Studies on the origin of choline in the brain of the rat.
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ABSTRACT:
SUBMITTER: Ansell GB
PROVIDER: S-EPMC1176843 | biostudies-other | 1971 May
REPOSITORIES: biostudies-other
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Project description:The concentration of unesterified choline in the plasma in the jugular vein of the rat (0.85 nmol/ml) was found to be three times that of the arterial supply to the brain (0.25 nmol/ml), indicating a higher efflux than uptake of unesterified choline by the brain. No such difference was found for the rabbit and no arterio-venous difference for phosphatidylcholine or lysophosphatidylcholine was observed in either species. No arterio-venous difference was found for choline in blood cells. The infusion of [Me-3H]choline into the circulation of the rat or rabbit indicated an uptake of radioactive choline by the brain and an efflux of non-radioactive choline. In the rabbit such an infusion produced a steady rise in the labelling of phosphatidylcholine and lysophosphatidylcholine in the plasma. When [14C2]ethanolamine was injected intraperitoneally into the rat there was a labelling of phosphatidylcholine, lysophosphatidylcholine and sphingomyelin in the plasma and cells of blood from the jugular vein and the arterial supply, as well as in the brain tissue. However, no labelling of unesterified choline in these tissues could be detected. Unesterified choline was shown to be liberated into the plasma when whole blood from the rat or man, but not the rabbit, was incubated for short periods at 30 degrees C.
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Project description:Choline acetyltransferase has the same affinity for acetyl-CoA, propionyl-CoA and butyryl-CoA (Km=1.4 micron). Choline acetyltransferase may use the two latter compounds as substrate, but the longer the acyl chain the lower will be Vmax. CoA is an inhibitor (Ki=1.8 micron). The position of the 3'-phosphate is of primary importance. Desphospho-CoA is a weak inhibitor (Ki=500 micron). 5'-AMP is already an inhibitor (Ki=2500 micron). Phosphopantetheine is not an inhibitor. Dextran Blue is a potent inhibitor (Ki=0.05 micron). Choline acetyltransferase binds to hydrophobic affinity columns. Because of its affinity for nucleotides, affinity for Dextran Blue and hydrophobicity, it is proposed that it contains the 'nucleotide fold', which is a common structural domain present in several enzymes binding nucleotides.
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Project description:[Me-(14)C]Choline was injected intracerebrally into the adult rat, and its uptake into the lipids and their water-soluble precursors in brain was studied. The radioactivity could be detected only in the choline-containing lipids and was confined to the base choline. The results indicated that initial phosphorylation of the free choline followed by the formation of CDP-choline and the subsequent transfer of the phosphorylcholine to a diglyceride is one of the principal routes by which choline lipids in brain are formed. Further evidence for this was obtained in experiments in which either phosphoryl[Me-(14)C]choline or [(32)P]orthophosphate was injected and the radioactivity in the choline-containing water-soluble and lipidbound components studied.
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Project description:Choline is essential for proper liver, muscle, brain, lipid metabolism, cellular membrane composition, and repair. Understanding genetic determinants of circulating choline metabolites can help identify new determinants of choline metabolism, requirements, and their link to disease endpoints. We conducted a scoping review to identify studies assessing the association of genetic polymorphisms on circulating choline and choline-related metabolite concentrations and subsequent associations with health outcomes. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement scoping review extension. Literature was searched to September 28, 2022, in 4 databases: Embase, MEDLINE, Web of Science, and the Biological Science Index. Studies of any duration in humans were considered. Any genome-wide association study (GWAS) investigating genetic variant associations with circulating choline and/or choline-related metabolites and any Mendelian randomization (MR) study investigating the association of genetically predicted circulating choline and/or choline-related metabolites with any health outcome were considered. Qualitative evidence is presented in summary tables. From 1248 total reviewed articles, 53 were included (GWAS = 27; MR = 26). Forty-two circulating choline-related metabolites were tested in association with genetic variants in GWAS studies, primarily trimethylamine N-oxide, betaine, sphingomyelins, lysophosphatidylcholines, and phosphatidylcholines. MR studies investigated associations between 52 total unique choline metabolites and 66 unique health outcomes. Of these, 47 significant associations were reported between 16 metabolites (primarily choline, lysophosphatidylcholines, phosphatidylcholines, betaine, and sphingomyelins) and 27 health outcomes including cancer, cardiovascular, metabolic, bone, and brain-related outcomes. Some articles reported significant associations between multiple choline types and the same health outcome. Genetically predicted circulating choline and choline-related metabolite concentrations are associated with a wide variety of health outcomes. Further research is needed to assess how genetic variability influences choline metabolism and whether individuals with lower genetically predicted circulating choline and choline-related metabolite concentrations would benefit from a dietary intervention or supplementation.
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Project description:Optical studies of ex vivo brain slices where blood is absent show that neural activity is accompanied by significant intrinsic optical signals (IOS) related to activity-dependent scattering changes in neural tissue. However, the neural scattering signals have been largely ignored in vivo in widely-used IOS methods where absorption contrast from hemoglobin was employed. Changes in scattering were observed on a time scale of seconds in previous brain slice IOS studies, similar to the time scale for the hemodynamic response. Therefore, potential crosstalk between the scattering and absorption changes may not be ignored if they have comparable contributions to IOS. In vivo, the IOS changes linked to neural scattering have been elusive. To isolate neural scattering signals in vivo, we employed 2 implantable optodes for small-separation (2?mm) transmission measurements of local brain tissue in anesthetized rats. This unique geometry enables us to separate neuronal activity-related changes in neural tissue scattering from changes in blood absorption based upon the direction of the signal change. The changes in IOS scattering and absorption in response to up-states of spontaneous neuronal activity in cortical or subcortical structures have strong correlation to local field potentials, but significantly different response latencies. We conclude that activity-dependent neural tissue scattering in vivo may be an additional source of contrast for functional brain studies that provides complementary information to other optical or MR-based systems that are sensitive to hemodynamic contrast.
