The effects of early stress and undernutrition on the behavior of young adult rats and the correlations between behavioral and brain parameters.
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Biomedical subjects
Publications and source records attributed to S Zamenhof.
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Maternal protein-energy restriction (25% of the ad libitum intake) during the first 10 days of pregnancy resulted in severely altered fetal growth rates. Fetal development was assessed by body weight, brain weight, brain DNA, and brain protein content on fetal days 16, 18, 20 and at term. The individual placentas were also examined (weight, DNA and protein content) on each of these fetal days. Progesterone was administered commencing with day 3 of pregnancy until the day Caesarian section was done, in an attempt to rehabilitate placental development. This treatment did not improve placental development on fetal days 16 or 18. However, fetal development was significantly improved on day 16 and day 20, as compared to the dietary-restricted group without progesterone.
Correlations between neonatal body weight, and body weight and several brain parameters at 30 days of age were studied in normal rats. At 30 days ('adolescence') cortex has already reached its final thickness and the rat exhibits long-term memory. Brain parameters included cerebral weight, DNA, protein and cholesterol contents and densities, as well as cortical and cerebral dimensions (cerebral sections). As expected, most of these parameters in 30-day-old animals were significantly correlated with each other. Unexpectedly, neonatal body weight was also significantly correlated with cholesterol content and density at 30 days, as well as with cortical and cerebral dimensions at 30 days. Thus, statistically, neonatal body weight already predetermines the extent of neuronal (cerebral) development at adolescence (30 days). This finding also makes it possible to make at birth statistical predictions about future brain development without having to sacrifice neonatal animals.
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It has been suggested that in the embryo hormonal steroids may act also as control factors for the growth of neural systems. In the present work progesterone was introduced onto the chorioallantoic membrane of the chick embryo on day 7 or days 7 and 10 of incubation. The embryo, dissected at day 10, showed significant increases in body weight and cerebral hemispheres weight. The response at day 13 was less pronounced; male embryos responded to progesterone more than the female embryos. Progesterone is a precursor to other corticosteroids, but corticosterone itself had a significant harmful effect on embryonal growth. Several possible explanations of these results have been offered. It appears that progesterone itself promotes the growth of the early embryo, but the effect depends on its age and sex.
The effect of an early addition of exogenous nutrients on brain growth has been investigated in chick embryo. The nutrients were introduced onto chorioallantoic membrane at day 6 or 7 of embryonal life, and the cerebral hemispheres examined at the end of neuronal proliferation for the following parameters: weight, DNA content (index of cell number) and protein content. L-Tryptophan produced significant inhibition, probably by creating amino acid imbalance and interference with the transport of other amino acids. D-Tryptophan (slower transport) was inactive. 5-Methyltryptophan produced significant inhibition, probably by causing deficiency of tryptophan utilization and of production of serotonin, which is a growth factor for early brain. Glycine stimulated brain growth, probably by conversion to glucose which is the main energy source for the embryo in this period. Brain weight and DNA were found to be significantly correlated with blood glucose level. It is concluded that, within genetic limits, early brain growth might be manipulated in both directions (inhibition or stimulation) by addition of proper nutrients during sensitive period of neuronal proliferation.
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Experimental rats were fed 2/3 (10g/24 hours) of adlibitum diet throughout pregnancy and post-weaning, thus far for six generations; their brain and body development was compared with those of controls fed ad libitum (15.5 g/24 hours). As expected from previous reports, neonatal F1 offspring exhibited highly significant decreases in body weight, cerebral wet weight, cerebral DNA and cerebral protein. However, neonatal decreases were not greater in F2 through F6 than in F1 indicating that there was no cumulative effect of this undernutrition on offspring's parameters over generations. Maternal body weight at mating (90 days) and percentage of females that did not litter steadily decreased over generations. The observed high mortality in F1 through F6 and the resulting strong natural selection in favor of best mothers and weanlings could explain these findings. The phenomena contributing to high mortality are multiple and involve maternal factors during pregnancy and before weaning, as well as offspring factors.
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Female rats were fed (A) protein-restricted diet 1 month prior to mating and throughout pregnancy, or (B) protein-free diet during 10-20 days of pregnancy. At birth, four parameters of the offspring, body weight, cerebral weight, cerebral DNA, and cerebral protein were well correlated with each other, and were significantly lower than in the controls fed stock diet. The malnourished population had on the average 30-70% "outstanding low" individuals (parameter values more than 2 SD below the mean of the control); this is 13-20 times more than in the control. Even in malnourished populations a certain number of individuals escaped malnutrition (parameter values not lower than the mean of the control): they appear to be those which in normal populations would be well above the average. These individuals escaped malnutrition not by taking advantage of their littermates: the latter, though malnourished, were still better than the average in the malnourished group. The mechanisms by which some of the malnourished females differentially provide enough nutrients for one of their fetuses, and more than the average for its littermates, may involve differential mobilization of maternal nutrient among individual mothers, as well as differential blood supply to individual placentas or placental transfer to individual fetuses.
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Female rats (F0) were maintained on a protein-restricted or a normal diet 1 month prior to mating and throughout pregnancy. Their female offspring (F1) were maintained on a normal protein diet and mated with normal males. In previously reported studies, the 2nd generation offspring (F2) of the malnourished rats have been found at birth to have significantly lower cerebral DNA ( a measure of cell number), cerebral weight, and cerebral protein than normal controls. We now report that these F2 animals show marked learining deficits at maturity on 2 different successive reversal tasks, even though they themselves have never directly experienced malnutrition. Thus, certain behavioral as well as biochemical effects of malnutrition appear to the next generation of animals.
The degree of participation (DP) of exogenous thymidine and thymine in overall DNA synthesis was studied in Lactobacillus acidophilus R-26. The DP of thymidine remains constant under a variety of conditions (except at low thymidine concentrations, when the DP is influenced by deoxyribonucleosides and folic acid). A 5-bromodeoxyuridine-resistant mutant was isolated, which displayed cross-resistance to 5-bromouracil and a significantly lower DP of thymidine than the parental strain. Thymine was poorly incorporated in the parental strain even in the presence of deoxyribosides. The results of this investigation would be compatible with the possibility of an alternative pathway for thymidylate synthesis other than the known thymidylate synthase pathway.
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