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After traumatic brain injury (TBI), neurons surviving the initial insult can undergo chronic (secondary) degeneration via poorly understood mechanisms, resulting in long-term cognitive impairment. Although a neuroinflammatory response is promptly activated after TBI, it is unknown whether it has a significant role in chronic phases of TBI (> 1 year after injury). Using a closed-head injury model of TBI in mice, we showed by MRI scans that TBI caused substantial degeneration at the lesion site within a few weeks and these did not expand significantly thereafter. However, chronic alterations in neurons were observed, with reduced dendritic spine density lasting >1 year after injury. In parallel, we found a long-lasting inflammatory response throughout the entire brain. Deletion of one allele of CX3CR1, a chemokine receptor, limited infiltration of peripheral immune cells and largely prevented the chronic degeneration of the injured brain and provided a better functional recovery in female, but not male, mice. Therefore, targeting persistent neuroinflammation presents a new therapeutic option to reduce chronic neurodegeneration. [ABSTRACT FROM AUTHOR]

Acute brain ischemia induces a local neuroinflammatory reaction and alters peripheral immune homeostasis at the same time. Recent evidence has suggested a key role of the gut microbiota in autoimmune diseases by modulating immune homeostasis. Therefore, we investigated the mechanistic link among acute brain ischemia, microbiota alterations, and the immune response after brain injury. Using two distinct models of acute middle cerebral artery occlusion, we show by next-generation sequencing that large stroke lesions cause gut microbiota dysbiosis, which in turn affects stroke outcome via immune-mediated mechanisms. Reduced species diversity and bacterial overgrowth of bacteroidetes were identified as hallmarks of poststroke dysbiosis, which was associated with intestinal barrier dysfunction and reduced intestinal motility as determined by in vivo intestinal bolus tracking. Recolonizing germ-free mice with dysbiotic poststroke microbiota exacerbates lesion volume and functional deficits after experimental stroke compared with the recolonization with a normal control microbiota. In addition, recolonization of mice with a dysbiotic microbiome induces a proinflammatory T-cell polarization in the intestinal immune compartment and in the ischemic brain. Using in vivo cell-tracking studies, we demonstrate the migration of intestinal lymphocytes to the ischemic brain. Therapeutic transplantation of fecal microbiota normalizes brain lesion-induced dysbiosis and improves stroke outcome. These results support a novel mechanism in which the gut microbiome is a target of stroke-induced systemic alterations and an effector with substantial impact on stroke outcome. [ABSTRACT FROM AUTHOR]

Inflammatory mechanisms contribute substantially to secondary tissue injury after brain ischemia. Regulatory T cells (Tregs) are key endogenous modulators of postischemic neuroinflammation. We investigated the potential of histone deacetylase inhibition (HDACi) to enhance Treg potency for experimental stroke in mice. HDACi using trichostatin A increased the number of Tregs and boosted their immunosuppressive capacity and interleukin (IL)-10 expression. In vivo treatment reduced infarct volumes and behavioral deficits after cortical brain ischemia, attenuated cerebral proinflammatory cytokine expression, and increased numbers of brain-invading Tregs. A similar effect was obtained using tubastatin, a specific inhibitor of HDAC6 and a key HDAC in Foxp3 regulation. The neuroprotective effect of HDACi depended on the presence of Foxp3+ Tregs, and in vivo and in vitro studies showed that the anti-inflammatory cytokine IL-10 was their main mediator. In summary, modulation of Treg function by HDACi is a novel and potent target to intervene at the center of neuroinflammation. Furthermore, this novel concept of modulating endogenous immune mechanisms might be translated to a broad spectrum of diseases, including primary neuroinflammatory and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

