scholarly journals Post-stroke dendritic arbor regrowth – a cortical repair process requiring the actin nucleator Cobl

2021 ◽  
Author(s):  
Yuanyuan Ji ◽  
Dennis Koch ◽  
Jule González Delgado ◽  
Madlen Günther ◽  
Otto W. Witte ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Molecular Mechanisms ◽  
Primary Motor Cortex ◽  
Recovery Process ◽  
Repair Process ◽  
Artery Occlusion ◽  
Stroke Recovery ◽  
Dendritic Arbor ◽  
Post Stroke ◽  
Actin Nucleator

AbstractIschemic stroke is a major cause of death and long-term disability. We demonstrate that middle cerebral artery occlusion in mice leads to a strong decline in dendritic arborization of penumbral neurons. These defects were subsequently repaired by an ipsilateral recovery process requiring the actin nucleator Cobl. Ischemic stroke and excitotoxicity, caused by calpain-mediated proteolysis, significantly reduced Cobl levels. In an apparently unique manner among excitotoxicity-affected proteins, this Cobl decline was rapidly restored by increased mRNA expression and Cobl then played a pivotal role in post-stroke dendritic arbor repair in peri-infarct areas. In Cobl KO mice, the dendritic repair window determined to span day 2-4 post-stroke in WT strikingly passed without any dendritic regrowth. Instead, Cobl KO penumbral neurons of the primary motor cortex continued to show the dendritic impairments caused by stroke. Our results thereby highlight a powerful post-stroke recovery process and identified causal molecular mechanisms critical during post-stroke repair.

scholarly journals Poststroke dendritic arbor regrowth requires the actin nucleator Cobl

PLoS Biology ◽  
2021 ◽  
Vol 19 (12) ◽  
pp. e3001399
Author(s):  
Yuanyuan Ji ◽  
Dennis Koch ◽  
Jule González Delgado ◽  
Madlen Günther ◽  
Otto W. Witte ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Molecular Mechanisms ◽  
Primary Motor Cortex ◽  
Recovery Process ◽  
Artery Occlusion ◽  
Dendritic Arbor ◽  
Unique Manner ◽  
Actin Nucleator ◽  
Cerebral Artery Occlusion

Ischemic stroke is a major cause of death and long-term disability. We demonstrate that middle cerebral artery occlusion (MCAO) in mice leads to a strong decline in dendritic arborization of penumbral neurons. These defects were subsequently repaired by an ipsilateral recovery process requiring the actin nucleator Cobl. Ischemic stroke and excitotoxicity, caused by calpain-mediated proteolysis, significantly reduced Cobl levels. In an apparently unique manner among excitotoxicity-affected proteins, this Cobl decline was rapidly restored by increased mRNA expression and Cobl then played a pivotal role in poststroke dendritic arbor repair in peri-infarct areas. In Cobl knockout (KO) mice, the dendritic repair window determined to span day 2 to 4 poststroke in wild type (WT) strikingly passed without any dendritic regrowth. Instead, Cobl KO penumbral neurons of the primary motor cortex continued to show the dendritic impairments caused by stroke. Our results thereby highlight a powerful poststroke recovery process and identified causal molecular mechanisms critical during poststroke repair.

scholarly journals Cellular-resolution monitoring of ischemic stroke pathologies in the rat cortex

2021 ◽  
Author(s):  
Sergiy Chornyy ◽  
Aniruddha Das ◽  
Julie A Borovicka ◽  
Davina Patel ◽  
Hugh H Chan ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Primary Motor Cortex ◽  
Activity Patterns ◽  
Recovery Process ◽  
Cortical Reorganization ◽  
Western World ◽  
Fluorescence Signal ◽  
Functional Changes ◽  
Post Stroke ◽  
Cortical Regions

Stroke is a leading cause of disability in the Western world. Current post-stroke rehabilitation treatments are only effective in approximately half of the patients. Therefore, there is a pressing clinical need for developing new rehabilitation approaches for enhancing the recovery process, which requires the use of appropriate animal models. Here we study the activity patterns of multiple cortical regions in the rat brain using two-photon microscopy. We longitudinally recorded the fluorescence signal from thousands of neurons labeled with a genetically-encoded calcium indicator before and after an ischemic stroke injury, and found substantial functional changes across motor, somatosensory, and visual cortical regions during the post-stroke cortical reorganization period. We show that a stroke injury in the primary motor cortex has an effect on the activity patterns of neurons not only in the motor and somatosensory cortices, but also in the more distant visual cortex, and that these changes include modified firing rates and kinetics of neuronal activity patterns in response to a sensory stimulus. Changes in neuronal population activity provided animal-specific, circuit-level information on the post-stroke cortical reorganization process, which may be essential for evaluating the efficacy of new approaches for enhancing the recovery process.

