Biology subjects

Boghozian, R.

Publications and source records attributed to Boghozian, R..

3 recordsLinked to original sources

bioRxiv2024

A pathogenic role for IL-10 signalling in capillary stalling and cognitive impairment in type 1 diabetes

Vascular pathology is associated with cognitive impairment in diseases such as type 1 diabetes, but precisely how capillary flow is affected and the underlying mechanisms remain elusive. Here we show that capillaries in the diabetic mouse brain are prone to stalling, with blocks composed primarily of erythrocyte plugs in branches off penetrating venules. Increased capillary obstructions were evident in both sexes and only partially reversed by insulin. Screening for circulating inflammatory cytokines revealed persistently high levels of interleukin-10 (IL-10) in diabetic mice. Contrary to expectation, stimulating IL-10 signalling increased capillary obstructions, whereas inhibiting IL-10 receptors with neutralizing antibodies or endothelial specific knockdown in diabetic mice, reversed these impairments. Chronic IL-10R blocking antibody treatment in diabetic mice also improved stimulus evoked cerebral blood flow, increased capillary widths in lower-order branches and reversed cognitive deficits. These data suggest IL-10 signalling plays an unexpected pathogenic role in cerebral microcirculatory defects and cognitive impairment.

neuroscience↗

bioRxiv2023

Sex and interferon gamma signalling regulate microglia migration in adult mouse cortex in vivo

Although microglia possess the unique ability to migrate, whether mobility is evident in all microglia, is sex dependent, and what molecular mechanisms drive this, is poorly understood in the adult brain. Using longitudinal in vivo imaging of sparsely labelled microglia, we find a relatively small population of microglia are mobile under normal conditions. Following injury (microbleed), the population of mobile microglia increased in a sex-dependent manner, with male microglia migrating significantly greater distances towards the microbleed relative to their female counterparts. To understand the signaling pathways involved, we interrogated the role of interferon gamma (IFN{gamma}). Our data show that in male mice, stimulating microglia with IFN{gamma} or inducible microglial specific knockdown of IFN{gamma} receptor 1 stimulates or inhibits migration, respectively, whereas female microglia were generally unaffected. These findings highlight the diversity of microglia migratory responses to injury, its dependence on sex and the signaling mechanisms that modulate this behavior.

neuroscience↗

bioRxiv2022

Optical opening of the blood brain barrier for targeted and ultra-sparse viral infection of cells in the mouse cortex

Adeno-associated viruses (AAVs) are used in a wide array of experimental situations for driving expression of biosensors, recombinases and opto/chemo-genetic actuators in the brain. However, conventional approaches for minimally invasive, spatially precise and ultra-sparse AAV mediated transduction of cells during imaging experiments, has remained a significant challenge. Here we show that intravenous injection of commercially available AAVs at different doses, combined with laser based perforation of single cortical capillaries through a cranial widow, allows for ultra-sparse, titrate-able, and micron level precision for delivery of viral vectors with relatively little inflammation or tissue damage. Further, we show the utility of this approach for eliciting sparse expression of GCaMP6, channel-rhodopsin or fluorescent reporters in neurons and astrocytes within specific functional domains in normal and stroke damaged cortex. This technique represents a facile approach for targeted delivery of viral vectors that should assist in the study of cell types and circuits in the cerebral cortex.

neuroscience↗