Lifetime Alcohol Use Influences the Association Between Future-Oriented Thought and White Matter Microstructure in Adolescents.

AIMS: Future orientation, or the ability to plan ahead and anticipate consequences, is a capacity that develops during adolescence, yet its underlying neurobiology is unknown. Previous independent reports suggest that reduced future orientation and altered white matter microstructure are associated with greater alcohol use in adolescents; however, these effects have not been studied in conjunction. This study investigated the association between future orientation and white matter microstructure as a function of lifetime alcohol use. METHODS: Seventy-seven adolescents (46 female; 15-21 years of age) underwent diffusion weighted imaging (DWI) and completed a fifteen-item Future Orientation Questionnaire. Regression analyses assessed the association between self-reported lifetime alcohol use and future orientation, and the association between future orientation and white matter microstructure, as a function of lifetime alcohol use. RESULTS: Adolescents with more lifetime alcohol use demonstrated lower future orientation. Voxel-wise DWI analyses revealed two regions, bilateral posterior corona radiata (PCR), where greater future orientation was associated with lower mean diffusivity in those with little or no history of alcohol use; however, this association was diminished with increasing rates of lifetime alcohol use. CONCLUSIONS: These findings replicate reports of reduced future orientation as a function of greater lifetime alcohol use and demonstrate an association between future orientation and white matter microstructure, in the PCR, a region containing afferent and efferent fibers connecting the cortex to the brain stem, which depends upon lifetime alcohol use. These findings provide novel information regarding the underlying neurobiology of future-oriented thought and how it relates to alcohol use.

SRF selectively controls tip cell invasive behavior in angiogenesis.

Efficient angiogenic sprouting is essential for embryonic, postnatal and tumor development. Serum response factor (SRF) is known to be important for embryonic vascular development. Here, we studied the effect of inducible endothelial-specific deletion of Srf in postnatal and adult mice. We find that endothelial SRF activity is vital for postnatal growth and survival, and is equally required for developmental and pathological angiogenesis, including during tumor growth. Our results demonstrate that SRF is selectively required for endothelial filopodia formation and cell contractility during sprouting angiogenesis, but seems dispensable for vascular remodeling. At the molecular level, we observe that vascular endothelial growth factor A induces nuclear accumulation of myocardin-related transcription factors (MRTFs) and regulates MRTF/SRF-dependent target genes including Myl9, which is important for endothelial cell migration in vitro. We conclude that SRF has a unique function in regulating migratory tip cell behavior during sprouting angiogenesis. We hypothesize that targeting the SRF pathway could provide an opportunity to selectively target tip cell filopodia-driven angiogenesis to restrict tumor growth.

A screen for mutations in zebrafish that affect myelin gene expression in Schwann cells and oligodendrocytes.

Myelin is the multi-layered glial sheath around axons in the vertebrate nervous system. Myelinating glia develop and function in intimate association with neurons and neuron-glial interactions control much of the life history of these cells. However, many of the factors that regulate key aspects of myelin development and maintenance remain unknown. To discover new molecules that are important for glial development and myelination, we undertook a screen of zebrafish mutants with previously characterized neural defects. We screened for myelin basic protein (mbp) mRNA by in situ hybridization and identified four mutants (neckless, motionless, iguana and doc) that lacked mbp expression in parts of the peripheral and central nervous systems (PNS or CNS), despite the presence of axons. In all four mutants electron microscopy revealed that myelin-forming glia were present and had formed loose wraps around axons but did not form compact myelin. We found that addition of exogenous retinoic acid (RA) rescued mbp expression in neckless mutant embryos, which lack endogenous RA synthesis. Timed application of the RA synthesis inhibitor DEAB to wild type embryos showed that RA signalling is required at least 48 h before the onset of myelin protein synthesis in both CNS and PNS.