Cerebrospinal fluid folate and the development of the cerebral cortex in congenital hydrocephalus

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Addressing a folate imbalance in fetal cerebrospinal fluid can decrease the incidence of congenital hydrocephalus

Fetal-onset hydrocephalus (HC), which affects between 1:500 and 1:5000 live human births, results from unequal production and drainage of cerebrospinal fluid (CSF) and is associated with abnormal development of the cerebral cortex leading to severe neurological deficits. We previously found that in the hydrocephalic Texas rat, the CSF of affected fetuses induced a cell cycle arrest in neural progenitor cells. Here, we show that alterations in folate metabolism in the CSF of the developing cerebrum are likely responsible for this effect. We identified 3 folate enzymes in the CSF and demonstrate that low levels of one of these, 10-formyltetrahydrofolate dehydrogenase, are associated with HC in the hydrocephalic Texas rat. Therefore, we tested whether supplementation with specific folate species would improve developmental outcome. After daily administration of a combination of tetrahydrofolic and 5-formyltetrahydrofolic acids to pregnant dams, there was a significant reduction in the incidence of HC and improved brain development. By contrast, supplementation with folic acid increased the incidence of congenital HC in this model. These results indicate the complexities of folate metabolism in the developing brain and suggest that folate imbalance leading to HC in the hydrocephalic Texas rat fetuses can be treated with maternal folate supplementation using specific folate metabolites and combinations thereof

Background

A study of the incidence of hydrocephalus and cortical development in HTx rat fetuses treated with folate supplement

Agrp neuron activity is required for alcohol-induced overeating

Alcohol intake associates with overeating in humans. This overeating is a clinical concern, but its causes are puzzling, because alcohol (ethanol) is a calorie-dense nutrient, and calorie intake usually suppresses brain appetite signals. The biological factors necessary for ethanol-induced overeating remain unclear, and societal causes have been proposed. Here we show that core elements of the brain's feeding circuits-the hypothalamic Agrp neurons that are normally activated by starvation and evoke intense hunger-display electrical and biochemical hyperactivity on exposure to dietary doses of ethanol in brain slices. Furthermore, by circuit-specific chemogenetic interference in vivo, we find that the Agrp cell activity is essential for ethanol-induced overeating in the absence of societal factors, in single-housed mice. These data reveal how a widely consumed nutrient can paradoxically sustain brain starvation signals, and identify a biological factor required for appetite evoked by alcohol

Subarachnoid cerebrospinal fluid is essential for normal development of the cerebral cortex

The central nervous system develops around a fluid filled space which persists in the adult within the ventricles and around the outside of the brain and spinal cord. Ventricular fluid has been found to act as a growth medium and stimulator of proliferation and differentiation to neural stem cells but the role of CSF in the subarachnoid space has not been fully investigated except for it role in the recently described “glymphatic” system. Fundamental changes occur in the control and coordination of CNS development upon completion of brain stem and spinal cord development and initiation of cortical development. These include changes in gene expression, change in fluid and fluid source from neural tube fluid to cerebrospinal fluid (CSF), change in fluid volume, composition and fluid flow pathway, with the addition of a critical need for fluid drainage. We used a number of experimental approaches to test a predicted critical role for cerebrospinal fluid in development of the cerebral cortex in rodents and humans. Data from fetuses affected by spina bifida and/or hydrocephalus are correlated with experimental evidence on proliferation and migration of cortical cells from the germinal epithelium. Further, direct evidence is presented from embryonic brain slice experiments demonstrating a requirement for CSF to contact both ventricular and pial surfaces of the developing cortex for normal proliferation and migration. We discuss the possibility that complications with the fluid system are likely to underlie developmental disorders affecting the cerebral cortex

Toward the Computational Design of Diastereomeric Resolving Agents: An Experimental and Computational Study of 1-Phenylethylammonium-2-phenylacetate Derivatives

The crystal structures, including two new polymorphs, of three diastereomerically related salt pairs formed by (R)-1-phenylethylammonium (1) with (S&R)-2-phenylpropanoate (2), (S&R)-2-phenylbutyrate (3), and (S&R)-mandelate (4) ions were characterized by low-temperature single crystal or powder X-ray diffraction. Thermal, solubility, and solution calorimetry measurements were used to determine the relative stabilities of the salt pairs and polymorphs. These were qualitatively predicted by lattice energy calculations combining realistic models for the dominant intermolecular electrostatic interactions and ab initio calculations for the ions' conformational energies due to the distortion of their geometries by the crystal packing forces. Crystal structure prediction studies were also performed for the highly polymorphic diastereomeric salt pair (R)-1-phenylethylammonium-(S&R)-2-phenylbutyrate (1−3) in an attempt to predict the separation efficiency without relying on experimental information. This joint experimental and computational investigation provides a stringent test for the reliability of lattice modeling approaches to explain the origins of chiral resolution via diastereomer formation (Pasteurian resolution). The further developments required for the computational screening of single-enantiomer resolving agents to achieve optimal chiral separation are discussed