Abstract W P96: Optogenetic Neuronal Stimulation Enhances Neurotrophin Expression in the Contralesional Motor Cortex After Stroke

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Michelle Y Cheng ◽  
Eric H Wang ◽  
Corinne L Bart ◽  
Alex R Bautista ◽  
Wyatt J Woodson ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Functional Recovery ◽  
Primary Motor Cortex ◽  
Recovery Process ◽  
Cortical Reorganization ◽  
Stroke Recovery ◽  
Post Stroke ◽  
Neuronal Stimulation ◽  
Activity Dependent

Objective: Functional recovery after stroke has been observed and is currently attributed to both brain remodeling and plasticity. One form of cortical reorganization involves the balance of interhemispheric interactions between ipsilesional and contralesional cortex. Stimulation of ipsilesional primary motor cortex (iM1) has been shown to be beneficial, however, the role of the contralesional M1 (cM1) remains controversial. Recently we showed that optogenetic stimulations of iM1 post-stroke promote functional recovery. In this study, we investigate the role of contralesional cortex in recovery by optogenetically stimulating iM1 or cM1 and examine the involvement of activity-dependent neurotrophins. Methods: Thy-1-ChR2-YFP line-18 transgenic male mice were used. Mice underwent stereotaxic surgery to implant a fiber cannula in either iM1 or cM1, followed by an intraluminal middle cerebral artery suture occlusion. Optogenetic stimulation began at day5 post-stroke and continued until day14 post-stroke. Sensorimotor behavior tests were used to assess their recovery at day 0, 2, 7, 10 and 14 post-stroke. Mice were sacrificed at day15 post-stroke and neurotrophin expressions were examined using quantitative PCR. Results: Repeated iM1 stimulations promoted functional recovery at day14 post-stroke, with improved motor performance on the rotating beam test (p<0.01). Real-time PCR revealed significant increases of neurotrophin expressions in contralesional M1 at day15 post-stroke, including brain-derived neurotrophic factor (BDNF) (p<0.05), nerve growth factor (NGF) (p<0.05) and neurotrophin 3 (NTF3) (p<0.05). BDNF and NTF3 expression were also significantly increased in the contralesional S1 of stimulated mice (p<0.05). Conclusion: Our data suggest that activity-dependent neurotrophins in the contralesional cortex may be an important mechanism mediating stroke recovery. Current studies include specific stimulation and inhibition of the iM1 or cM1 post-stroke to elucidate the neurocircuitry mediating stroke recovery. In addition, the expression of neurotrophins will be examined in these studies to elucidate their role in the recovery process.

LncRNAs a New Target for Post-Stroke Recovery

2020 ◽  
Vol 26 (26) ◽  
pp. 3115-3121
Author(s):  
Jun Yang ◽  
Jingjing Zhao ◽  
Xu Liu ◽  
Ruixia Zhu
Keyword(s):  
Ischemic Stroke ◽  
Microglial Activation ◽  
Vital Role ◽  
Stroke Recovery ◽  
Biological Processes ◽  
Current Development ◽  
Post Stroke ◽  
Cascade Processes ◽  
Non Coding Rnas ◽  
Neuron Injury

LncRNAs (long non-coding RNAs) are endogenous molecules, involved in complicated biological processes. Increasing evidence has shown that lncRNAs play a vital role in the post-stroke pathophysiology. Furthermore, several lncRNAs were reported to mediate ischemia cascade processes include apoptosis, bloodbrain barier breakdown, angiogenesis, microglial activation induced neuroinflammation which can cause neuron injury and influence neuron recovery after ischemic stroke. In our study, we first summarize current development about lncRNAs and post-stroke, focus on the regulatory roles of lncRNAs on pathophysiology after stroke. We also reviewed genetic variation in lncRNA associated with functional outcome after ischemic stroke. Additionally, lncRNA-based therapeutics offer promising strategies to decrease brain damage and promote neurological recovery following ischemic stroke. We believe that lncRNAs will become promising for the frontier strategies for IS and can open up a new path for the treatment of IS in the future.

