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Lesions and neurologic disability in inflammatory CNS diseases such as multiple sclerosis (MS) result from the translocation of leukocytes and humoral factors from the vasculature, first across the endothelial blood-brain barrier (BBB) and then across the astrocytic glia limitans (GL). Factors secreted by reactive astrocytes open the BBB by disrupting endothelial tight junctions (TJs), but the mechanisms that control access across the GL are unknown. Here, we report that in inflammatory lesions, a second barrier composed of reactive astrocyte TJs of claudin 1 (CLDN1), CLDN4, and junctional adhesion molecule A (JAM-A) subunits is induced at the GL. In a human coculture model, CLDN4-deficient astrocytes were unable to control lymphocyte segregation. In models of CNS inflammation and MS, mice with astrocyte-specific Cldn4 deletion displayed exacerbated leukocyte and humoral infiltration, neuropathology, motor disability, and mortality. These findings identify a second inducible barrier to CNS entry at the GL. This barrier may be therapeutically targetable in inflammatory CNS disease.

Inflammation of the central nervous system (CNS) induces endothelial blood–brain barrier (BBB) opening as well as the formation of a tight junction barrier between reactive astrocytes at the Glia Limitans. We hypothesized that the CNS parenchyma may acquire protection from the reactive astrocytic Glia Limitans not only during neuroinflammation but also when BBB integrity is compromised in the resting state. Previous studies found that astrocyte-derived Sonic hedgehog (SHH) stabilizes the BBB during CNS inflammatory disease, while endothelial-derived desert hedgehog (DHH) is expressed at the BBB under resting conditions. Here, we investigated the effects of endothelial Dhh on the integrity of the BBB and Glia Limitans. We first characterized DHH expression within endothelial cells at the BBB, then demonstrated that DHH is down-regulated during experimental autoimmune encephalomyelitis (EAE). Using a mouse model in which endothelial Dhh is inducibly deleted, we found that endothelial Dhh both opens the BBB via the modulation of forkhead box O1 (FoxO1) transcriptional activity and induces a tight junctional barrier at the Glia Limitans. We confirmed the relevance of this glial barrier system in human multiple sclerosis active lesions. These results provide evidence for the novel concept of “chronic neuroinflammatory tolerance” in which BBB opening in the resting state is sufficient to stimulate a protective barrier at the Glia Limitans that limits the severity of subsequent neuroinflammatory disease. In summary, genetic disruption of the BBB generates endothelial signals that drive the formation under resting conditions of a secondary barrier at the Glia Limitans with protective effects against subsequent CNS inflammation. The concept of a reciprocally regulated CNS double barrier system has implications for treatment strategies in both the acute and chronic phases of multiple sclerosis pathophysiology.

Under neuroinflammatory conditions, astrocytes acquire a reactive phenotype that drives acute inflammatory injury as well as chronic neurodegeneration. We hypothesized that astrocytic Delta-like 4 (DLL4) may interact with its receptor NOTCH1 on neighboring astrocytes to regulate astrocyte reactivity via downstream juxtacrine signaling pathways. Here we investigated the role of astrocytic DLL4 on neurovascular unit homeostasis under neuroinflammatory conditions. We probed for downstream effectors of the DLL4-NOTCH1 axis and targeted these for therapy in two models of CNS inflammatory disease. We first demonstrated that astrocytic DLL4 is upregulated during neuroinflammation, both in mice and humans, driving astrocyte reactivity and subsequent blood-brain barrier permeability and inflammatory infiltration. We then showed that the DLL4-mediated NOTCH1 signaling in astrocytes directly drives IL-6 levels, induces STAT3 phosphorylation promoting upregulation of astrocyte reactivity markers, pro-permeability factor secretion and consequent blood-brain barrier destabilization. Finally we revealed that blocking DLL4 with antibodies improves experimental autoimmune encephalomyelitis symptoms in mice, identifying a potential novel therapeutic strategy for CNS autoimmune demyelinating disease. As a general conclusion, this study demonstrates that DLL4-NOTCH1 signaling is not only a key pathway in vascular development and angiogenesis, but also in the control of astrocyte reactivity during neuroinflammation.

