic HMGB1 and CAMK2N1 in mice

BackgroundLow-intensity focused ultrasound stimulation (LIFUS) has been developed to enhance neurological repair and remodelling during the late acute stage of ischaemic stroke in rodents. However, the cellular and molecular mechanisms...

Effect and mechanisms of resveratrol in animal models of ischemic stroke: A systematic review and Bayesian meta-analysis

Resveratrol (RSV) holds promise as cerebroprotective treatment in cerebral ischemia. This systematic review aims to assess the effects and mechanisms of RSV in animal models of ischemic stroke. We searched Medline, Embase and Web of Science to identify 75 and 57 eligible rodent studies for qualitative and quantitative syntheses, respectively. Range of evidence met 10 of 13 STAIR criteria. Median (Q1, Q3) quality score was 7 (5, 8) on the CAMARADES 15-item checklist. Bayesian meta-analysis showed SMD estimates (95% CI) favoring RSV: infarct size (−1.72 [−2.03; −1.41]), edema size (−1.61 [−2.24; −0.98]), BBB impairment (−1.85 [−2.54; −1.19]), neurofunctional impairment (−1.60 [−1.92; −1.29]), and motor performance (1.39 [0.64; 2.08]); and less probably neuronal survival (0.63 [−1.40; 2.48]) and apoptosis (−0.96 [−2.87; 1.02]). Species (rat vs mouse) was associated to a larger benefit. Sensitivity analyses confirmed robustness of the estimates. Reduction of oxidative stress, inflammation, and apoptosis underlie these effects. Our results quantitatively state the beneficial effects of RSV on structural and functional outcomes in rodent stroke models, update the evidence on the mechanisms of action, and provide an exhaustive list of targeted signaling pathways. Current evidence highlights the need for conducting further high-quality preclinical research to better inform clinical research.

Dual contrast CEST MRI for pH-weighted imaging in stroke.

pH enhanced (pHenh ) CEST imaging combines the pH sensitivity from amide and guanidino signals, but the saturation parameters have not been optimized. We propose pHdual as a variant of pHenh that suppresses background signal variations, while enhancing pH sensitivity and potential for imaging ischemic brain injury of stroke. Simulation and in vivo rodent stroke experiments of pHenh MRI were performed with varied RF saturation powers for both amide and guanidino protons to optimize the contrast between lesion/normal tissues, while simultaneously minimizing signal variations across different types of normal tissues. In acute stroke, contrast and volume ratio measured by pHdual imaging were compared with an amide-CEST approach, and perfusion and diffusion MRI. Simulation experiments indicated that amide and guanidino CEST signals exhibit unique sensitivities across different pH ranges, with pHenh producing greater sensitivity over a broader pH regime. The pHenh data of rodent stroke brain demonstrated that the lesion/normal tissue contrast was maximized for an RF saturation power pair of 0.5 μT at 2.0 ppm and 1.0 μT at 3.6 ppm, whereas an optimal contrast-to-variation ratio (CVR) was obtained with a 0.7 μT saturation at 2.0 ppm and 0.8 μT at 3.6 ppm. In acute stroke, CVR optimized pHenh (i.e., pHdual ) achieved a higher sensitivity than the three-point amide-CEST approach, and distinct patterns of lesion tissue compared to diffusion and perfusion MRI. pHdual MRI improves the sensitivity of pH-weighted imaging and will be a valuable tool for assessing tissue viability in stroke.

Gait disorders induced by photothrombotic cerebellar stroke in mice

Patients with cerebellar stroke display relatively mild ataxic gaits. These motor deficits often improve dramatically; however, the neural mechanisms of this improvement have yet to be elucidated. Previous studies in mouse models of gait ataxia, such as ho15J mice and cbln1-null mice, have shown that they have a dysfunction of parallel fiber-Purkinje cell synapses in the cerebellum. However, the effects of cerebellar stroke on the locomotor kinematics of wild-type mice are currently unknown. Here, we performed a kinematic analysis of gait ataxia caused by a photothrombotic stroke in the medial, vermal, and intermediate regions of the cerebellum of wild-type mice. We used the data and observations from this analysis to develop a model that will allow locomotive prognosis and indicate potential treatment regimens following a cerebellar stroke. Our analysis showed that mice performed poorly in a ladder rung test after a stroke. During walking on a treadmill, the mice with induced cerebellar stroke had an increased duty ratio of the hindlimb caused by shortened duration of the swing phase. Overall, our findings suggest that photothrombotic cerebellar infarction and kinematic gait analyses will provide a useful model for quantification of different types of acute management of cerebellar stroke in rodents.