Abstract WP7: Leukoaraiosis And Outcomes After Intra-arterial Therapy In Acute Ischemic Stroke

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Dan-Victor V Giurgiutiu ◽  
Albert J Yoo ◽  
Kaitlin Fitzpatrick ◽  
Zeshan Chaudhry ◽  
Lee H Schwamm ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Artery Occlusion ◽  
Post Stroke ◽  
Good Functional Outcome ◽  
Grade 3 ◽  
Risk Of Hemorrhage

Background: Selecting patients most likely to benefit (MLTB) from intra-arterial therapy (IAT) is essential to assure favorable outcomes after intervention for acute ischemic stroke (AIS). Leukoaraiosis (LA) has been linked to infarct growth, risk of hemorrhage after IV rt-PA, and poor post-stroke outcomes. We investigated whether LA severity is associated with AIS outcomes after IAT. Methods: We analyzed consecutive AIS subjects from our institutional GWTG-Stroke database enrolled between 01/01/2007-06/30/2009, who met our pre-specified criteria for MLTB: CTA and MRI within 6 hours from last known well, NIHSS score ≥8, baseline DWI volume (DWIv) ≤ 100 cc, and proximal artery occlusion and were treated with IAT. LA volume (LAv) was assessed on FLAIR using validated, semi-automated protocols. We analyzed CTA to assess collateral grade; post-IAT angiogram for recanalization status (TICI score ≥2B); and the 24-hour CT for symptomatic ICH (sICH). Logistic regression was used to determine independent predictors of good functional outcome (mRS≤ 2) and mortality at 90 days post-stroke. Results: There were 48 AIS subjects in this analysis (mean age 69.2, SD±13.8; 55% male; median LAv 4cc, IQR 2.2-8.8cc; median NIHSS 15, IQR 13-19; median DWIv 15.4cc, IQR 9.2-20.3cc). Of these, 34 (72%) received IV rt-PA; 3 (6%) had sICH; 21 (44.7%) recanalized; and 23 (50%) had collateral grade ≥3. At 90 days, 15/48 (36.6%) were deceased and 15/48 had mRS≤ 2. In univariate analysis, recanalization (OR 6.2, 95%CI 1.5-25.5), NIHSS (OR 0.8 per point, 95%CI 0.64-0.95), age (OR 0.95 per yr, 95%CI 0.89-0.99) were associated with good outcome, whereas age (OR 1.1, 95%CI 1.01-1.14) and HTN (OR 5.6, 95%CI 1.04-29.8) were associated with mortality. In multivariable analysis including age, NIHSS, recanalization, collateral grade, and LAv, only recanalization independently predicted good functional outcome (OR 21.3, 95%CI 2.3-199.9) and reduced mortality (OR 0.15, 95%CI 0.02-1.12) after IAT. Conclusions: LA severity is not associated with poor outcome in patients selected MLTB for IAT. Among AIS patients considered likely to benefit from IAT, only recanalization independently predicted good functional outcome and decreased mortality.

Abstract TP79: Inhibition of Toll Like Receptor-4 (tlr4) Improves Neurobehavioral Outcomes After Acute Ischemic Stroke in Diabetic Rats

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Yasir Abdul ◽  
Mohammed Abdelsaid ◽  
Wieguo Li ◽  
Guangkuo Dong ◽  
Adviye Ergul
Keyword(s):  
Ischemic Stroke ◽  
Immune System ◽  
Functional Outcomes ◽  
Therapeutic Potential ◽  
Adaptive Immune System ◽  
Artery Occlusion ◽  
Stroke Recovery ◽  
Microvascular Endothelial Cell ◽  
Poor Recovery ◽  
Tlr4 Receptor

