A novel role of meningeal lymphatics in sex-dependent stress susceptibility to depression in mice
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ABSTRACT:
PROVIDER: PRJNA831131 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18901227_1.fastq.gz | Fastqsanger.gz | |||
| SRR18901227_2.fastq.gz | Fastqsanger.gz | |||
| SRR18901228_1.fastq.gz | Fastqsanger.gz | |||
| SRR18901228_2.fastq.gz | Fastqsanger.gz | |||
| SRR18901229_1.fastq.gz | Fastqsanger.gz |
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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:Major depressive disorder (MDD) is a pervasive and debilitating syndrome characterized by mood disturbances, anhedonia, and alterations in cognition. While the prevalence of MDD is twice as high for women compared to men, little is known about the molecular mechanisms that drive sex differences in depression susceptibility. We discovered that Slit Guidance Ligand 1 (SLIT1), a secreted protein essential for axonal navigation and molecular guidance in cellular migration, is downregulated in the ventromedial prefrontal cortex (vmPFC) of depressed women compared to healthy controls, but not depressed men. This sex-specific downregulation of Slit1 was also observed in the vmPFC of mice exposed to chronic variable stress. To identify a causal, sex-specific role for SLIT1 in depression-related behavioral abnormalities, we performed knockdown (KD) of Slit1 expression in the vmPFC of male and female mice. When combined with stress exposure, vmPFC Slit1 KD reflected the human condition by inducing a sex-specific increase in anxiety- and depression-like behavioral abnormalities in female mice with no effect seen in male mice. Further, we found that vmPFC Slit1 KD caused a pronounced reduction in dendritic arborization and concomitant alterations to electrophysiological properties of vmPFC pyramidal neurons in females. Additionally, RNA-sequencing analysis of the vmPFC following Slit1 KD in female mice revealed an augmented transcriptional stress signature. Together, our findings establish a crucial role for SLIT1 in regulating neurophysiological and transcriptional responses to stress within the vmPFC, and provide mechanistic insight into novel signaling pathways and molecular factors influencing sex differences in depression susceptibility.
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Project description:Aging is a major risk factor for many neurological pathologies, including Alzheimer’s disease (AD). However, the mechanisms underlying brain aging and cognitive decline remain elusive. Body tissues are perfused by interstitial fluid (ISF), which is locally reabsorbed via the lymphatic vascular network. In contrast, the parenchyma of the central nervous system (CNS) is devoid of lymphatic vasculature; in the brain, removal of cellular debris and toxic molecules, such as amyloid beta (A) peptides, is mediated by a combination of transcellular mechanisms of transport across the blood−brain and blood−cerebrospinal fluid (CSF) barriers, phagocytosis and digestion by resident microglia and recruited monocytes/macrophages, and CSF influx and ISF efflux through a paravascular route. The recent characterization of meningeal lymphatic vessels prompted a reassessment of the conventional pathways of CNS waste clearance. The role of this vasculature in brain function, specifically in the context of aging and AD, is still poorly understood. Here we show that meningeal lymphatic vessels play an essential role in maintaining brain homeostasis by draining macromolecules from the CNS (CSF and ISF) into the cervical lymph nodes. Using pharmacological, surgical, and genetic models we show that impairment of meningeal lymphatic function in adult mice slows paravascular influx of CSF macromolecules and efflux of ISF macromolecules, and induces cognitive impairment. Treatment with a lymphangiogenic factor, vascular endothelial growth factor C (VEGF-C), enhances meningeal lymphatic drainage of CSF macromolecules, improving brain perfusion and learning and memory performance in aged mice. Disruption of meningeal lymphatic vessels in transgenic mouse models of AD promotes amyloid deposition in the meninges, which closely correlates with human meningeal pathology, and aggravates overall disease severity. Our findings suggest that meningeal lymphatic dysfunction may be an aggravating factor in AD pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.
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Project description:Aging is a major risk factor for many neurological pathologies, including Alzheimer’s disease (AD). However, the mechanisms underlying brain aging and cognitive decline remain elusive. Body tissues are perfused by interstitial fluid (ISF), which is locally reabsorbed via the lymphatic vascular network. In contrast, the parenchyma of the central nervous system (CNS) is devoid of lymphatic vasculature; in the brain, removal of cellular debris and toxic molecules, such as amyloid beta (A) peptides, is mediated by a combination of transcellular mechanisms of transport across the blood−brain and blood−cerebrospinal fluid (CSF) barriers, phagocytosis and digestion by resident microglia and recruited monocytes/macrophages, and CSF influx and ISF efflux through a paravascular route. The recent characterization of meningeal lymphatic vessels prompted a reassessment of the conventional pathways of CNS waste clearance. The role of this vasculature in brain function, specifically in the context of aging and AD, is still poorly understood. Here we show that meningeal lymphatic vessels play an essential role in maintaining brain homeostasis by draining macromolecules from the CNS (CSF and ISF) into the cervical lymph nodes. Using pharmacological, surgical, and genetic models we show that impairment of meningeal lymphatic function in adult mice slows paravascular influx of CSF macromolecules and efflux of ISF macromolecules, and induces cognitive impairment. Treatment with a lymphangiogenic factor, vascular endothelial growth factor C (VEGF-C), enhances meningeal lymphatic drainage of CSF macromolecules, improving brain perfusion and learning and memory performance in aged mice. Disruption of meningeal lymphatic vessels in transgenic mouse models of AD promotes amyloid deposition in the meninges, which closely correlates with human meningeal pathology, and aggravates overall disease severity. Our findings suggest that meningeal lymphatic dysfunction may be an aggravating factor in AD pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.
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