Undernutrition and Cerebellar Development

Chase, H. Peter; Lindsley, Warren; OʼBrien, Donough

doi:10.1038/221554a0

Cited by 117 publications

(33 citation statements)

References 10 publications

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“…Our value of 1.62mg/g indicates that DNA isolation from newborn brain is virtually quantitative, and the 8.25% of 5-hydroxymethylcytosine in these samples therefore appears to be a valid estimate of its concentration in the bulk DNA. In the adult brain, DNA contents of 1.7-1.8mg/g have been reported (Fish & Winick, 1969;Chase et al, 1969). This value is 0.7mg/g greater than the 1.1 mg/g of adult DNA obtained in the present experiments.…”

Section: Resultscontrasting

confidence: 43%

Modification of brain deoxyribonucleic acid base content with maturation in normal and malnourished rats

Penn

1976

Biochemical Journal

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The mol percentage of 5-hydroxymethylcytosine is 2.2 times greater in the adult than in 2-day-old rat brain DNA. The concentration of 5-hydroxymethylcytosine falls in corresponding liver DNA preparations. This normal increase in brain 5-hydroxymethylcytosine is abolished in rats placed on an 8 %-protein diet 5 days after birth.The pyrimidine 5-hydroxymethylcytosine has been reported to characterize a central-nervous-system DNA species that is enzymically and chemically labile (Penn et al., 1972). This DNA was implicated in higher functions of the central nervous system, presumably through modulation of synaptic activity by a fraction localized in the synaptosomal mitochondria (N. W. Penn, S. Schell, R. Suwalski & K. Bojanowski, unpublished work). In support of this interpretation, further study has demonstrated that the effects of barbiturate, alcohol and morphine are antagonized by DNA pyrimidines and their metabolically allied cofactors (Penn, 1974(Penn, , 1975a. Time-intervals involved in reversal of drug action, barbiturate binding to DNA fractions and the specificity for DNA components as antagonists suggest a direct interaction between these drugs and a DNA receptor(s).The acute actions of these drugs are mediated primarily or in part at the central-nervous-system synapse. It thus appeared that the DNA species characterized by 5-hydroxymethylcytosine, or the concentration of this base in DNA, might increase as the synaptic architecture of the brain was completed. We therefore investigated hydroxymethylcytosine concentrations in newborn and adult, normal and retarded rat brain DNA, by using liver DNA as a reference preparation. Materials and MethodsThe 8 % (low-protein) diet for rats was purchased from ICN Life Sciences, Cleveland, OH, U.S.A. The original procedure for DNA isolation was used (Penn et al., 1972) 1972), and homogenized in solution A (Solution A/ brain = 10:1, v/w). Brains from 2-day-old rats were similarly processed, combining tissue from two newborn animals for each sample. Livers from four 2-day-old animals, similarly prepared, were combined for each determination. To retard development, 5-day-old rats were placed on an 8%-protein diet, separated from the mother 2 weeks later and maintained on the diet until they were killed 2 months after birth. Animals from three litters were used.The individual nucleotide bases were determined after formic acid hydrolysis. Appropriate portions were chromatographed in duplicate in propan-2-ol-/12M-HCl/water (170:41:39, by vol) (Wyatt, 1951) for precise evaluation of base ratios. Cytosine and 5-hydroxymethylcytosine were determined as total cytosines by this system, which does not resolve these pyrimidines. The ratio between the two componentswasdeterminedbyduplicatetwo-dimensional chromatographic runs in sodium acetate (0

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Section: Resultscontrasting

confidence: 43%

Modification of brain deoxyribonucleic acid base content with maturation in normal and malnourished rats

Penn

1976

Biochemical Journal

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“…This condition also reduces myelin lipid formation [5], but causes little or no decrease in cerebral DNA. The main effect under these circumstances is on the cerebellum [6]. In addition, body weights were only slightly reduced in animals injected with phenylalanine compared with control animals, yet the brain weights and total lipid weights were reduced more in phenylalanine-injected animals than in undernourished animals of less than half the body weight (table I).…”

Section: Discussionmentioning

confidence: 83%

Effect of Excess Phenylalanine and of Other Amino Acids on Brain Developmen in the Infant Rat

Hp¹,

OʼBrien²

1970

Pediatr Res

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The effects of excess phenylalanine and of a number of other amino acids on brain weight, total brain lipid, and formation of the myelin lipid cerebroside sulfate (sulfatide) have been studied in the newborn rat. Brain weight, amount of brain lipids, and the formation in vivo of sulfatide were reduced as a result of injections of phenylalanine or of certain other amino acids. Total brain cholesterol, cerebroside, and sulfatide were all significantly reduced in phenylalanine-injected animals, although sulfatide was the only lipid that was reduced per gram wet weight of brain. The in vitro activity of the brain enzyme, galactolipid sulfotransferase, which catalyzes the formation of sulfatide from cerebroside and adenosine 3'-phosphate 5'-phosphosulfate (PAPS), was significantly reduced only when exogenous PAPS was not added to the assay medium. This finding suggests that in the brains of animals injected with phenylalanine there was impairment in the formation of PAPS from ATP and sulfate. In both cerebrums and cerebellums of animals injected with phenylalanine for the first 18 days of life, the amount of brain DNA and protein was reduced. Speculation

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“…There is also evidence that certain disorders of human behavioral development, such as those associated with autism, mental retardation, undernutrition, and developmental methylmercury neurotoxicity are sometimes accompanied by cerebellar damage or hypoplasia (51,(61)(62)(63). There are also many human neurological disorders associated with pathology to the hippocampus and/or related structures, including ischemia (64), Down's syndrome (65), schizophrenia (66), undernutrition (67), hypoglycemia (68), hypothyroidism (69), early exposure to lead (70,71), and fetal alcohol exposure (72,73).…”

Section: Applications To Developmental Learning Disordersmentioning

confidence: 99%

Eyeblink conditioning in the infant rat: an animal model of learning in developmental neurotoxicology.

Stanton

Freeman

1994

Environ Health Perspect

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Classical conditioning of the eyeblink reflex is a relatively simple procedure for studying associative learning that was first developed for use with human subjects more than half a century ago. The use of this procedure in laboratory animals by psychologists and neuroscientists over the past 30 years has produced a powerful animal model for studying the behavioral and biological mechanisms of learning. As a result, eyeblink conditioning is beginning to be pursued as a very promising model for predicting and understanding human learning and memory disorders. Among the many advantages of this procedure are (a) the fact that it can be carried out in the same manner in both humans and laboratory animals; (b) the many ways in which it permits one to characterize changes in learning at the behavioral level; (c) the readiness with which hypotheses regarding the neurological basis of behavioral disorders can be formulated and tested; (d) the fact that it can be used in the same way across the life-span; and (e) its ability to distinguish, from normative groups, populations suffering from neurological conditions associated with impaired learning and memory, including those produced by exposure to neurotoxicants. In this article, we argue that these properties of eyeblink conditioning make it an excellent model system for studying early impairments of learning and memory in developmental neurotoxicology. We also review progress that has been made in our laboratory in developing a rodent model of infant eyeblink conditioning for this purpose. -Environ Health Perspect 102(Suppl 2):131-139 (1994).

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Undernutrition and Cerebellar Development

Cited by 117 publications

References 10 publications

Modification of brain deoxyribonucleic acid base content with maturation in normal and malnourished rats

Modification of brain deoxyribonucleic acid base content with maturation in normal and malnourished rats

Effect of Excess Phenylalanine and of Other Amino Acids on Brain Developmen in the Infant Rat

Eyeblink conditioning in the infant rat: an animal model of learning in developmental neurotoxicology.

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