The C9orf72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Non‐canonical translation of the expanded repeat results in abundant poly‐GA inclusion pathology throughout the CNS. (GA)149‐CFP expression in mice triggers motor deficits and neuroinflammation. Since poly‐GA is transmitted between cells, we investigated the therapeutic potential of anti‐GA antibodies by vaccinating (GA)149‐CFP mice. To overcome poor immunogenicity, we compared the antibody response of multivalent ovalbumin‐(GA)10 conjugates and pre‐aggregated carrier‐free (GA)15. Only ovalbumin‐(GA)10 immunization induced a strong anti‐GA response. The resulting antisera detected poly‐GA aggregates in cell culture and patient tissue. Ovalbumin‐(GA)10 immunization largely rescued the motor function in (GA)149‐CFP transgenic mice and reduced poly‐GA inclusions. Transcriptome analysis showed less neuroinflammation in ovalbumin‐(GA)10‐immunized poly‐GA mice, which was corroborated by semiquantitative and morphological analysis of microglia/macrophages. Moreover, cytoplasmic TDP‐43 mislocalization and levels of the neurofilament light chain in the CSF were reduced, suggesting neuroaxonal damage is reduced. Our data suggest that immunotherapy may be a viable primary prevention strategy for ALS/FTD in C9orf72 mutation carriers. Synopsis: The study proposes active immunization targeting poly‐GA as a prevention approach for pre‐symptomatic C9orf72 mutation carriers at risk of developping ALS/FTD. Immunization using Ovalbumin‐(GA)10 largely rescued motor deficits in a poly‐GA mouse model. Ovalbumin‐(GA)10 immunization drives strong anti‐GA response without apparent side effects.Ovalbumin‐(GA)10 immunization reduces motor deficits and poly‐GA inclusions.Ovalbumin‐(GA)10 immunization attenuates neuroinflammation, neuroaxonal damage and reduces cytoplasmic TDP‐43 mislocalization. [ABSTRACT FROM AUTHOR]

Background: The discrepancy between experimental research and clinical trial outcomes is a persistent challenge in preclinical studies, particularly in stroke research. A possible factor contributing to this issue is the lack of standardization across experimental stroke models, leading to poor reproducibility in multicenter studies. This study addresses this gap by aiming to enhance reproducibility and the efficacy of multicenter studies through the harmonization of protocols and training of involved personnel., Methods: We established a set of standard operating procedures for various stroke models and the Neuroscore. These standard operating procedures were implemented across multiple research centers, followed by specialized, in-person training for all participants. We measured the variability in infarct volume both before and after the implementation of these standardized protocols and training sessions., Results: The standardization process led to a significant reduction in variability of infarct volume across different stroke models (40%-50% reduction), demonstrating the effectiveness of our harmonized protocols and training. Additionally, the implementation of the Neuroscore system across centers showed low variability and consistent results up to 28 days poststroke, underscoring its utility in chronic phase evaluations., Conclusions: The harmonization of protocols and surgeon training significantly reduced variability in experimental outcomes across different centers. This improvement can increase the comparability of data between research groups and enhance the statistical power of multicenter studies. Our findings also establish the Neuroscore as a reliable tool for long-term assessment in stroke research, paving the way for more consistent and impactful multicenter preclinical studies., Competing Interests: None.