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Project description:Prenatal COVID-19 infection is anticipated by the U.S. Centers for Disease Control to affect fetal development similarly to other common respiratory coronaviruses through effects of the maternal inflammatory response on the fetus and placenta. Plasma choline levels were measured at 16 weeks gestation in 43 mothers who had contracted common respiratory viruses during the first 6-16 weeks of pregnancy and 53 mothers who had not. When their infants reached 3 months of age, mothers completed the Infant Behavior Questionnaire-Revised (IBQ-R), which assesses their infants' level of activity (Surgency), their fearfulness and sadness (Negativity), and their ability to maintain attention and bond to their parents and caretakers (Regulation). Infants of mothers who had contracted a moderately severe respiratory virus infection and had higher gestational choline serum levels (?7.5 mM consistent with U.S. Food and Drug Administration dietary recommendations) had significantly increased development of their ability to maintain attention and to bond with their parents (Regulation), compared to infants whose mothers had contracted an infection but had lower choline levels (<7.5 mM). For infants of mothers with choline levels ?7.5 ?M, there was no effect of viral infection on infant IBQ-R Regulation, compared to infants of mothers who were not infected. Higher choline levels obtained through diet or supplements may protect fetal development and support infant early behavioral development even if the mother contracts a viral infection in early gestation when the brain is first being formed.
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Project description:In Wilson disease, excessive copper accumulates in patients' livers and may, upon serum leakage, severely affect the brain according to current viewpoints. Present remedies aim at avoiding copper toxicity by chelation, for example, by D-penicillamine (DPA) or bis-choline tetrathiomolybdate (ALXN1840), the latter with a very high copper affinity. Hence, ALXN1840 may potentially avoid neurological deterioration that frequently occurs upon DPA treatment. As the etiology of such worsening is unclear, we reasoned that copper loosely bound to albumin, that is, mimicking a potential liver copper leakage into blood, may damage cells that constitute the blood-brain barrier, which was found to be the case in an in vitro model using primary porcine brain capillary endothelial cells. Such blood-brain barrier damage was avoided by ALXN1840, plausibly due to firm protein embedding of the chelator bound copper, but not by DPA. Mitochondrial protection was observed, a prerequisite for blood-brain barrier integrity. Thus, high-affinity copper chelators may minimize such deterioration in the treatment of neurologic Wilson disease.
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Project description:Choline is an essential nutrient for humans. Metabolically choline is used for the synthesis of membrane phospholipids (e.g. phosphatidylcholine), as a precursor of the neurotransmitter acetylcholine, and, following oxidation to betaine, choline functions as a methyl group donor in a pathway that produces S-adenosylmethionine. As a methyl donor choline influences DNA and histone methylation--two central epigenomic processes that regulate gene expression. Because the fetus and neonate have high demands for choline, its dietary intake during pregnancy and lactation is particularly important for normal development of the offspring. Studies in rodents have shown that high choline intake during gestation improves cognitive function in adulthood and prevents memory decline associated with old age. These behavioral changes are accompanied by electrophysiological, neuroanatomical, and neurochemical changes and by altered patterns of expression of multiple cortical and hippocampal genes including those encoding key proteins that contribute to the biochemical mechanisms of learning and memory. These actions of choline are observed long after the exposure to the nutrient ended (months) and correlate with fetal hepatic and cerebral cortical choline-evoked changes in global- and gene-specific DNA cytosine methylation and with dramatic changes of the methylation pattern of lysine residues 4, 9 and 27 of histone H3. Moreover, gestational choline modulates the expression of DNA (Dnmt1, Dnmt3a) and histone (G9a/Ehmt2/Kmt1c, Suv39h1/Kmt1a) methyltransferases. In addition to the central role of DNA and histone methylation in brain development, these processes are highly dynamic in adult brain, modulate the expression of genes critical for synaptic plasticity, and are involved in mechanisms of learning and memory. A recent study documented that in a cohort of normal elderly people, verbal and visual memory function correlated positively with the amount of dietary choline consumption. It will be important to determine if these actions of choline on human cognition are mediated by epigenomic mechanisms or by its influence on acetylcholine or phospholipid synthesis.
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Project description:The synaptic uptake of choline via the high-affinity, hemicholinium-3-dependent choline transporter (CHT) strongly influences the capacity of cholinergic neurons to sustain acetylcholine (ACh) synthesis and release. To advance research on the impact of CHT capacity in humans, we established the presence of the neuronal CHT protein in human T lymphocytes. Next, we demonstrated CHT-mediated choline transport in human T cells. To address the validity of T cell-based choline uptake as a proxy for brain CHT capacity, we isolated T cells from the spleen, and synaptosomes from cortex and striatum, of wild type and CHT-overexpressing mice (CHT-OXP). Choline uptake capacity in T cells from CHT-OXP mice was two-fold higher than in wild type mice, mirroring the impact of CHT over-expression on synaptosomal CHT-mediated choline uptake. Monitoring T lymphocyte CHT protein and activity may be useful for estimating human CNS cholinergic capacity and for testing hypotheses concerning the contribution of CHT and, more generally, ACh signaling in cognition, neuroinflammation and disease.
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