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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE168756 | GEO | 2022/06/12

REPOSITORIES: GEO

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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

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

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

| PRJNA713828 | ENA

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

Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis.

Project description:Traumatic brain injury (TBI) is a leading global cause of death and disability. Here we demonstrate in an experimental mouse model of TBI that mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that begin within hours and last out to at least one month post-injury. To investigate a mechanism underlying impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics. We demonstrate that increased ICP can contribute to meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction before TBI leads to increased neuroinflammation and negative cognitive outcomes. Finally, we report that rejuvenation of meningeal lymphatic drainage function in aged mice can ameliorate TBI-induced gliosis. These findings provide insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.

| S-EPMC7483525 | biostudies-literature

Significance of developmental meningeal lymphatic dysfunction in experimental post-traumatic injury.

Project description:Understanding the pathological mechanisms unfolding after chronic traumatic brain injury (TBI) could reveal new therapeutic entry points. During the post-TBI sequel, the involvement of cerebrospinal fluid drainage through the meningeal lymphatic vessels was proposed. Here, we used K14-VEGFR3-Ig transgenic mice to analyze whether a developmental dysfunction of meningeal lymphatic vessels modifies post-TBI pathology. To this end, a moderate TBI was delivered by controlled cortical injury over the temporal lobe in male transgenic mice or their littermate controls. We performed MRI and a battery of behavioral tests over time to define the post-TBI trajectories. In vivo analyses were integrated by ex-vivo quantitative and morphometric examinations of the cortical lesion and glial cells. In post-TBI K14-VEGFR3-Ig mice, the recovery from motor deficits was protracted compared to littermates. This outcome is coherent with the observed slower hematoma clearance in transgenic mice during the first two weeks post-TBI. No other genotype-related behavioral differences were observed, and the volume of cortical lesions imaged by MRI in vivo, and confirmed by histology ex-vivo, were comparable in both groups. However, at the cellular level, post-TBI K14-VEGFR3-Ig mice exhibited an increased percentage of activated Iba1 microglia in the hippocampus and auditory cortex, areas that are proximal to the lesion. Although not impacting or modifying the structural brain damage and post-TBI behavior, a pre-existing dysfunction of meningeal lymphatic vessels is associated with morphological microglial activation over time, possibly representing a sub-clinical pathological imprint or a vulnerability factor. Our findings suggest that pre-existing mLV deficits could represent a possible risk factor for the overall outcome of TBI pathology.

| S-EPMC9184565 | 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

CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature.

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.

| S-EPMC6214619 | biostudies-literature

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