The importance of the brain-heart interaction has been increasingly recognized as a critical physiological axis that is altered in disease. In this review, we explore the intricate relationship between the central nervous system and cardiovascular health, focusing particularly on immunological mechanisms that influence the course of both neurological and cardiovascular diseases. While previous studies have established a key role of the autonomic nervous system in linking brain and the heart, more recent studies have expanded our understanding of the multifaceted inter-organ interactions. As such, circulating mediators include immune cells of the adaptive and innate immune system and their secreted immunogenic factors have come into the focus as mediators along this bidirectional communication. Hence, in this review we briefly discuss the contribution of the autonomic nervous system and then focus on innate and adaptive immune mechanisms along the heart-to-brain and brain-to-heart axes, illustrating how cardiovascular diseases affect cognitive functions and how brain pathologies lead to cardiac complications., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aim: To explore the regulatory mechanisms of microglia-mediated cytotoxic CD8 + T-cell infiltration in the white matter injury of perioperative stroke (PIS)., Methods: Adult male C57BL/6 mice were subjected to ileocolic bowel resection (ICR) 24 h prior to permanent distant middle cerebral artery occlusion (dMCAO) to establish model PIS. White matter injury, functional outcomes, peripheral immune cell infiltration, and microglia phenotype were assessed up to 28 days after dMCAO using behavioral phenotyping, immunofluorescence staining, transmission electron microscopy, western blot, and FACS analysis., Results: We found surgery aggravated white matter injury and deteriorated sensorimotor deficits up to 28 days following PIS. The PIS mice exhibited significantly increased activation of peripheral and central CD8 + T cells, while significantly reduced numbers of mature oligodendrocytes compared to IS mice. Neutralizing CD8 + T cells partly reversed the aggravated demyelination following PIS. Pharmacological blockage or genetic deletion of receptor-interacting protein kinase 1 (RIPK1) activity could alleviate CD8 + T-cell infiltration and demyelination in PIS mice., Conclusion: Surgery exacerbates demyelination and worsens neurological function by promoting infiltration of CD8 + T cells and microglia necroptosis, suggesting that modulating interactions of CD8 + T cells and microglia could be a novel therapeutic target of long-term neurological deficits of PIS., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Incomplete reperfusion of the microvasculature ('no-reflow') after ischaemic stroke damages salvageable brain tissue. Previous ex vivo studies suggest pericytes are vulnerable to ischaemia and may exacerbate no-reflow, but the viability of pericytes and their association with no-reflow remains under-explored in vivo. Using longitudinal in vivo two-photon single-cell imaging over 7 days, we showed that 87% of pericytes constrict during cerebral ischaemia and remain constricted post reperfusion, and 50% of the pericyte population are acutely damaged. Moreover, we revealed ischaemic pericytes to be fundamentally implicated in capillary no-reflow by limiting and arresting blood flow within the first 24 h post stroke. Despite sustaining acute membrane damage, we observed that over half of all cortical pericytes survived ischaemia and responded to vasoactive stimuli, upregulated unique transcriptomic profiles and replicated. Finally, we demonstrated the delayed recovery of capillary diameter by ischaemic pericytes after reperfusion predicted vessel reconstriction in the subacute phase of stroke. Cumulatively, these findings demonstrate that surviving cortical pericytes remain both viable and promising therapeutic targets to counteract no-reflow after ischaemic stroke., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: Understanding neuroinflammation after acute ischemic stroke is a crucial step on the way to an individualized post-stroke treatment. Microglia activation, an essential part of neuroinflammation, can be assessed using [ 18 F]GE-180 18 kDa translocator protein positron emission tomography (TSPO-PET). However, the commonly used 60-90 min post-injection (p.i.) time window was not yet proven to be suitable for post-stroke neuroinflammation assessment. In this study, we compare semi-quantitative estimates derived from late time frames to quantitative estimates calculated using a full 0-90 min dynamic scan in a mouse photothrombotic stroke (PT) model., Materials and Methods: Six mice after PT and six sham mice were included in the study. For a half of the mice, we acquired four serial 0-90 min scans per mouse (analysis cohort) and calculated standardized uptake value ratios (SUVRs; cerebellar reference) for the PT volume of interest (VOI) in five late 10 min time frames as well as distribution volume ratios (DVRs) for the same VOI. We compared late static 10 min SUVRs and the 60-90 min time frame of the analysis cohort to the corresponding DVRs by linear fitting. The other half of the animals received a static 60-90 min scan and was used as a validation cohort. We extrapolated DVRs by using the static 60-90 min p.i. time window, which were compared to the DVRs of the analysis cohort., Results: We found high linear correlations between SUVRs and DVRs in the analysis cohort for all studied 10 min time frames, while the fits of the 60-70, 70-80, and 80-90 min p.i. time frames were the ones closest to the line of identity. For the 60-90 min time window, we observed an excellent linear correlation between SUVR and DVR regardless of the phenotype (PT vs . sham). The extrapolated DVRs of the validation cohort were not significantly different from the DVRs of the analysis group., Conclusion: Simplified quantification by a reference tissue ratio of the late 60-90 min p.i. [ 18 F]GE-180 PET image can replace full quantification of a dynamic scan for assessment of microglial activation in the mouse PT model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zatcepin, Heindl, Schillinger, Kaiser, Lindner, Bartenstein, Kopczak, Liesz, Brendel and Ziegler.)

