Abstract W MP41: Potentiation of Gaba-Mediated Synaptic Inhibition in the Recovery Phase: A Novel Therapeutic Target for Stroke

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Takeshi Hiu ◽  
Tonya Bliss ◽  
Jeanne Paz ◽  
Eric Wang ◽  
Zoya Farzampour ◽  
...  
Keyword(s):  
Pyramidal Cells ◽  
Recovery Phase ◽  
Synaptic Activity ◽  
Stroke Recovery ◽  
Functional Changes ◽  
Post Stroke ◽  
Array Tomography ◽  
Neuronal Inhibition ◽  
Gaba Signaling ◽  
Novel Therapeutic

Background: Stroke is a major cause of disability yet pharmacotherapy targeting the recovery phase is lacking. Cortical circuit reorganization adjacent to the stroke site promotes recovery, thus elucidating mechanisms that promote this plasticity could lead to new therapeutics. Tonic neuronal inhibition, mediated by extrasynaptic GABA A receptors,inhibits post-stroke recovery. However, effects of phasic (synaptic) GABA signaling - which promotes plasticity during development - are unknown. Here we use a combined approach of i) array tomography to determine the composition of GABA synapses in the post-stroke mouse brain, ii) electrophysiology to determine whether stroke leads to functional changes in GABA-mediated phasic inhibition, and (iii) treatment with zolpidem, an FDA-approved GABA agonist, to modulate recovery. Results: We found, using array tomography, a 1.7-fold increase in the number of GABAergic synapses containing the α1 receptor subunit in layer 5 of the peri-infarct cortex (synapse number/μm 3 : 0.039±0.006 (control) vs 0.064±0.006 (stroke); P<0.01), but not in layer 2/3. There was an associated increase in spontaneous inhibitory post-synaptic currents (sIPSC) specific to layer 5 pyramidal neurons (sIPSC charge (fC): -403±27.8 (control) vs -724±166 (stroke); p=0.03). This effect was transient, occurring during the onset of functional recovery. To test whether the increased phasic inhibitory GABAergic signaling promotes stroke recovery, we treated animals with zolpidem, an agonist with high affinity for α1 subunit-containing GABA A receptors. Low dose zolpidem increased GABA A phasic signaling in layer 5 pyramidal cells and notably increased the rate and extent of behavioral recovery without altering infarct size. Conclusions: These data provide the first evidence that enhanced GABA A -mediated synaptic activity during the recovery phase improves stroke outcome. These data identify modulation of phasic GABA signaling as a novel therapeutic strategy for stroke, indicate zolpidem as a potential drug to improve recovery, and underscore the necessity to distinguish the role of tonic and phasic GABA inhibition in stroke recovery.

Abstract 116: Single-synapse Analysis Of Synaptic Remodeling In The Post-stroke Rodent Brain

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Takeshi Hiu ◽  
Tonya M Bliss ◽  
Andrew Olson ◽  
Kristina D Micheva ◽  
Kevin Tran ◽  
...  
Keyword(s):  
Quantitative Information ◽  
Artery Occlusion ◽  
Cortical Lesion ◽  
Imaging Method ◽  
Functional Changes ◽  
Post Stroke ◽  
Array Tomography ◽  
Synaptic Markers ◽  
Gabaergic Synapses ◽  
Synaptic Circuitry

Introduction: The mechanisms of functional recovery after stroke are thought to be based on structural and functional changes in brain circuits adjacent to or connected with the stroke site. Deciphering these changes at the synaptic level is key to understanding the re-organization of the synaptic circuitry (i.e. the connectome). Quantitative information about such synapse rearrangements after stroke has been inadequate however, due to the technical limitations of available methodologies. Here we describe the use of array tomography, a new high-resolution proteomic imaging method, to determine the composition of glutamate and GABA synapses in the post-stroke mouse brain. Methods: A cortical lesion was induced in 12-week-old C57BL/6J male mice using the distal middle cerebral artery occlusion model of ischemia. Small tissue sections were removed from the peri-infarct cortex and ribbons of serial ultrathin (70 nm) sections were obtained using an ultramicrotome. Ribbons were stained with antibodies for the synaptic markers SynapsinI, VGlut1, VGlut2, PSD-95, GAD, VGAT. Analysis of the resultant staining pattern was used to identify subtypes of glutamatergic and GABAergic synapses. Results: At 1 week post-stroke, an increase in GABAergic synapses was observed in layer 5 of the peri-infarct cortex. A sub-analysis of the type of inhibitory interneurons (e.g. parvalbumin, somatostatin) expressing these synapses is pending. In addition, a trend for an increase of VGlut1+2 synapses was also observed. However, there were no detectable differences in total synapse number between stroke-injured and naïve animals, thus suggesting that VGluT2 expression may be upregulated in existing glutamatergic VGluT1 synapses after stroke. Further analysis will be extended to cortical layers 2/3 and 4. Conclusion: These results provide new information about the organization of synaptic circuitry and its plasticity after stroke. Furthermore, it demonstrates how array tomography enables a previously unobtainable level of volumetric visualization and quantification of synapses.