Introduction: Diabetes increases the risk of occurrence and poor recovery of ischemic stroke injury. Activation of adaptive immune system and resulting inflammation contributes to neurovascular injury and deterioration of neurological functions post stroke in diabetes. We have shown that activation of TLR4, a key player in the innate immune system, decreases brain microvascular endothelial cell survival after hypoxic injury in diabetic conditions. Our previous work also demonstrated greater bleeding/edema and poor recovery after stroke in diabetes. Current study tested the hypothesis that activation of TLR4 contributes to worsened stroke injury in diabetes and its inhibition can improve functional outcomes. Methods: Low dose of Streptozotocin (30mg/kg) and high fat diet were used to induce type 2 diabetes in male Wistar rats. Middle cerebral artery occlusion for 60 mins was performed in 13 weeks old animals. Expression of TLR4 receptor in brain homogenates and cerebral microvasculature were assessed by immunoblotting (relative density). Another set of animals was treated with TLR4 inhibitor TAK242 (3mg/kg; i.p. after reperfusion, 24 and 48 hours). Neurobehavioral deficits were measured by composite score and adhesive removal test at baseline, day 1 and 3 post ischemic stroke. Results: Ischemic stroke increased the expression of TLR4 receptor in ischemic hemisphere (0.50±0.06 sham, 0.68±0.02 control and 1.24±2.0* diabetic; *p<0.05 vs sham) as well as in microvasculature (0.55±035 sham, 1.34±0.24 control and 9.49±2.5* diabetic; *p<0.05 vs sham) and this was significantly higher in diabetic animals. Diabetes worsened functional outcomes and inhibition of TLR4 significantly improved the deficits (Table). Conclusions: Our findings that TLR4 is highly upregulated in the microvasculature and that beneficial effects of TLR4 inhibition are more profound in diabetes suggest that vascular TLR4 holds a therapeutic potential for stroke recovery in diabetes.

scholarly journals Pleiotropic Effects of Exosomes as a Therapy for Stroke Recovery

2020 ◽  
Vol 21 (18) ◽  
pp. 6894
Author(s):  
Yuji Ueno ◽  
Kenichiro Hira ◽  
Nobukazu Miyamoto ◽  
Chikage Kijima ◽  
Toshiki Inaba ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Membrane Vesicles ◽  
Recombinant Tissue Plasminogen Activator ◽  
Artery Occlusion ◽  
Outcome Data ◽  
Stroke Recovery ◽  
Therapeutic Effects ◽  
Stroke Survivors ◽  
Axonal Outgrowth ◽  
Inflammatory Reactions

Stroke is the leading cause of disability, and stroke survivors suffer from long-term sequelae even after receiving recombinant tissue plasminogen activator therapy and endovascular intracranial thrombectomy. Increasing evidence suggests that exosomes, nano-sized extracellular membrane vesicles, enhance neurogenesis, angiogenesis, and axonal outgrowth, all the while suppressing inflammatory reactions, thereby enhancing functional recovery after stroke. A systematic literature review to study the association of stroke recovery with exosome therapy was carried out, analyzing species, stroke model, source of exosomes, behavioral analyses, and outcome data, as well as molecular mechanisms. Thirteen studies were included in the present systematic review. In the majority of studies, exosomes derived from mesenchymal stromal cells or stem cells were administered intravenously within 24 h after transient middle cerebral artery occlusion, showing a significant improvement of neurological severity and motor functions. Specific microRNAs and molecules were identified by mechanistic investigations, and their amplification was shown to further enhance therapeutic effects, including neurogenesis, angiogenesis, axonal outgrowth, and synaptogenesis. Overall, this review addresses the current advances in exosome therapy for stroke recovery in preclinical studies, which can hopefully be preparatory steps for the future development of clinical trials involving stroke survivors to improve functional outcomes.

scholarly journals β-Oscillations Reflect Recovery of the Paretic Upper Limb in Subacute Stroke

2020 ◽  
Vol 34 (5) ◽  
pp. 450-462 ◽  
Author(s):  
Chih-Wei Tang ◽  
Fu-Jung Hsiao ◽  
Po-Lei Lee ◽  
Yun-An Tsai ◽  
Ya-Fang Hsu ◽  
...  
Keyword(s):  
Motor Function ◽  
Upper Limb ◽  
Primary Motor Cortex ◽  
Hand Movement ◽  
Stroke Recovery ◽  
Stroke Survivors ◽  
Healthy Controls ◽  
Functional Changes ◽  
Post Stroke ◽  
Subacute Stroke