Introduction The transgenic murine Cre/loxP system is deployed to investigate the role of central nervous system (CNS) cell‐specific gene alterations in both healthy conditions and models of neurologic disease. The Aldh1l1‐Cre/ERT2 line is widely used to target astrocytes with high coverage and specificity within the CNS. Specificity outside the CNS, however, has not been well‐characterized, and Aldh1l1‐Cre/ERT2‐mediated recombination within the spleen has been reported. In many CNS diseases, infiltrating immune cells from the periphery drive or regulate pathogenesis. We tested whether flox‐mediated recombination from Aldh1l1‐Cre/ERT2 occurs in immune cells in addition to astrocytes and whether these cells traffic from the spleen into the spinal cord during experimental autoimmune encephalomyelitis (EAE), a model of CNS autoimmune disease. Methods Two astrocyte‐targeted mouse lines were generated with the red fluorescent reporter, tdTomato, by crossing the Cre‐recombinase lines, Tg(Aldh1l1‐Cre/ERT2)1Khakh and Tg(Gfap‐Cre)73.12Mvs, with the reporter line, Gt(ROSA)26Sor. Aldh1l1‐Cre/ERT2 was activated with 5 days of intraperitoneal tamoxifen, whereas Gfap‐Cre was constitutively active. EAE was induced 2 weeks after tamoxifen, and then spleens and spinal cords were harvested and processed for flow cytometry at various time points after disease onset in EAE versus healthy controls. Results In EAE, Aldh1l1‐Cre/ERT2, but not Gfap‐Cre, induced multiple tdTomato+ immune cell subpopulations in the spleen and spinal cord, including macrophages, monocytes, neutrophils, eosinophils, B cells, CD4+, and CD8+ T cells. Conclusion Use of Aldh1l1‐Cre/ERT2 should therefore account for recombination in both astrocytes and immune cells in disease models involving peripheral immune cell infiltration into the CNS.

Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Krüppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation. Conversely, in mice with lineage-selective Klf6 inactivation, OLP undergo maturation arrest followed by apoptosis, and CNS myelination fails. Overlapping transcriptional and chromatin occupancy analyses place Klf6 at the nexus of a novel gp130-Klf-importin axis, which promotes differentiation and viability in part via control of nuclear trafficking. Klf6 acts as a gp130-sensitive transactivator of the nuclear import factor importin-α5 (Impα5), and interfering with this mechanism interrupts step-wise differentiation. Underscoring the significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and Impα5 expression, OLP maturation arrest and apoptosis, and failure of CNS myelination.

The mapping of eye-specific, geniculocortical inputs to primary visual cortex (V1) is highly sensitive to the balance of correlated activity between the two eyes during a restricted postnatal critical period for ocular dominance plasticity. This critical period is likely to have amplified expression of genes and proteins that mediate synaptic plasticity. DNA microarray analysis of transcription in mouse V1 before, during, and after the critical period identified 31 genes that were up-regulated and 22 that were down-regulated during the critical period. The highest-ranked up-regulated gene, cardiac troponin C, codes for a neuronal calcium-binding protein that regulates actin binding and whose expression is activity-dependent and relatively selective for layer-4 star pyramidal neurons. The highest-ranked down-regulated gene, synCAM, also has actin-based function. Actin-binding function, G protein signaling, transcription, and myelination are prominently represented in the critical period transcriptome. Monocular deprivation during the critical period reverses the expression of nearly all critical period genes. The profile of regulated genes suggests that synaptic stability is a principle driver of critical period gene expression and that alteration in visual activity drives homeostatic restoration of stability.

