John Tonkiss

Prenatal Malnutrition-Induced Changes in Blood Pressure: Dissociation of Stress and Nonstress Responses Using Radiotelemetry

A link between prenatal malnutrition and hypertension in human populations has recently been proposed. Rat models of prenatal malnutrition have provided major support for this theory on the basis of tail-cuff measurements. However, this technique requires restraint and elevated temperature, both potential sources of stress. To determine the effect of prenatal protein malnutrition on blood pressure under nonstress conditions, 24-hour radiotelemetric measurements were taken in the home cage. Male rats born to dams fed a 6% casein diet for 5 weeks before mating and throughout pregnancy were studied in early adulthood (from 96 days of age). During the waking phase of their cycle but not the sleep phase, prenatal malnutrition gave rise to small but significant elevations of diastolic blood pressure and heart rate compared with well-nourished controls. Direct effects of stress on blood pressure responses were determined in a second experiment using an olfactory stressor. Prenatally malnourished rats showed a greater increase in both systolic and diastolic pressures compared with well-nourished controls during the first exposure to ammonia. A different pattern of change of cardiovascular responses was also observed during subsequent presentations of the stressor. These findings of a small baseline increase in diastolic pressure consequent to prenatal malnutrition, but an augmented elevation of both systolic and diastolic pressures after first exposure to stress, suggest the need to reevaluate interpretation of the large elevations in blood pressure previously observed in malnourished animals using the stressful tail-cuff procedure.

Prenatal protein malnutrition affects exploratory behavior of female rats in the elevated plus-maze test

To study the effects of prenatal protein deficiency in the exploration of the elevated plus-maze, an ethological procedure was used. Female rats were provided with 25% (control) or with 6% (low-protein) casein diets before and during pregnancy. After birth eight pups in each litter (six males and two females) were fostered to a control mother. After weaning (21 days of age) all animals received a lab chow diet until behavioral testing began at 70 days of age. Individual prenatally malnourished (n = 12) and well-nourished (n = 12) females were placed at the center of the elevated plus-maze and allowed to explore for a 5-min session. One session was given per day for 6 consecutive days. The following variables were recorded: percentage of open arm entries; percentage of time spent in open arms; total arm entries; time in the center platform; latency to first open arm entry; number of attempts to enter an open arm; number of rearings; number of head-dips. The results showed a significant effect of malnutrition on six behaviors (percent open arm entries, percent time spent in open arms, attempts to enter open arms, rearings, head-dips, and latency to first open arm entry) and a significant diet by session interaction on two behaviors (attempts to enter open arms and head-dips). These results indicate increased exploration of the open arms in prenatally malnourished as compared with well-nourished control rats, suggestive of lower anxiety and/or a higher impulsiveness in these animals.

Malnutrition and Reactivity to Drugs Acting in the Central Nervous System

There is a well-established body of data demonstrating that protein or protein-calorie malnutrition experienced early in life is associated with neuroanatomical, neurochemical, as well as behavioral alterations in both animals and humans. A number of studies has focused on the following question: are the neuroanatomical and/or neurochemical changes produced by early malnutrition responsible for the altered behaviors reported in malnourished animals? A tool that has been used to help answer this question is the administration of drugs with specific actions in the various neurotransmitter systems in the central nervous system (CNS). This neuropharmacological approach has produced a considerable amount of data demonstrating that malnourished animals react to drugs differently from controls, suggesting that the altered behavioral expression of these animals could be partly explained by the alterations in the brain function following malnutrition. The present review will provide an overview of the literature investigating the reactivity of malnourished animals to psychoactive drugs acting through GABAergic, catecholaminergic, serotonergic, opioid and cholinergic neurotransmitter systems. Altered responsiveness to psychoactive drugs in malnourished animals may be especially relevant to understanding the consequences of malnutrition in human populations.

Prenatal protein malnutrition affects avoidance but not escape behavior in the elevated T-maze test

An elevated T-maze was used to study the effects of prenatal protein deficiency on inhibitory avoidance and escape behaviors. Female rats were provided with a 25% (control) or a 6% (low protein) casein diets before and during pregnancy. After birth, eight pups in each litter (six males and two females) were fostered to a lactating well-nourished mother. After weaning (21 days of age) all animals received a lab chow diet. Behavioral testing of these offspring began at 70 days of age. To assess inhibitory avoidance, prenatally malnourished and control rats were placed individually at the end of an enclosed arm in an elevated T-maze (one enclosed and two open arms) and the time taken to emerge from this arm was recorded. The same procedure was repeated in 2 subsequent trials given at 30-s intervals. Thirty seconds after the last of these trials, the rat was placed at the end of one open arm and the time taken to withdraw from this arm was measured, thus estimating escape latency. To assess retention, inhibitory avoidance and escape were measured again 72 h later. Prenatally malnourished males and females did not significantly increase avoidance latency from trials 1-3, in contrast to male and female controls. Only control female rats significantly reduced their avoidance latency on the retention test. No significant differences in escape latency were found between diet groups. These results suggest that prenatal malnutrition results in a reduction of anxiety, and that there are gender-specific responses to this test.

