| 1. |
- Bice, Annie R., et al.
(författare)
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Homotopic contralesional excitation suppresses spontaneous circuit repair and global network reconnections following ischemic stroke
- 2022
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Ingår i: eLife. - 2050-084X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Understanding circuit-level manipulations that affect the brain’s capacity for plasticity will inform the design of targeted interventions that enhance recovery after stroke. Following stroke, increased contralesional activity (e.g. use of the unaffected limb) can negatively influence recovery, but it is unknown which specific neural connections exert this influence, and to what extent increased contralesional activity affects systems-and molecular-level biomarkers of recovery. Here, we combine optogenetic photostimulation with optical intrinsic signal imaging (OISI) to examine how contralesional excitatory activity affects cortical remodeling after stroke in mice. Following photothrombosis of left primary somatosensory forepaw (S1FP) cortex, mice either recovered spontaneously or received chronic optogenetic excitation of right S1FP over the course of 4 weeks. Contralesional excitation suppressed perilesional S1FP remapping and was associated with abnormal patterns of stimulus-evoked activity in the unaffected limb. This maneuver also prevented the restoration of resting-state functional connectivity (RSFC) within the S1FP network, RSFC in several networks functionally-distinct from somatomotor regions, and resulted in persistent limb-use asymmetry. In stimulated mice, perilesional tissue exhibited transcriptional changes in several genes relevant for recovery. Our results suggest that contralesional excitation impedes local and global circuit reconnection through suppression of cortical activity and several neuroplasticity-related genes after stroke, and highlight the importance of site selection for therapeutic intervention after focal ischemia.
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| 2. |
- Hakon, Jakob, et al.
(författare)
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Inhibiting metabotropic glutamate receptor 5 after stroke restores brain function and connectivity
- 2024
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Ingår i: Brain : a journal of neurology. - 1460-2156. ; 147:1, s. 186-200
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Tidskriftsartikel (refereegranskat)abstract
- Stroke results in local neural disconnection and brain-wide neuronal network dysfunction leading to neurological deficits. Beyond the hyper-acute phase of ischemic stroke, there is no clinically-approved pharmacological treatment that alleviates sensorimotor impairments. Functional recovery after stroke involves the formation of new or alternative neuronal circuits including existing neural connections. The type-5 metabotropic glutamate receptor (mGluR5) has been shown to modulate brain plasticity and function, and is a therapeutic target in neurological diseases outside of stroke. We investigated whether mGluR5 influences functional recovery and network reorganization rodent models of focal ischemia. Using multiple behavioral tests we observed that treatment with negative allosteric modulators (NAMs) of mGluR5 (MTEP, fenobam, and AFQ056) for 12 days, starting 2 or 10 days after stroke, restored lost sensorimotor functions, without diminishing infarct size. Recovery was evident within hours after initiation of treatment and progressed over the subsequent 12 days. Recovery was prevented by activation of mGluR5 with the positive allosteric modulator VU0360172, and accelerated in mGluR5 KO mice compared to wild-type mice. After stroke, multisensory stimulation by enriched environments (EE) enhanced recovery, a result prevented by VU0360172, implying a role of mGluR5 in EE-mediated recovery. Additionally, MTEP treatment in conjunction with EE housing provided an additive recovery enhancement compared to either MTEP or EE alone. Using optical intrinsic signal imaging, we observed brain-wide disruptions in resting-state functional connectivity after stroke that were prevented by mGluR5 inhibition in distinct areas of contralesional sensorimotor and bilateral visual cortices. The levels of mGluR5 protein in mice and in tissue samples of stroke patients were unchanged after stroke. We conclude that neuronal circuitry subserving sensorimotor function after stroke is depressed by a mGluR5-dependent maladaptive plasticity mechanism that can be restored by mGluR5 inhibition. Post-acute stroke treatment with mGluR5 NAMs combined with rehabilitative training may represent a novel post-acute stroke therapy.
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| 3. |
- Häggman Henrikson, Jens, et al.
