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Age-associated suppression of exploratory activity during sickness is linked to meningeal lymphatic dysfunction and microglia activation

ABSTRACT: Age-associated suppression of exploratory activity during sickness is linked to meningeal lymphatic dysfunction and microglia activation

PROVIDER: PRJNA713828 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13944311_1.fastq.gz	Fastqsanger.gz
	SRR13944311_2.fastq.gz	Fastqsanger.gz
	SRR13944312_1.fastq.gz	Fastqsanger.gz
	SRR13944312_2.fastq.gz	Fastqsanger.gz
	SRR13944313_1.fastq.gz	Fastqsanger.gz

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Age-associated suppression of exploratory activity during sickness is linked to meningeal lymphatic dysfunction and microglia activation [ablation]

Project description:The objective of this study is to assess the contribution of meningeal lymphatic vessels to microglia response to peripheral inflammation. To this end, we sequence CD11b+ cells sorted from whole brain of adult mice with intact meningeal lymphatic vessels or mice with experimental meningeal lymphatic ablation, two hours following 1μg IL-1β or saline vehicle intraperitoneal injection. The two-hour timepoint was selected for analysis because that corresponds with the peak of the behavioral response as defined by a decrease in locomotor activity and the connection between behavior and microglia activation is of particular interest in this study.

2022-06-12 | GSE168755 | GEO

Age-associated suppression of exploratory activity during sickness is linked to meningeal lymphatic dysfunction and microglia activation [aged]

Project description:The objective of this study is to assess the contribution of meningeal lymphatic vessels to microglia response to peripheral inflammation. Aged mice (over 2 years old) were selected as a physiologically and clinically relevant model for lymphatic dysfunction because previous reporting demonstrates meningeal lymphatic function declines with age. We sequence CD11b+ cells sorted from whole brain of aged mice two hours following 1μg IL-1β or saline vehicle intraperitoneal injection. To facilitate comparison and integration with adult mouse and experimental lymphatic ablation data, identical methods were employed.

2022-06-12 | GSE168754 | GEO

Age-associated suppression of exploratory activity during sickness is linked to meningeal lymphatic dysfunction and microglia activation [aged]

Project description:Age-associated suppression of exploratory activity during sickness is linked to meningeal lymphatic dysfunction and microglia activation [aged]

| PRJNA713918 | ENA

Age-associated suppression of exploratory activity during sickness is linked to meningeal lymphatic dysfunction and microglia activation [ablation]

Project description:Age-associated suppression of exploratory activity during sickness is linked to meningeal lymphatic dysfunction and microglia activation [ablation]

| PRJNA713919 | ENA

Age-associated suppression of exploratory activity during sickness is linked to meningeal lymphatic dysfunction and microglia activation.

Project description:Peripheral inflammation triggers a transient, well-defined set of behavioral changes known as sickness behavior1-3, but the mechanisms by which inflammatory signals originating in the periphery alter activity in the brain remain obscure. Emerging evidence has established meningeal lymphatic vasculature as an important interface between the central nervous system (CNS) and the immune system, responsible for facilitating brain solute clearance and perfusion by cerebrospinal fluid (CSF)4,5. Here, we demonstrate that meningeal lymphatics both assist microglial activation and support the behavioral response to peripheral inflammation. Ablation of meningeal lymphatics results in a heightened behavioral response to IL-1β-induced inflammation and a dampened transcriptional and morphological microglial phenotype. Moreover, our findings support a role for microglia in tempering the severity of sickness behavior with specific relevance to aging-related meningeal lymphatic dysfunction. Transcriptional profiling of brain myeloid cells shed light on the impact of meningeal lymphatic dysfunction on microglial activation. Furthermore, we demonstrate that experimental enhancement of meningeal lymphatic function in aged mice is sufficient to reduce the severity of exploratory abnormalities but not pleasurable consummatory behavior. Finally, we identify dysregulated genes and biological pathways, common to both experimental meningeal lymphatic ablation and aging, in microglia responding to peripheral inflammation that may result from age-related meningeal lymphatic dysfunction.

| S-EPMC10103743 | biostudies-literature

Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis

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.

2020-07-25 | GSE155063 | GEO

Age-associated suppression of exploratory activity during sickness is linked to meningeal lymphatic dysfunction and microglia activation

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-06-12 | GSE168756 | GEO

Project description:The meningeal lymphatic network—housed within the dural meninges surrounding the brain— is critical for cerebrospinal fluid (CSF) drainage. Through continuous brain interstitial fluid (ISF) mixing with CSF via the glymphatic system, this lymphatic network facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer’s disease (AD), attenuated meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins—including amyloid beta—in the CNS. Alleviating this age-related meningeal lymphatic dysfunction represents a promising therapeutic strategy to alleviate AD pathology. However, the mechanisms underlying this lymphatic decline remain elusive. Here we demonstrate that age-related alterations in meningeal immunity contribute to meningeal lymphatic impairment. Single-cell RNA-sequencing of dural lymphatic endothelial cells in aged mice demonstrated a response signature to the cytokine IFNγ, which was elevated in the aged dura due to meningeal T cell accumulation. Chronic elevation of IFNγ in the meninges of young mice via AAV-mediated overexpression altered lymphatic adherans junctions and impaired CSF drainage to deep cervical lymph nodes—comparable to the deficits observed in aged mice. Direct disruption of lymphatic junctions via CSF-delivered VE-Cadherin disrupting antibodies was sufficient to phenocopy impairments in CSF drainage. Therapeutically, IFNγ neutralization in aged mice alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable therapeutic target to normalize CSF drainage in aged mice and alleviate the pathology in AD mice associated with impaired waste removal.

2023-03-10 | GSE217312 | GEO

2023-03-10 | GSE217276 | GEO

Immunotherapy against amyloid beta is modulated by meningeal lymphatic function I

Project description:A growing body of evidence points to passive immunotherapy as a promising therapeutic strategy against AD. Herein, we show that meningeal lymphatic vasculature becomes dysfunctional in AD transgenic mice and that manipulating meningeal lymphatic drainage affects the outcome of anti-Aβ immunotherapy.

2021-03-11 | GSE141849 | GEO

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