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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2018)

The network of blood vessels in the central nervous system is critically important for nutrient delivery and waste removal in higher organisms. A special set of properties distinguishes blood vessels in the central nervous system from those in other organs, because these vessels must provide an extra layer of protection and responsiveness to the real-time demands of neurons. Much is known about way the normal physiology of neurons induces changes in local blood vessels to re-direct nutrient flow and relieve the buildup of waste products. However, there are many potential interactions between neurons and blood vessels about which we know very little. Whether vessels respond to different types of neuronal dysfunction, and if neural activity plays an important role in development of the vascular network are two such unexplored questions. This dissertation is comprised of several projects which all address the underlying mechanisms, consequences, and applications of, neural-vascular interactions in retinal development and disease.

The aim of the first study (Chapter 2) was to determine whether early spontaneous neural activity is the postnatal mouse retina is related to contemporaneous angiogenesis. We found that activity of the cholinergic retinal circuitry was necessary to establish proper layer-specific vascular development and to turn on blood-retinal barrier properties, and elucidated the signaling pathways involved in this process.

The aim of the second study (Chapter 3) was to determine whether specific injury to neurons in the retina would alter transcription in endothelial and microglial cells. We found a number of transcriptomic changes in these cells that may represent RNA originating from non-microvascular cells.

These studies describe new findings concerning the basis for intercellular communication between neurons and blood vessels in the retina, both during development and disease. A better understanding of neurovascular interactions may promote novel therapeutic strategies and biomarker discovery for blinding diseases of development and aging.

    Cover page: Neural-Vascular Interactions in Retinal Development and Disease
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2021)
    Fibrosis is a common pathological response to inflammation in many peripheral tissues and can prevent tissue regeneration and repair. Here, we identified persistent fibrotic scarring in the CNS following immune cell infiltration in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Using lineage tracing and single-cell sequencing in EAE, we determined that the majority of the fibrotic scar is derived from proliferative CNS fibroblasts, not pericytes or infiltrating bone marrow-derived cells. Ablating proliferating fibrotic cells using cell-specific expression of herpes thymidine kinase led to an increase in oligodendrocyte lineage cells within the inflammatory lesions and a reduction in motor disability. We further identified that interferon-gamma pathway genes are enriched in CNS fibrotic cells, and the fibrotic cell-specific deletion of Ifngr1 resulted in reduced fibrotic scarring in EAE. These data delineate a framework for understanding the CNS fibrotic response.
      Cover page: CNS fibroblasts form a fibrotic scar in response to immune cell infiltration
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2019)
      Blood vessels in the CNS form a specialized and critical structure, the blood-brain barrier (BBB). We present a resource to understand the molecular mechanisms that regulate BBB function in health and dysfunction during disease. Using endothelial cell enrichment and RNA sequencing, we analyzed the gene expression of endothelial cells in mice, comparing brain endothelial cells with peripheral endothelial cells. We also assessed the regulation of CNS endothelial gene expression in models of stroke, multiple sclerosis, traumatic brain injury and seizure, each having profound BBB disruption. We found that although each is caused by a distinct trigger, they exhibit strikingly similar endothelial gene expression changes during BBB disruption, comprising a core BBB dysfunction module that shifts the CNS endothelial cells into a peripheral endothelial cell-like state. The identification of a common pathway for BBB dysfunction suggests that targeting therapeutic agents to limit it may be effective across multiple neurological disorders.
        Cover page: Profiling the mouse brain endothelial transcriptome in health and disease models reveals a core blood–brain barrier dysfunction module
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2020)
        The blood vessels in the central nervous system (CNS) have a series of unique properties, termed the blood-brain barrier (BBB), which stringently regulate the entry of molecules into the brain, thus maintaining proper brain homeostasis. We sought to understand whether neuronal activity could regulate BBB properties. Using both chemogenetics and a volitional behavior paradigm, we identified a core set of brain endothelial genes whose expression is regulated by neuronal activity. In particular, neuronal activity regulates BBB efflux transporter expression and function, which is critical for excluding many small lipophilic molecules from the brain parenchyma. Furthermore, we found that neuronal activity regulates the expression of circadian clock genes within brain endothelial cells, which in turn mediate the activity-dependent control of BBB efflux transport. These results have important clinical implications for CNS drug delivery and clearance of CNS waste products, including Aβ, and for understanding how neuronal activity can modulate diurnal processes.
          Cover page: Neuronal Activity Regulates Blood-Brain Barrier Efflux Transport through Endothelial Circadian Genes
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