The gut microbiome has been implicated as a key regulator of brain function in health and disease. But the impact of gut microbiota on functional brain connectivity is unknown. We used resting-state functional magnetic resonance imaging in germ-free and normally colonized mice under naive conditions and after ischemic stroke. We observed a strong, brain-wide increase of functional connectivity in germ-free animals. Graph theoretical analysis revealed significant higher values in germ-free animals, indicating a stronger and denser global network but with less structural organization. Breakdown of network function after stroke equally affected germ-free and colonized mice. Results from histological analyses showed changes in dendritic spine densities, as well as an immature microglial phenotype, indicating impaired microglia-neuron interaction in germ-free mice as potential cause of this phenomenon. These results demonstrate the substantial impact of bacterial colonization on brain-wide function and extend our so far mainly (sub) cellular understanding of the gut-brain axis., Competing Interests: All authors declare no competing interests., (© 2021.)

The CNS is ensheathed by the meninges and cerebrospinal fluid, and recent findings suggest that these CNS-associated border tissues have complex immunological functions. Unlike myeloid lineage cells, lymphocytes in border compartments have yet to be thoroughly characterized. Based on single-cell transcriptomics, we here identified a highly location-specific composition and expression profile of tissue-resident leukocytes in CNS parenchyma, pia-enriched subdural meninges, dura mater, choroid plexus and cerebrospinal fluid. The dura layer of the meninges contained a large population of B cells under homeostatic conditions in mice and rats. Murine dura B cells exhibited slow turnover and long-term tissue residency, and they matured in experimental neuroinflammation. The dura also contained B lineage progenitors at the pro-B cell stage typically not found outside of bone marrow, without direct influx from the periphery or the skull bone marrow. This identified the dura as an unexpected site of B cell residence and potentially of development in both homeostasis and neuroinflammation., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Rationale: Arterial inflammation manifested as atherosclerosis is the leading cause of mortality worldwide. Genome-wide association studies have identified a prominent role of HDAC (histone deacetylase)-9 in atherosclerosis and its clinical complications including stroke and myocardial infarction., Objective: To determine the mechanisms linking HDAC9 to these vascular pathologies and explore its therapeutic potential for atheroprotection., Methods and Results: We studied the effects of Hdac9 on features of plaque vulnerability using bone marrow reconstitution experiments and pharmacological targeting with a small molecule inhibitor in hyperlipidemic mice. We further used 2-photon and intravital microscopy to study endothelial activation and leukocyte-endothelial interactions. We show that hematopoietic Hdac9 deficiency reduces lesional macrophage content while increasing fibrous cap thickness thus conferring plaque stability. We demonstrate that HDAC9 binds to IKK (inhibitory kappa B kinase)-α and β, resulting in their deacetylation and subsequent activation, which drives inflammatory responses in both macrophages and endothelial cells. Pharmacological inhibition of HDAC9 with the class IIa HDAC inhibitor TMP195 attenuates lesion formation by reducing endothelial activation and leukocyte recruitment along with limiting proinflammatory responses in macrophages. Transcriptional profiling using RNA sequencing revealed that TMP195 downregulates key inflammatory pathways consistent with inhibitory effects on IKKβ. TMP195 mitigates the progression of established lesions and inhibits the infiltration of inflammatory cells. Moreover, TMP195 diminishes features of plaque vulnerability and thereby enhances plaque stability in advanced lesions. Ex vivo treatment of monocytes from patients with established atherosclerosis reduced the production of inflammatory cytokines including IL (interleukin)-1β and IL-6., Conclusions: Our findings identify HDAC9 as a regulator of atherosclerotic plaque stability and IKK activation thus providing a mechanistic explanation for the prominence of HDAC9 as a vascular risk locus in genome-wide association studies. Its therapeutic inhibition may provide a potent lever to alleviate vascular inflammation. Graphical Abstract: A graphical abstract is available for this article.