Effect of Prenatal Protein Deprivation on Postnatal Granule Cell Generation in the Hippocampal Dentate Gyrus

The effect of prenatal malnutrition, produced by protein deprivation, on postnatal neurogenesis of granule cells in the fascia dentata of the rat hippocampal formation was examined by injecting tritiated thymidine on P8 and P15 and sacrificing the pups on P30, or by injecting on P30 and sacrificing on P90. The number of labeled granule cells was significantly decreased in prenatally malnourished rats injected on P8, and unaffected in those injected on P15. In contrast, the number of labeled granule cells in prenatally malnourished rats was significantly increased in animals injected in P30. The study shows that prenatal malnutrition significantly alters the postnatal pattern of granule cell neurogenesis in rat hippocampal formation and that the effect persists despite nutritional rehabilitation at birth.

Prenatal protein malnutrition affects the social interactions of juvenile rats

The effects of prenatal protein malnutrition on juvenile social behavior was investigated in male and female rats. Animals were provided with 25% (control) or 6% (low protein) casein diets before and during pregnancy. After birth eight pups in each litter (six males and two females) were fostered to lactating control mothers. After weaning (21 days of age) all animals received a lab chow diet until behavioral testing began at 45 days of age. To assess social interaction, pairs of rats of the same gender, consisting of one malnourished and one control rat, were placed in a familiar rectangular arena on 3 consecutive days. Playful social behavior (pin), nonplayful social behaviors (anogenital sniff, walk-over, side-mount, and allogroom), and nonsocial behavior (rear) were recorded in 10-min sessions. Prenatal malnutrition significantly decreased both playful and nonplayful social behaviors, and increased nonsocial rearing. No significant gender differences were observed. The finding that early social behavior is altered by prenatal malnutrition opens the possibility that such changes may play an important role in determining some of the later behavioral differences described in the adult animal.

Fetal protein malnutrition impairs acquisition of a DRL task in adult rats

Developing rats were either malnourished or adequately nourished during the prenatal period by feeding their dams diets of 6% (low) or 25% (adequate) casein content 5 weeks prior to mating and throughout pregnancy. All pups received adequate nutrition from the day of birth onwards. Beginning at 160 days of age male rats were tested in a DRL-18 sec operant task. It was found that prenatal malnutrition impaired performance during acquisition, though asymptomatic levels were not significantly different. Subsequent limited hold DRL-18 sec schedules in which late as well as early responses went unrewarded indicated that the timing ability of the prenatally malnourished rats was excellent and similar to that of the controls. These late effects of fetal protein malnutrition are discussed in terms of the difficulty in adapting to the change from CRF to DRL-18 sec (possibilities include a reduced ability to develop a timing strategy or increased sensitivity to the change in reinforcement contingencies), while retaining the ability to time responses accurately once the task was acquired.

An analysis of spatial navigation in prenatally protein malnourished rats

Developing rats were either malnourished or adequately nourished during the prenatal period by feeding their dams diets of low (6% casein) or adequate (25% casein) protein content 5 weeks prior to mating and throughout pregnancy. All pups received adequate nutrition from the day of birth onwards. Male offspring were tested in one of two spatial navigation tests in the Morris water tank. In proximal-cue tests (postnatal days 16-20), the position of a platform, which provided a means to escape from swimming, was denoted by an obvious visual cue located directly on the platform. In distal-cue tests (postnatal days 20-27 and adult ages, days 70-71 and days 220-221), the escape platform was submerged below the surface of the water so that the rats were required to use extramaze visual cues to guide them to the platform. Neither proximal-cue nor distal-cue navigation was significantly impaired in the prenatally malnourished rats relative to controls, at any of the ages tested.

Prenatal protein malnourished rats show changes in sleep/wake behavior as adults.

Prenatal protein malnutrition significantly elevates brain levels of serotonin in rats, and these levels remain elevated throughout their lives. This biogenic amine is involved in the regulation of many physiological functions, including the normal sleep/wake cycle. The present study examined the effects of prenatal protein malnutrition on the sleep/wake cycle of freely moving adult rats. Six prenatally protein malnourished (6% casein) and 10 well‐nourished (25% casein) male rats (90–120‐day‐old) were chronically implanted with a standard set of electrodes (to record cortical electroencephalogram, neck muscle electromyogram, electrooculogram, and hippocampal theta wave) to objectively measure states of sleep and wakefulness. Six‐hour polygraphic recordings were made between 10.00 and 16.00 h; a time when the rats normally sleep. Prenatally malnourished rats spent 20% more time in slow wave sleep (SWS) compared to the well‐nourished rats. The total percentage of time spent in rapid eye movement (REM) sleep was 61% less in prenatally malnourished rats compared to well‐nourished control rats. These findings demonstrate the adverse consequences of prenatal protein malnutrition on the quality and quantity of adult sleep in rats. These sleep changes are potentially detrimental to normal social behavior and cognitive functions. Prenatally malnourished rats are an excellent animal model to study the role of endogenous serotonin in the regulation of the normal sleep/wake cycle.

Prenatal malnutrition effect on pyramidal and granule cell generation in the hippocampal formation

The effects of prenatal malnutrition produced by protein deprivation on the neurogenesis of granule and pyramidal cells in the rat hippocampal formation was investigated by injecting pregnant rats with tritiated thymidine on E12, E16, or E20 and sacrificing the pups on P30. Granule cell neurogenesis was significantly decreased in the pups injected on E20, but not in E12 or E16 groups. There was no effect on the generation of pyramidal cells at the times noted, indicating a differential effect of prenatal malnutrition on the generation of these two different neuronal types in the hippocampal formation.