Profiling the mouse brain endothelial transcriptome in health and disease models reveals a core blood-brain barrier dysfunction module.

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

Glial inflammatory responses regulate neurocognitive recovery following viral encephalitis

The concept of the brain as an immune privileged organ has been slowly shifting as an in-creasing number of studies have demonstrated that even under homeostatic conditions, commu-nication between the nervous and immune system is essential for proper brain function. Given their roles in innate and adaptive immunity, glial cells and infiltrating immune cells have been placed at the center of this communication axis. Microglia, astrocytes, and T cells have all been shown to receive and convey information to all neural cell types in a coordinated effort to re-spond to injury and infection and initiate reparative mechanisms as well as influence cognitive processing through the section of cytokines. Considering the necessity of homeostatic neuroim-mune interactions for normal cognitive function, we sought to understand how alterations in the neuroimmune landscape, which occur in aging, viral encephalitis, neurodegeneration, and other neuroinflammatory conditions, may influence cognitive capability. Here, we use an in vivo model of viral encephalitis with high survival rates in adult mice, induced by a mutant West Nile viral strain (WNV-NS5-E218A), to study the impact of persistent glial activation and T cell infiltration, and subsequently, its influence on spatial learning capabili-ties in the post-infectious CNS. We first demonstrate that T cell-derived interferon (IFN)-γ sig-naling to microglia underlies spatial learning deficits associated with our recovery model of WNV and a newly established model of Zika encephalitis. Virally infected animals experience changes in cognitive function via the loss of presynaptic termini or neural apoptosis with elimina-tion of postsynaptic termini, respectively (Chapter 2). Additionally, we show that in our WNV recovery model, astrocytes are a source of the anti-neurogenic cytokine, interleukin (IL)-1β, that continuously signals via neural stem cells to inhibit neural correlates of memory. Such neural cor-related are measured by a decrease in proliferating neurons within the hippocampal denate gyrus, persistent synapse loss, alterations to neural activity, and a lack of spatial learning recovery (Chapter 3). The finding in these and subsequent chapters suggest that neuroimmune dysregula-tion can lead to defects in neurocognitive function, while also shedding light on targetable mech-anisms that may drive cognitive dysfunction in viral encephalitis as well as other neurodegenera-tive diseases

Profiling the mouse brain endothelial transcriptome in health and disease models reveals a core blood-brain barrier dysfunction module

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