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 The regulation of glycemia in the recovery phase after stroke counteracts the detrimental effect of obesity-induced type 2 diabetes on neurological recovery

2020 ◽  
Author(s):  
Ada Admin ◽  
Ingrid Lovise Augestad ◽  
Hiranya Pintana ◽  
Martin Larsson ◽  
Camilla Krizhanovskii ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Clinical Situation ◽  
Recovery Phase ◽  
Artery Occlusion ◽  
Stroke Recovery ◽  
Neurological Recovery ◽  
Standard Diet ◽  
Dipeptidyl Peptidase 4 ◽  
Post Stroke ◽  
The Impact

The interplay between obesity and T2D in post-stroke recovery is unclear. Moreover, the impact of glucose control during the chronic phase after stroke is undetermined. <p>We investigated whether obesity-induced T2D impairs neurological recovery after stroke by using a clinically relevant experimental design. We also investigated the potential efficacy of two clinically-used T2D drugs: the dipeptidyl peptidase-4 inhibitor linagliptin and the sulfonylurea glimepiride.</p> <p>We induced transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (after 7 months of high-fat diet (HFD)) and age-matched controls. After stroke, we replaced HFD with standard diet for 8 weeks to mimic the post-stroke clinical situation. Linagliptin or glimepiride were administered daily from 3 days after tMCAO for 8 weeks.<b> </b>We assessed neurological recovery weekly by upper-limb grip strength. Brain damage, neuroinflammation, stroke-induced neurogenesis and atrophy of parvalbumin (PV)+ interneurons were quantified by immunohistochemistry.</p> <p>T2D/obesity impaired post-stroke neurological recovery in association with hyperglycemia, neuroinflammation and atrophy of PV+ interneurons. Both drugs counteracted these effects. In non-diabetic mice, only linagliptin accelerated recovery.</p> These findings shed light on the interplay between obesity and T2D in stroke recovery. Moreover, they promote the use of rehabilitative strategies based on efficacious glycemia regulation, even if initiated days after stroke.

scholarly journals The regulation of glycemia in the recovery phase after stroke counteracts the detrimental effect of obesity-induced type 2 diabetes on neurological recovery

2020 ◽  
Author(s):  
Ada Admin ◽  
Ingrid Lovise Augestad ◽  
Hiranya Pintana ◽  
Martin Larsson ◽  
Camilla Krizhanovskii ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Clinical Situation ◽  
Recovery Phase ◽  
Artery Occlusion ◽  
Stroke Recovery ◽  
Neurological Recovery ◽  
Standard Diet ◽  
Dipeptidyl Peptidase 4 ◽  
Post Stroke ◽  
The Impact

The interplay between obesity and T2D in post-stroke recovery is unclear. Moreover, the impact of glucose control during the chronic phase after stroke is undetermined. <p>We investigated whether obesity-induced T2D impairs neurological recovery after stroke by using a clinically relevant experimental design. We also investigated the potential efficacy of two clinically-used T2D drugs: the dipeptidyl peptidase-4 inhibitor linagliptin and the sulfonylurea glimepiride.</p> <p>We induced transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (after 7 months of high-fat diet (HFD)) and age-matched controls. After stroke, we replaced HFD with standard diet for 8 weeks to mimic the post-stroke clinical situation. Linagliptin or glimepiride were administered daily from 3 days after tMCAO for 8 weeks.<b> </b>We assessed neurological recovery weekly by upper-limb grip strength. Brain damage, neuroinflammation, stroke-induced neurogenesis and atrophy of parvalbumin (PV)+ interneurons were quantified by immunohistochemistry.</p> <p>T2D/obesity impaired post-stroke neurological recovery in association with hyperglycemia, neuroinflammation and atrophy of PV+ interneurons. Both drugs counteracted these effects. In non-diabetic mice, only linagliptin accelerated recovery.</p> These findings shed light on the interplay between obesity and T2D in stroke recovery. Moreover, they promote the use of rehabilitative strategies based on efficacious glycemia regulation, even if initiated days after stroke.