Objective Sleep‐dependent memory processing occurs in animals including humans, and disturbed sleep negatively affects memory. Sleep disturbance and memory dysfunction are common in multiple sclerosis (MS), but little is known about the contributions of sleep disturbance to memory in MS. We investigated whether subjective sleep disturbance is linked to worse memory in early MS independently of potential confounders. Methods Persons with early MS (n = 185; ≤5.0 years diagnosed) and demographically matched healthy controls (n = 50) completed four memory tests to derive a memory composite, and four speeded tests to derive a cognitive efficiency composite. Z‐scores were calculated relative to healthy controls. Sleep disturbance was defined by the Insomnia Severity Index score ≥ 10. ANCOVAs examined differences in memory and cognitive efficiency between patients with and without sleep disturbance controlling for potential confounds (e.g., mood, fatigue, disability, T2 lesion volume, gray matter volume). Comparisons were made to healthy controls. Results Seventy‐four (40%) patients reported sleep disturbance. Controlling for all covariates, patients with sleep disturbance had worse memory (z = −0.617; 95% CI: −0.886, −0.348) than patients without disturbance (z = −0.171, −0.425, 0.082, P = .003). Cognitive efficiency did not differ between groups. Relative to healthy controls, memory was worse among patients with sleep disturbance, but not among patients without sleep disturbance. Interpretation Sleep disturbance contributes to MS memory dysfunction, which may help explain differential risk for memory dysfunction in persons with MS, especially since sleep disturbance is common in MS. Potential mechanisms linking sleep disturbance and memory are discussed, as well as recommendations for further mechanistic and interventional research.

Neurological disease has been a central focus in the ongoing ethical debate over the use of invasive placebo controls, especially sham surgery. The risk to research subjects and necessary use of deception involved in these procedures must be balanced against the methodological need to control for bias and the placebo effect. We review a framework formulated for the ethical assessment of sham surgery in the context of research evaluating novel procedures for neurological conditions. Special issues raised include the growing evidence of expectation and conditioning effects in a number of neurological diseases, the escalating scale of risk from different types of invasive placebo interventions, and the increasing use of cross-over designs, which allow a switch from placebo to active intervention without additional procedures.

Over the last two decades, the field of human social neuroscience has accelerated people's understanding of the neuroanatomical substrates of decision making, particularly in domains of moral behavior. Behavioral neurology, in turn, has advanced its characterization of specific decision-making impairments in various neurodegenerative diseases. These conditions provide the opportunity to learn how a loss of function or dysregulation of previously normal pathways may influence many behaviors of moral significance. A rapidly aging population and the growing recognition of these cognitive impairments require a practical and ethical framework for clinicians, including internists, geriatricians, neurologists, and psychiatrists. Here, a working framework for the clinician confronting impairments in moral decision making in patients with neurodegenerative disease is presented.

Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive, often fatal viral infection of the brain without a known treatment. Recently, case reports have demonstrated survival from PML with therapies that improve cell-mediated immunity, including interleukin-7 (IL-7) or the chemokine receptor type 5 (CCR5) antagonist, maraviroc (MVC). We present the first known case of a patient with PML successfully treated with both IL-7 and MVC. A 63-year-old woman presented to our center with a 6-month history of progressive left hemiparesis. Extensive laboratory testing was negative except for a severe CD4 lymphocytopenia (140/μL). Serial brain MRIs done prior to presentation revealed an enlarging, non-enhancing T2-hyperintense lesion in the right fronto-parietal white matter. PML was confirmed through detection of the JC virus by PCR in the cerebrospinal fluid and by brain biopsy, and she was started on mirtazapine and mefloquine. She continued to deteriorate and was then given a course of recombinant IL-7. Though she remained clinically stable after IL-7 treatment and serum JCV PCR decreased from 1000 copies/mL to a nadir of 238 copies/mL, a repeat MRI 3 months later showed lesion enlargement. MVC was then initiated. Now, more than 2 years after initial presentation, she remains stable and serum JCV PCR is undetectable. This case demonstrates successful treatment of PML in a patient with idiopathic CD4 lymphocytopenia and highlights the potential benefits of IL-7 and MVC in the treatment of PML. Treatment with IL-7 and MVC led to clinical stability and improvement in JC virus titers.