The organization of brain areas in functionally connected networks, their dynamic changes, and perturbations in disease states are subject of extensive investigations. Research on functional networks in humans predominantly uses functional magnetic resonance imaging (fMRI). However, adopting fMRI and other functional imaging methods to mice, the most widely used model to study brain physiology and disease, poses major technical challenges and faces important limitations. Hence, there is great demand for alternative imaging modalities for network characterization. Here, we present a refined protocol for in vivo widefield calcium imaging of both cerebral hemispheres in mice expressing a calcium sensor in excitatory neurons. We implemented a stringent protocol for minimizing anesthesia and excluding movement artifacts which both imposed problems in previous approaches. We further adopted a method for unbiased identification of functional cortical areas using independent component analysis (ICA) on resting-state imaging data. Biological relevance of identified components was confirmed using stimulus-dependent cortical activation. To explore this novel approach in a model of focal brain injury, we induced photothrombotic lesions of the motor cortex, determined changes in inter- and intrahemispheric connectivity at multiple time points up to 56 days post-stroke and correlated them with behavioral deficits. We observed a severe loss in interhemispheric connectivity after stroke, which was partially restored in the chronic phase and associated with corresponding behavioral motor deficits. Taken together, we present an improved widefield calcium imaging tool accounting for anesthesia and movement artifacts, adopting an advanced analysis pipeline based on human fMRI algorithms and with superior sensitivity to recovery mechanisms in mouse models compared to behavioral tests. This tool will enable new studies on interhemispheric connectivity in murine models with comparability to human imaging studies for a wide spectrum of neuroscience applications in health and disease., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Analysis of entire transparent rodent bodies after clearing could provide holistic biological information in health and disease, but reliable imaging and quantification of fluorescent protein signals deep inside the tissues has remained a challenge. Here, we developed vDISCO, a pressure-driven, nanobody-based whole-body immunolabeling technology to enhance the signal of fluorescent proteins by up to two orders of magnitude. This allowed us to image and quantify subcellular details through bones, skin and highly autofluorescent tissues of intact transparent mice. For the first time, we visualized whole-body neuronal projections in adult mice. We assessed CNS trauma effects in the whole body and found degeneration of peripheral nerve terminals in the torso. Furthermore, vDISCO revealed short vascular connections between skull marrow and brain meninges, which were filled with immune cells upon stroke. Thus, our new approach enables unbiased comprehensive studies of the interactions between the nervous system and the rest of the body.

Stroke induces a multiphasic systemic immune response, but the consequences of this response on atherosclerosis-a major source of recurrent vascular events-have not been thoroughly investigated. We show that stroke exacerbates atheroprogression via alarmin-mediated propagation of vascular inflammation. The prototypic brain-released alarmin high-mobility group box 1 protein induced monocyte and endothelial activation via the receptor for advanced glycation end products (RAGE)-signaling cascade and increased plaque load and vulnerability. Recruitment of activated monocytes via the CC-chemokine ligand 2-CC-chemokine receptor type 2 pathway was critical in stroke-induced vascular inflammation. Neutralization of circulating alarmins or knockdown of RAGE attenuated atheroprogression. Blockage of β3-adrenoreceptors attenuated the egress of myeloid monocytes after stroke, whereas neutralization of circulating alarmins was required to reduce systemic monocyte activation and aortic invasion. Our findings identify a synergistic effect of the sympathetic stress response and alarmin-driven inflammation via RAGE as a critical mechanism of exacerbated atheroprogression after stroke., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Neuroinflammation contributes substantially to stroke pathophysiology. Cerebral invasion of peripheral leukocytes-particularly T cells-has been shown to be a key event promoting inflammatory tissue damage after stroke. While previous research has focused on the vascular invasion of T cells into the ischemic brain, the choroid plexus (ChP) as an alternative cerebral T-cell invasion route after stroke has not been investigated. We here report specific accumulation of T cells in the peri-infarct cortex and detection of T cells as the predominant population in the ipsilateral ChP in mice as well as in human post-stroke autopsy samples. T-cell migration from the ChP to the peri-infarct cortex was confirmed by in vivo cell tracking of photoactivated T cells. In turn, significantly less T cells invaded the ischemic brain after photothrombotic lesion of the ipsilateral ChP and in a stroke model encompassing ChP ischemia. We detected a gradient of CCR2 ligands as the potential driving force and characterized the neuroanatomical pathway for the intracerebral migration. In summary, our study demonstrates that the ChP is a key invasion route for post-stroke cerebral T-cell invasion and describes a CCR2-ligand gradient between cortex and ChP as the potential driving mechanism for this invasion route.