Post-stroke recovery updates

2018 ◽  
Vol 19 (1) ◽  
pp. 53-57
Author(s):  
Ana Maria Bumbea ◽  
Roxana Carmen Dumitraşcu ◽  
Bogdan Ştefan Bumbea ◽  
Anca Emanuela Muşetescu ◽  
Otilia Rogoveanu ◽  
...  
Keyword(s):  
Stroke Recovery ◽  
Post Stroke

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.

scholarly journals Post-Stroke Social Isolation Reduces Cell Proliferation in the Dentate Gyrus and Alters miRNA Profiles in the Aged Female Mice Brain

2020 ◽  
Vol 22 (1) ◽  
pp. 99
Author(s):  
Aleah Holmes ◽  
Yan Xu ◽  
Juneyoung Lee ◽  
Michael E. Maniskas ◽  
Liang Zhu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dentate Gyrus ◽  
Social Isolation ◽  
Census Data ◽  
Elderly Women ◽  
Stroke Recovery ◽  
Tissue Loss ◽  
Female Mice ◽  
Post Stroke ◽  
The Brain

Social isolation and loneliness are risk factors for stroke. Elderly women are more likely to be isolated. Census data shows that in homeowners over the age of 65, women are much more likely to live alone. However, the underlying mechanisms of the detrimental effects of isolation have not been well studied in older females. In this study, we hypothesized that isolation impairs post-stroke recovery in aged female mice, leading to dysregulated microRNAs (miRNAs) in the brain, including those previously shown to be involved in response to social isolation (SI). Aged C57BL/6 female mice were subjected to a 60-min middle cerebral artery occlusion and were randomly assigned to either single housing (SI) or continued pair housing (PH) immediately after stroke for 15 days. SI immediately after stroke led to significantly more brain tissue loss after stroke and higher mortality. Furthermore, SI significantly delayed motor and sensory recovery and worsened cognitive function, compared to PH. A decrease in cell proliferation was seen in the dentate gyrus of SI mice assessed by bromodeoxyuridine (BrdU) labeling. miRNAome data analysis revealed changes in several miRNAs in the brain, such as miR-297a-3p and miR-200c-3p, which are known to regulate pathways involved in cell proliferation. In conclusion, our data suggest that SI can lead to a poor post-stroke recovery in aged females and dysregulation of miRNAs and reduced hippocampal cell proliferation.

scholarly journals Rehabilitation strategy for post-stroke recovery using an innovative elbow exoskeleton

2019 ◽  
Vol 233 (6) ◽  
pp. 668-680 ◽  
Author(s):  
Soumya K Manna ◽  
Venketesh N Dubey
Keyword(s):  
Acute Stage ◽  
Joint Torque ◽  
Stroke Recovery ◽  
Structural Description ◽  
Post Stroke ◽  
Single Structure ◽  
Rate Of Recovery ◽  
Last Stage ◽  
Working Region ◽  
Rehabilitation Strategy

Intensive and adaptive rehabilitation therapy is beneficial for post-stroke recovery. Three modes of rehabilitation are generally performed at different stages after stroke: external force-based control in the acute stage, assistive force-based rehabilitation in the midway of recovery and resistive force-based rehabilitation in the last stage. To achieve the above requirements, an innovative elbow exoskeleton has been developed to incorporate the three modes of rehabilitation in a single structure. The structure of the exoskeleton has been designed in such a way that the whole working region is divided into three where each region can provide a different mode of rehabilitation. Recovery rate can be varied for individuals since it depends on various parameters. To evaluate the rate of recovery, three joint parameters have been identified: range of angular movement, angular velocity and joint torque. These parameters are incorporated into the framework of planning a novel rehabilitation strategy, which is discussed in this article along with the structural description of the designed exoskeleton.

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