Maze Learning by Adult Rats after Inhibition of Neuronal Multiplication in Utero

Abstract

ExtractRats whose mothers received hydroxyurea (HU, 1 or 2 g/kg) at 14 days of gestation had a 30% deficit in both brain and body weight at birth, when compared with controls. Number of brain cells at birth (mainly neurons) was reduced by 33-34%. A severe reduction in postnatal whole brain growth (31-33% in adulthood) was observed, but the cerebellum was relatively spared. In the Hebb-Williams maze text in adulthood HU animals made 28% more errors than controls over 12 problems. The differences were much more marked on certain problems and for HU animals with particularly small brains. In a T-maze spatial discrimination test in adulthood HU rats either saline (10 ml/kg body weight) of HU (26) (1 or 2 g/kg body weight) suspended in a corresponding volume of saline. On the day of birth (21 or 22 days of gestational age), litters were reduced to eight animals (four males, four females) and fostered to a saline-treated mother giving birth on the same day. Both control (saline-treated) and HU animals were so fostered. A number of excess animals from each litter was killed for estimation of brain DNA (25). At 25 days of age half of the animals in each litter were killed and the whole brain and cerebellum was dissected out and weighed. The remaining animals (up to two males, two females) were weaned and subsequently housed two per cage. learned the initial response normally but, when required to HEBB-WILLIAMS MAZEreverse this response, showed a significant tendency to make more perseverative errors than controls.Rats aged 13-15 weeks were tested in a Hebb-Williams . maze (20). The light cycle was 12 hr of red, beginning at 07.00 Speculation hr, and 12 hr of white. Animals were kept at about 80% of Rats exposed to an inhibitor of cell division at the beginning of the major period of brain neurogenesis showed deficits in learning ability in adulthood. The large number of mentally retarded human children whose handicap is without known etiology may have suffered a similar early loss of neurons, and if so, this preparation could provide a useful animal model.The period of neuronal multiplication in the mammalian central nervous system is relatively short and, except in the cerebellum and hippocampus (2), occurs well before the major phase of brain growth and physiologic development. For example, in man neuron formation is largely complete by 20 weeks of gestation (a), whereas rat brain neurogenesis, as assessed by accumulation of DNA, occurs between approximately 13 and 20 days of gestation (5).It has been suggested (6) that in man certain forms of mental retardation, involving microcephaly, but the etiology thkir predicted free-feeding weight throughout the period of testing, and were run for a food reward, in two sessions/day, during the red phase of their light cycle. T-MAZERats aged 20--23 weeks were tested in a water T-maze as described previously for guinea pigs (1). The light cycle was 12 hr of red, beginning at 12.00 hr, and 12 hr of white. Rats were required to swim and make a left-right discrimination in order to...

Effects of hydroxyurea on postnatal growth and behaviour of rats

“…The findings of the present study are generally in agreement with the results reported by BUTCHER et al [5] and BRUNNER et al [4] but differ in some respects from those of ADLARD and DOaaING [1]. The latter authors described a decrease in postnatal brain growth in 25-day-old pups as well as 23-week-old female rats from mothers treated with 2000 mg/kg of HU on day 14 of pregnancy.…”

“…In the present study the brain weight to body weight ratio was not significantly altered in 60-day-old rats. Furthermore, ADLARD and DOBBrNG [1] did not demonstrate an increase in the postnatal mortality rate. This difference may be partly explained by the fact that in the present experiment the pups were not fostered, and those most severely affected by HU treatment died before the day of autopsy and determination of brain weight.…”

“…In addition, ADLARD and DOBBING [1] give an account of delayed brain growth of rats in association with an increase in errors in maze discrimination tests in animals whose mothers had received 2000 mg/kg of HU on day 14 of pregnancy.…”

Nutritionally Small-for-Dates Rats: Their Subsequent Growth, Regional Brain 5-Hydroxytryptamine Turnover, and Behavior

“…This was again in contrast to I R animals where a selective effect on cerebellum and midbrain was found. These findings in the brain accord well with the effects of inhibitors of D N A synthesis (hydroxyurea, cytosine arabinoside) when given to fetal or postnatal rats (2,4).…”

“…Litters were reduced to eight animals (five males, of different postnatal environments with the effects of prenatal three females) at birth, and at 5 days of age were fostered in one of growth restriction. Animal experiments, however, allow these three ways: (I) between control mothers (control young, C), (2) variables to be controlled in a systematic way. from a control to an underfed mother (IR young), and (3) from an An animal model has recently been proposed for the human underfed to a control mother (FNR young).…”