Experimental reproducibility between laboratories is a major translational obstacle worldwide, particularly in studies investigating immunomodulatory therapies in relation to brain disease. In recent years increasing attention has been drawn towards the gut microbiota as a key factor in immune cell polarization. Moreover, manipulation of the gut microbiota has been found effective in a diverse range of brain disorders. Within this study we aimed to test the impact of microbiota differences between mice from different sources on the post-stroke neuroinflammatory response. With this rationale, we have investigated the correlation between microbiota differences and the immune response in mice from three commercial breeders with the same genetic background (C57BL/6). While overall bacterial load was comparable, we detected substantial differences in species diversity and microbiota composition on lower taxonomic levels. Specifically, we investigated segmented filamentous bacteria (SFB)-which have been shown to promote T cell polarization-and found that they were absent in mice from one breeder but abundant in others. Our experiments revealed a breeder specific correlation between SFB presence and the ratio of Treg to Th17 cells. Moreover, recolonization of SFB-negative mice with SFB resulted in a T cell shift which mimicked the ratios found in SFB-positive mice. We then investigated the response to a known experimental immunotherapeutic approach, CD28 superagonist (CD28SA), which has been previously shown to expand the Treg population. CD28SA treatment had differing effects between mice from different breeders and was found to be ineffective at inducing Treg expansion in SFB-free mice. These changes directly corresponded to stroke outcome as mice lacking SFB had significantly larger brain infarcts. This study demonstrates the major impact of microbiota differences on T cell polarization in mice during ischemic stroke conditions, and following immunomodulatory therapies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is characterized by deposition of amyloid plaques, neurofibrillary tangles, and neuroinflammation. In order to study microglial contribution to amyloid plaque phagocytosis, we developed a novel ex vivo model by co-culturing organotypic brain slices from up to 20-month-old, amyloid-bearing AD mouse model (APPPS1) and young, neonatal wild-type (WT) mice. Surprisingly, co-culturing resulted in proliferation, recruitment, and clustering of old microglial cells around amyloid plaques and clearance of the plaque halo. Depletion of either old or young microglial cells prevented amyloid plaque clearance, indicating a synergistic effect of both populations. Exposing old microglial cells to conditioned media of young microglia or addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) was sufficient to induce microglial proliferation and reduce amyloid plaque size. Our data suggest that microglial dysfunction in AD may be reversible and their phagocytic ability can be modulated to limit amyloid accumulation. This novel ex vivo model provides a valuable system for identification, screening, and testing of compounds aimed to therapeutically reinforce microglial phagocytosis., (© 2016 The Authors.)

Stroke causes 5.7 million deaths annually. This ranks stroke as the second most common cause of death and, additionally, it is a major cause of disability. Because of an ageing population, stroke incidence and costs will greatly increase in the future. This makes stroke an ongoing social and economic burden, in contrast to the only very limited therapeutic options. In the last decade vast sums were spent on translational research focused on neuroprotective strategies in the acute phase of ischaemic stroke. A plethora of candidate agents were tested in experimental models and preclinical studies, but none was proven effective in clinical trials. This gave rise to discussions about the possible reasons for this failure, ending up mainly with criticism of methodological aspects of the preclinical and clinical studies, or of the relevance of animal studies in drug development. Indeed, the question could rather be whether neuroprotection is the right target for successful stroke treatment. In this context, a paradigm change can currently be observed: the focus of experimental and translational stroke research is shifting from early neuroprotection to delayed mechanisms such as stroke-associated comorbidities, regeneration and plasticity. In this review we highlight a few recently emerging fields in translational stroke research. One such topic is the crosstalk between immunity and the injured brain as key pathomechanism in stroke. On one hand, innate and adaptive immune cells play an important role in the fate of injured brain tissue after stroke; on the other, peripheral immune alterations are critically involved in post-stroke comorbidities. Another emerging research area is the analysis of mechanisms involved in regeneration and neuronal plasticity after stroke. Here, we discuss the current understanding of basic mechanisms involved after brain injury, clinical imaging approaches and therapeutic strategies to promote regeneration in stroke patients.