Clinicopathologic correlation of aniridia: Optical coherence tomography angiography and histopathologic observations

To describe optical coherence tomography angiography (OCTA) findings in a patient with aniridia and correlate with representative histopathology.OCTA images of the macula of a pediatric aniridic patient, who has nystagmus and impaired vision bilaterally, demonstrate a complete absence of the foveal avascular zone (FAZ) in both the superficial and deep vascular complexes (SVC and DVC). In addition, larger superficial blood vessels were found to be abnormally diving from the SVC into the DVC. Similarly, immunofluorescence with confocal microscopy imaging of a retinal histopathology specimen from a 2 month old aniridic patient demonstrated larger vessels diving in the same manner.This study highlights the clinical, imaging and histopathologic findings of aniridia. Supine OCTA imaging, performed during examination under anesthesia, allowed for visualization of retinal microvasculature in eyes with nystagmus. The histopathology images helped validate OCTA findings that, with further investigation, may lead to new information about the development of abnormal retinal microvasculature

Distinct Neuronal Projections from the Hypothalamic Ventromedial Nucleus Mediate Glycemic and Behavioral Effects

The hypothalamic ventromedial nucleus (VMN) is implicated both in autonomic control of blood glucose and in behaviors including fear and aggression, but whether these divergent effects involve the same or distinct neuronal subsets and their projections is unknown. To address this question, we used an optogenetic approach to selectively activate the subset of VMN neurons that express neuronal nitric oxide synthase 1 (VMN(NOS1) neurons) implicated in glucose counterregulation. We found that photo-activation of these neurons elicits 1) robust hyperglycemia achieved by activation of counterregulatory responses (CRRs) usually reserved for the physiological response to hypoglycemia, and 2) defensive immobility behavior. Moreover, we show that the glucagon, but not corticosterone, response to insulin-induced hypoglycemia is blunted by photo-inhibition of the same neurons. To investigate the neurocircuitry by which VMN(NOS1) neurons mediate these effects, and to determine whether these diverse effects are dissociable from one another, we activated downstream VMN(NOS1) projections in either the anterior bed nucleus of the stria terminalis (aBNST) or the periaqueductal gray (PAG). While glycemic responses are fully recapitulated by activation of VMN(NOS1) projections to the aBNST, freezing immobility occurred only upon activation of VMN(NOS1) terminals in the PAG. These findings support previous evidence of a VMN--\u3eaBNST neurocircuit involved in glucose counterregulation and demonstrate that activation of VMN(NOS1) neuronal projections supplying the PAG robustly elicits defensive behaviors

Astrocytic junctional adhesion molecule-A regulates T-cell entry past the glia limitans to promote central nervous system autoimmune attack

International audienceAbstract Contact-mediated interactions between the astrocytic endfeet and infiltrating immune cells within the perivascular space are underexplored, yet represent potential regulatory check-points against CNS autoimmune disease and disability. Reactive astrocytes upregulate junctional adhesion molecule-A, an immunoglobulin-like cell surface receptor that binds to T cells via its ligand, the integrin, lymphocyte function-associated antigen-1. Here, we tested the role of astrocytic junctional adhesion molecule-A in regulating CNS autoinflammatory disease. In cell co-cultures, we found that junctional adhesion molecule-A-mediated signalling between astrocytes and T cells increases levels of matrix metalloproteinase-2, C–C motif chemokine ligand 2 and granulocyte-macrophage colony-stimulating factor, pro-inflammatory factors driving lymphocyte entry and pathogenicity in multiple sclerosis and experimental autoimmune encephalomyelitis, an animal model of CNS autoimmune disease. In experimental autoimmune encephalomyelitis, mice with astrocyte-specific JAM-A deletion (mGFAP:CreJAM-Afl/fl) exhibit decreased levels of matrix metalloproteinase-2, reduced ability of T cells to infiltrate the CNS parenchyma from the perivascular spaces and a milder histopathological and clinical course of disease compared with wild-type controls (JAM-Afl/fl). Treatment of wild-type mice with intraperitoneal injection of soluble junctional adhesion molecule-A blocking peptide decreases the severity of experimental autoimmune encephalomyelitis, highlighting the potential of contact-mediated astrocyte–immune cell signalling as a novel translational target against neuroinflammatory disease

Astrocytic tight junctions control inflammatory CNS lesion pathogenesis

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

Astrocytic tight junctions control inflammatory CNS lesion pathogenesis

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