Meningeal lymphatics-microglia axis regulates synaptic physiology [ligation]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1126617 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29487464_1.fastq.gz | Fastqsanger.gz | |||
| SRR29487464_2.fastq.gz | Fastqsanger.gz | |||
| SRR29487465_1.fastq.gz | Fastqsanger.gz | |||
| SRR29487465_2.fastq.gz | Fastqsanger.gz |
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Project description:Meningeal lymphatics serve as the primary outlet for cerebrospinal fluid, and their dysfunction is associated with various neurodegenerative conditions. Previous studies have demonstrated that dysfunctional meningeal lymphatics evoke behavioral deficits, but the neural mechanisms underlying those behavioral changes remained elusive. Here, we show that prolonged impairment of meningeal lymphatics alters the balance of cortical excitatory and inhibitory synaptic inputs by reducing inhibitory synapses, accompanied by deficits in novelty recognition tasks. These synaptic and behavioral alterations are mediated by microglia, which exhibit transcriptomic, morphological, and functional alterations as a result of lymphatic dysfunction. Notably, microglial expression of Il6 increases, thereby mediating the reduction in inhibitory synapses via neuronal signaling. Interestingly, improving the function of meningeal lymphatics in aged mice restores the numbers of functional inhibitory synapses and cortical network activity. Our findings suggest that dysfunctional meningeal lymphatics adversely impact cortical circuitry through a microglia−IL-6-dependent mechanism, providing a potential target for the treatment of aging-associated cognitive decline.
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Project description:Meningeal lymphatics serve as the primary outlet for cerebrospinal fluid, and their dysfunction is associated with various neurodegenerative conditions. Previous studies have demonstrated that dysfunctional meningeal lymphatics evoke behavioral deficits, but the neural mechanisms underlying those behavioral changes remained elusive. Here, we show that prolonged impairment of meningeal lymphatics alters the balance of cortical excitatory and inhibitory synaptic inputs by reducing inhibitory synapses, accompanied by deficits in novelty recognition tasks. These synaptic and behavioral alterations are mediated by microglia, which exhibit transcriptomic, morphological, and functional alterations as a result of lymphatic dysfunction. Notably, microglial expression of Il6 increases, thereby mediating the reduction in inhibitory synapses via neuronal signaling. Interestingly, improving the function of meningeal lymphatics in aged mice restores the numbers of functional inhibitory synapses and cortical network activity. Our findings suggest that dysfunctional meningeal lymphatics adversely impact cortical circuitry through a microglia−IL-6-dependent mechanism, providing a potential target for the treatment of aging-associated cognitive decline.
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Project description:Meningeal lymphatics-microglia axis regulates synaptic physiology [acz.vehicle]
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Project description:Meningeal lymphatics-microglia axis regulates synaptic physiology [egfp/vegfc]
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Project description:Major depressive disorder is one of the most common mental health conditions. Meningeal lymphatics are essential for drainage of molecules in the cerebrospinal fluid to the peripheral immune system. Their potential role in depression-like behaviour has not been investigated. Here, we show in mice, sub-chronic variable stress as a model of depression-like behaviour impairs meningeal lymphatics in females but not in males. Manipulations of meningeal lymphatics regulate the sex difference in the susceptibility to stress-induced depression- and anxiety-like behaviors in mice, as well as alterations of the medial prefrontal cortex and the ventral tegmental area, brain regions critical for emotional regulation. Together, our findings suggest meningeal lymphatic impairment contributes to susceptibility to stress in mice, and that restoration of the meningeal lymphatics might have potential for modulation of depression-like behaviour.
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Project description:Microglia are thought to originate exclusively from primitive macrophage progenitors in the yolk sac (YS) and persist throughout life without contributions from definitive hematopoiesis. Here, using Ms4a3-Cre lineage tracing, pharmacological manipulation, and RNA-sequencing, we elucidated the presence and unique features of monocyte-derived macrophages (MDMs) in the brain parenchyma at baseline and during microglia repopulation. Using parabiosis and skull transplantation, we show that MDMs derived from both peripheral blood and skull bone marrow can repopulate microglia-depleted brains, and they display distinct transcriptional profiles compared to YS-derived microglia. Blood-derived macrophages possess a disease-associated microglia (DAM)-like phenotype, while skull-derived macrophages mirror injury-responsive microglia (IRM) and exhibit significant interactions with T cells. Repetitive microglia depletion and subsequent MDM engraftment in 5xFAD mice led to increased amyloid burden, suggesting differential responses of resident microglia and MDMs towards amyloid pathology. Our results reveal the heterogeneous origins and functions of microglia during cell turnover and neurodegeneration, offering insights that may guide microglia-targeted immunomodulatory strategies for neurological disorders.
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Project description:The goal of this study is to use bulk RNA-sequencing of the right brain hemisphere to observe the effects of TBI in the context of pre-existing meningeal lymphatic dysfunction in mice. We find that pre-existing meningeal lymphatic dysfunction potentiates the inflammatory response to TBI, suggesting an important role for the meningeal lymphatics in injury site drainage and proper recovery.
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Project description:Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfill two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.
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Project description:Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfill two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.
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Project description:Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease [2 of 3]
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