(författare)
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Enhanced functional recovery by levodopa is associated with decreased levels of synaptogyrin following stroke in aged mice
- 2020
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Ingår i: Brain Research Bulletin. - : Elsevier BV. - 0361-9230. ; 155, s. 61-66
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Tidskriftsartikel (refereegranskat)abstract
- Levodopa is a precursor to dopamine that has been shown to improve functional recovery following stroke partly achieved through mechanisms of brain plasticity. This study investigates if dopamine might affect plasticity by having a direct effect on synaptic plasticity through alterations in neurotransmitter release and re-uptake. Synaptogyrin is a synaptic vesicle protein that has been suggested to be involved in dopamine re-uptake in the synaptic terminal. Therefore, we investigated if levodopa has an effect on the expression of synaptogyrin 1. Thy1-YFP mice were subjected to photothrombosis as an experimental model of stroke. Starting two days after surgery they were treated with either levodopa or a vehicle solution (saline) on a daily basis until day seven following surgery. On day seven they were sacrificed and their brains stained for Dopamine 1 receptor (D1R), Dopamine 2 receptor (D2R) and Parvalbumin (PV). Neu-N stainings were used to estimate infarct size. A second group of mice were subjected to photothrombosis and also treated with either levodopa or a vehicle solution in the same manner as previously mentioned. On day seven they were then sacrificed, and samples of brain tissue were taken for protein determination. Western blots were carried out to investigate possible differences in synaptogyrin expression between the two groups. Immunofluorescent stains showed the presence of dopamine receptors on the YFP-positive neurons and on PV-expressing neurones. Our Western Blot analysis showed a significant decrease in the expression of synaptogyrin in levodopa-treated mice. Our stains showed co-localisation with Thy-1 neurones and PV-expressing neurones for both D1 and D2 receptors. This indicates that dopamine has the ability to bind to, and directly influence cortical neurons, as well as inhibitory interneurons. We discovered a considerable decrease in synaptogyrin expression through levodopa treatment, suggesting that this might be a mechanism for regulating brain plasticity.
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| 4. |
- Michalettos, Georgios, et al.
(författare)
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Effect of Anti-inflammatory Treatment with AMD3100 and CX3CR1 Deficiency on GABAA Receptor Subunit and Expression of Glutamate Decarboxylase Isoforms After Stroke
- 2021
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Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 58:11, s. 5876-5889
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Tidskriftsartikel (refereegranskat)abstract
- Following stroke, attenuation of detrimental inflammatory pathways might be a promising strategy to improve long-term outcome. In particular, cascades driven by pro-inflammatory chemokines interact with neurotransmitter systems such as the GABAergic system. This crosstalk might be of relevance for mechanisms of neuronal plasticity, however, detailed studies are lacking. The purpose of this study was to determine if treatment with 1,1′-[1,4-phenylenebis(methylene)]bis[1,4,8,11-tetraazacyclotetradecane] (AMD3100), an antagonist to the C-X-C chemokine receptor type 4 (CXCR4) and partial allosteric agonist to CXCR7 (AMD3100) alone or in combination with C-X3-C chemokine receptor type 1 (CX3CR1) deficiency, affect the expression of GABAA subunits and glutamate decarboxylase (GAD) isoforms. Heterozygous, CX3CR1-deficient mice and wild-type littermates were subjected to photothrombosis (PT). Treatment with AMD3100 (0.5 mg/kg twice daily i.p.) was administered starting from day 2 after induction of PT until day 14 after the insult. At this time point, GABAA receptor subunits (α3, β3, δ), GAD65 and GAD67, and CXCR4 were analyzed from the peri-infarct tissue and homotypic brain regions of the contralateral hemisphere by quantitative real-time PCR and Western Blot. Fourteen days after PT, CX3CR1 deficiency resulted in a significant decrease of the three GABAA receptor subunits in both the lesioned and the contralateral hemisphere compared to sham-operated mice. Treatment with AMD3100 promoted the down-regulation of GABAA subunits and GAD67 in the ipsilateral peri-infarct area, while the β3 subunit and the GAD isoforms were up-regulated in homotypic regions of the contralateral cortex. Changes in GABAA receptor subunits and GABA synthesis suggest that the CXCR4/7 and CX3CR1 signaling pathways are involved in the regulation of GABAergic neurotransmission in the post-ischemic brain.
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| 5. |
- Talhada, Daniela, et al.
(författare)
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Plasticity-enhancing effects of levodopa treatment after stroke
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:19
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Tidskriftsartikel (refereegranskat)abstract
- Dopaminergic treatment in combination with rehabilitative training enhances long-term recovery after stroke. However, the underlying mechanisms on structural plasticity are unknown. Here, we show an increased dopaminergic innervation of the ischemic territory during the first week after stroke induced in Wistar rats subjected to transient occlusion of the middle cerebral ar-tery (tMCAO) for 120 min. This response was also found in rats subjected to permanent focal ische-mia induced by photothrombosis (PT) and mice subjected to PT or tMCAO. Dopaminergic branches were detected in the infarct core of mice and rats in both stroke models. In addition, the Nogo A pathway was significantly downregulated in rats treated with levodopa (LD) compared to vehicle-treated animals subjected to tMCAO. Specifically, the number of Nogo A positive oligodendrocytes as well as the levels of Nogo A and the Nogo A receptor were significantly downregulated in the peri-infarct area of LD-treated animals, while the number of Oligodendrocyte transcription factor 2 positive cells increased in this region after treatment. In addition, we observed lower protein levels of Growth Associated Protein 43 in the peri-infarct area compared to sham-operated animals with-out treatment effect. The results provide the first evidence of the plasticity-promoting actions of dopaminergic treatment following stroke.
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