Cerebroprotective Effect of 17β-Estradiol Replacement Therapy in Ovariectomy-Induced Post-Menopausal Rats Subjected to Ischemic Stroke: Role of MAPK/ERK1/2 Pathway and PI3K-Independent Akt Activation.

Despite the overwhelming advances in the understanding of the pathogenesis of stroke, a devastating disease affecting millions of people worldwide, currently there are only a limited number of effective treatments available. Preclinical and clinical studies show that stroke is a sexually dimorphic disorder, affecting males and females differently. Strong experimental evidence indicates that estrogen may play a role in this difference and that exogenous 17β-estradiol (E2) is neuroprotective against stroke in both male and female rodents. However, the molecular mechanisms by which E2 intervenes in ischemia-induced cell death, revealing these sex differences, remain unclear. The present study was aimed to determine, in female rats, the molecular mechanisms of two well-known pro-survival signaling pathways, MAPK/ERK1/2 and PI3K/Akt, that mediate E2 neuroprotection in response to acute ischemic stroke. E2 pretreatment reduced brain damage and attenuated apoptotic cell death in ovariectomized female rats after an ischemic insult. Moreover, E2 decreased phosphorylation of ERK1/2 and prevented ischemia/reperfusion-induced dephosphorylation of both Akt and the pro-apoptotic protein, BAD. However, MAPK/ERK1/2 inhibitor PD98059, but not the PI3K inhibitor LY294002, attenuated E2 neuroprotection. Thus, these results suggested that E2 pretreatment in ovariectomized female rats modulates MAPK/ERK1/2 and activates Akt independently of PI3K to promote cerebroprotection in ischemic stroke. A better understanding of the mechanisms and the influence of E2 in the female sex paves the way for the design of future successful hormone replacement therapies.

Prenatal alcohol alters inflammatory signatures in enteric portal tissues following adult-onset cerebrovascular ischemic stroke

Prenatal alcohol exposure (PAE) impairs recovery from cerebrovascular ischemic stroke in adult rodents. Since the gut becomes dysbiotic following stroke, we assessed links between PAE and enteric portal inflammation. Adult control and PAE rat offspring received a unilateral endothelin-1-induced occlusion of the middle cerebral artery. Post-stroke behavioral disabilities and brain cytokines were assessed. Mesenteric adipose and liver transcriptomes were assessed from stroke-exposed and stroke-naive offspring. We identified, in the liver of stroke-naive animals, a moderate correlation between PAE and a gene network for inflammatory necroptosis. PAE inhibited the acute-phase brain inflammatory cytokine response to stroke. Post-stroke neurological function was correlated with an adipose gene network associated with B-lymphocyte differentiation and nuclear factor κB (NF-κB) signaling and with a liver pro-inflammatory gene network. Collectively, PAE inhibits brain inflammation but results in an inflammatory signature in enteric portal tissues after stroke, suggesting that PAE persistently and adversely impacts the gut-brain axis following adult-onset disease.

Machine Learning-assisted Quantitative Mapping of Intracortical Axonal Plasticity Following a Focal Cortical Stroke in Rodents.

Stroke destroys neurons and their connections leading to focal neurological deficits. Although limited, many patients exhibit a certain degree of spontaneous functional recovery. Structural remodeling of the intracortical axonal connections is implicated in the reorganization of cortical motor representation maps, which is considered to be an underlying mechanism of the improvement in motor function. Therefore, an accurate assessment of intracortical axonal plasticity would be necessary to develop strategies to facilitate functional recovery following a stroke. The present study developed a machine learning-assisted image analysis tool based on multi-voxel pattern analysis in fMRI imaging. Intracortical axons originating from the rostral forelimb area (RFA) were anterogradely traced using biotinylated dextran amine (BDA) following a photothrombotic stroke in the mouse motor cortex. BDA-traced axons were visualized in tangentially sectioned cortical tissues, digitally marked, and converted to pixelated axon density maps. Application of the machine learning algorithm enabled sensitive comparison of the quantitative differences and the precise spatial mapping of the post-stroke axonal reorganization even in the regions with dense axonal projections. Using this method, we observed a substantial extent of the axonal sprouting from the RFA to the premotor cortex and the peri-infarct region caudal to the RFA. Therefore, the machine learningassisted quantitative axonal mapping developed in this study can be utilized to discover intracortical axonal plasticity that may mediate functional restoration following stroke.