Background. Recovery of upper limb function post-stroke can be partly predicted by initial motor function, but the mechanisms underpinning these improvements have yet to be determined. Here, we sought to identify neural correlates of post-stroke recovery using longitudinal magnetoencephalography (MEG) assessments in subacute stroke survivors. Methods. First-ever, subcortical ischemic stroke survivors with unilateral mild to moderate hand paresis were evaluated at 3, 5, and 12 weeks after stroke using a finger-lifting task in the MEG. Cortical activity patterns in the β-band (16-30 Hz) were compared with matched healthy controls. Results. All stroke survivors (n=22; 17 males) had improvements in action research arm test (ARAT) and Fugl-Meyer upper extremity (FM-UE) scores between 3 and 12 weeks. At 3 weeks post-stroke the peak amplitudes of the movement-related ipsilesional β-band event-related desynchronization (β-ERD) and synchronization (β-ERS) in primary motor cortex (M1) were significantly lower than the healthy controls (p<0.001) and were correlated with both the FM-UE and ARAT scores (r=0.51-0.69, p<0.017). The decreased β-ERS peak amplitudes were observed both in paretic and non-paretic hand movement particularly at 3 weeks post-stroke, suggesting a generalized disinhibition status. The peak amplitudes of ipsilesional β-ERS at week 3 post-stroke correlated with the FM-UE score at 12 weeks (r=0.54, p=0.03) but no longer significant when controlling for the FM-UE score at 3 weeks post-stroke. Conclusions. Although early β-band activity does not independently predict outcome at 3 months after stroke, it mirrors functional changes, giving a potential insight into the mechanisms underpinning recovery of motor function in subacute stroke.

scholarly journals Infarct topography and functional outcomes

2017 ◽  
Vol 38 (9) ◽  
pp. 1517-1532 ◽  
Author(s):  
Mark R Etherton ◽  
Natalia S Rost ◽  
Ona Wu
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Functional Outcomes ◽  
Brain Regions ◽  
Stroke Recovery ◽  
Acute Ischemia ◽  
Post Stroke ◽  
Neurologic Outcomes ◽  
Recovery Potential

Acute ischemic stroke represents a major cause of long-term adult disability. Accurate prognostication of post-stroke functional outcomes is invaluable in guiding patient care, targeting early rehabilitation efforts, selecting patients for clinical research, and conveying realistic expectations to families. The involvement of specific brain regions by acute ischemia can alter post-stroke recovery potential. Understanding the influences of infarct topography on neurologic outcomes holds significant promise in prognosis of functional recovery. In this review, we discuss the recent evidence of the contribution of infarct location to patient management decisions and functional outcomes after acute ischemic stroke.

scholarly journals Longitudinal Effects of Lesions on Functional Networks after Stroke

2013 ◽  
Vol 33 (8) ◽  
pp. 1279-1285 ◽  
Author(s):  
Smadar Ovadia-Caro ◽  
Kersten Villringer ◽  
Jochen Fiebach ◽  
Gerhard Jan Jungehulsing ◽  
Elke van der Meer ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Resting State ◽  
Large Scale ◽  
Clinical Symptoms ◽  
Resting State Fmri ◽  
Functional Change ◽  
Stroke Recovery ◽  
Focal Lesion ◽  
Supporting Evidence ◽  
Post Stroke

While ischemic stroke reflects focal damage determined by the affected vascular territory, clinical symptoms are often more complex and may be better explained by additional indirect effects of the focal lesion. Assumed to be structurally underpinned by anatomical connections, supporting evidence has been found using alterations in the functional connectivity of resting-state functional magnetic resonance imaging (fMRI) data in both sensorimotor and attention networks. To assess the generalizability of this phenomenon in a stroke population with heterogeneous lesions, we investigated the distal effects of lesions on a global level. Longitudinal resting-state fMRI scans were acquired at three consecutive time points, beginning during the acute phase (days 1, 7, and 90 post-stroke) in 12 patients after ischemic stroke. We found a preferential functional change in affected networks (i.e., networks containing lesions changed more during recovery when compared with unaffected networks). This change in connectivity was significantly correlated with clinical changes assessed with the National Institute of Health Stroke Scale. Our results provide evidence that the functional architecture of large-scale networks is critical to understanding the clinical effect and trajectory of post-stroke recovery.

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