Perinatal strokes, occurring during vital periods of brain development, can significantly disrupt neurological maturation. While the inflammatory response initiated by the stroke originates within the central nervous system, there is compelling evidence that an extensive peripheral inflammatory reaction, both acute and chronic, plays a crucial role. This reaction is driven by key inflammatory mediators and has a direct impact on the outcomes of ischemic brain injuries. Microglia, the brain's resident immune cells, are central to the brain’s response to injury and development. Upon activation by stroke, these cells contribute to the pathology while also participating in attempts to repair the brain. Recent findings emphasize the significance of inflammation as a risk factor for enduring neurodevelopmental impairments, though a thorough understanding of the dynamics between systemic inflammation, microglia activity, and behavioural consequences is still lacking. To explore this further, we induced cortical lesions in mouse pups at postnatal day 14 (P14) using middle cerebral artery occlusion (MCAO). We assessed motor functions through gridwalk test, examining both immediate and long-term effects. Peripheral blood samples were also analysed to identify correlations between systemic inflammation levels and individual behavioural outcomes. Furthermore, we explored the impact of microglia depletion using a 7-days treatment with the CSFR-1 inhibitor, PLX-5622, to better understand their role in the context of perinatal stroke. Overall, we found that ischemic stroke induces long-lasting motor impairments in mice, thus validating an animal model for perinatal stroke. Moreover, I characterized the neuroinflammatory response after stroke opening new questions about microglia. The treatment used to rescue this phenotype exacerbates neuronal death, although further analysis will be needed to determine the role of microglia-induced neuroinflammation after a perinatal brain injury. Finally, stroked animals clustered based on their motor recovery presented a different cytokines profile during the acute phase post stroke, opening the possibility to the identification of novel prognostic biomarkers.
Perinatal strokes, occurring during vital periods of brain development, can significantly disrupt neurological maturation. While the inflammatory response initiated by the stroke originates within the central nervous system, there is compelling evidence that an extensive peripheral inflammatory reaction, both acute and chronic, plays a crucial role. This reaction is driven by key inflammatory mediators and has a direct impact on the outcomes of ischemic brain injuries. Microglia, the brain's resident immune cells, are central to the brain’s response to injury and development. Upon activation by stroke, these cells contribute to the pathology while also participating in attempts to repair the brain. Recent findings emphasize the significance of inflammation as a risk factor for enduring neurodevelopmental impairments, though a thorough understanding of the dynamics between systemic inflammation, microglia activity, and behavioural consequences is still lacking. To explore this further, we induced cortical lesions in mouse pups at postnatal day 14 (P14) using middle cerebral artery occlusion (MCAO). We assessed motor functions through gridwalk test, examining both immediate and long-term effects. Peripheral blood samples were also analysed to identify correlations between systemic inflammation levels and individual behavioural outcomes. Furthermore, we explored the impact of microglia depletion using a 7-days treatment with the CSFR-1 inhibitor, PLX-5622, to better understand their role in the context of perinatal stroke. Overall, we found that ischemic stroke induces long-lasting motor impairments in mice, thus validating an animal model for perinatal stroke. Moreover, I characterized the neuroinflammatory response after stroke opening new questions about microglia. The treatment used to rescue this phenotype exacerbates neuronal death, although further analysis will be needed to determine the role of microglia-induced neuroinflammation after a perinatal brain injury. Finally, stroked animals clustered based on their motor recovery presented a different cytokines profile during the acute phase post stroke, opening the possibility to the identification of novel prognostic biomarkers.
The role of microglia-mediated neuroinflammation in a mouse model of perinatal stroke
D'URSO, MATTEO
2023/2024
Abstract
Perinatal strokes, occurring during vital periods of brain development, can significantly disrupt neurological maturation. While the inflammatory response initiated by the stroke originates within the central nervous system, there is compelling evidence that an extensive peripheral inflammatory reaction, both acute and chronic, plays a crucial role. This reaction is driven by key inflammatory mediators and has a direct impact on the outcomes of ischemic brain injuries. Microglia, the brain's resident immune cells, are central to the brain’s response to injury and development. Upon activation by stroke, these cells contribute to the pathology while also participating in attempts to repair the brain. Recent findings emphasize the significance of inflammation as a risk factor for enduring neurodevelopmental impairments, though a thorough understanding of the dynamics between systemic inflammation, microglia activity, and behavioural consequences is still lacking. To explore this further, we induced cortical lesions in mouse pups at postnatal day 14 (P14) using middle cerebral artery occlusion (MCAO). We assessed motor functions through gridwalk test, examining both immediate and long-term effects. Peripheral blood samples were also analysed to identify correlations between systemic inflammation levels and individual behavioural outcomes. Furthermore, we explored the impact of microglia depletion using a 7-days treatment with the CSFR-1 inhibitor, PLX-5622, to better understand their role in the context of perinatal stroke. Overall, we found that ischemic stroke induces long-lasting motor impairments in mice, thus validating an animal model for perinatal stroke. Moreover, I characterized the neuroinflammatory response after stroke opening new questions about microglia. The treatment used to rescue this phenotype exacerbates neuronal death, although further analysis will be needed to determine the role of microglia-induced neuroinflammation after a perinatal brain injury. Finally, stroked animals clustered based on their motor recovery presented a different cytokines profile during the acute phase post stroke, opening the possibility to the identification of novel prognostic biomarkers.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/71589