Distinctions between the Koizumi and Zea Longa methods for middle cerebral artery occlusion (MCAO) model: a systematic review and meta-analysis of rodent data

Ischemic stroke in rodents is usually induced by intraluminal middle cerebral artery occlusion (MCAO) via the common carotid artery plugging filament invented by Koizumi et al. (MCAO-KM), or the external carotid artery plugging filament created by Zea Longa et al. (MCAO-LG). A systematic review of the distinctions between them is currently lacking. Here, we performed a meta-analysis in terms of model establishment, cerebral blood flow (CBF), and cerebral ischemia–reperfusion injury (CIRI) between them, Weighted Mean Differences and Standardized Mean Difference were used to analyze the combined effects, Cochrane's Q test and the I2 statistic were applied to determine heterogeneity, sensitivity analysis and subgroup analysis were performed to explore the source of heterogeneity. Literature mining suggests that MCAO-KM brings shorter operation time (p = 0.007), higher probability of plugging filament (p < 0.001) and molding establishment (p = 0.006), lower possibility of subarachnoid hemorrhage (p = 0.02), larger infarct volume (p = 0.003), severer brain edema (p = 0.002), and neurological deficits (p = 0.03). Nevertheless, MCAO-LG shows a more adequate CBF after ischemia–reperfusion (p < 0.001), a higher model survival rate (p = 0.02), and a greater infarct rate (p = 0.007). In conclusion, the MCAO-KM method is simple to operate with a high modeling success rate, and is suitable for the study of brain edema under long-term hypoperfusion, while the MCAO-LG method is highly challenging for novices, and is suitable for the study of CIRI caused by complete ischemia–reperfusion. These findings are expected to benefit the selection of intraluminal filament MCAO models before undertaking ischemic stroke preclinical effectiveness trials.

Mandibular characteristics of early Glires (Mammalia) reveal mixed rodent and lagomorph morphotypes.

Glires (rodents, lagomorphs and their fossil kin) is the most speciose and arguably most diversified clade of living placentals. Different lineages within the Glires evolved basically opposite chewing movements: a mostly transversal power stroke in lagomorphs, and a mostly proal power stroke in rodents, but the ancestral condition for Glires is still unclear. To address this knowledge gap, we studied the mandibles of Chinese Palaeocene Glires representing the duplicidentate (lagomorph-like; Mimotona) and simplicidentate (rodent-like; Eomylus and Heomys) lineages. To assess the mechanical resistance of mandibles to bending and torsion, we calculated the section modulus. The dentaries differ greatly in morphology and the region where the maximum grinding force was likely applied. The early Palaeocene Mimotona lii and the middle Palaeocene Mimotona robusta and Heomys orientalis all show a pattern of increasing strength moving posteriorly along the mandible, similar to sciurids and the mountain beaver. By contrast, the late Palaeocene Eomylus sp. mandible was strongest in the m1 region, a pattern seen in lagomorphs and the stem placental Zofialestes. Our results indicate the early diversification of mandible structure of Glires, demonstrate a mixture of duplicidentate and simplicidentate characters among the basal Glires and suggest an early occurrence of a lagomorph-like morphotype. This article is part of the theme issue 'The mammalian skull: development, structure and function'.

Erratum for Research Article "Patient-derived glial enriched progenitors repair functional deficits due to white matter stroke and vascular dementia in rodents" by I. Llorente et al.

Erratum for Research Article "Patient-derived glial enriched progenitors repair functional deficits due to white matter stroke and vascular dementia in rodents" by I. Llorente et al.

Engineered extracellular vesicles for ischemic stroke treatment

Engineered extracellular vesicles for ischemic stroke treatment