Perinatal steroid exposure and respiratory control during early postnatal life

Numerous factors involved in general homeostasis are able to modulate respiratory motor output. These include placental-derived steroids, which are necessary for maternal physiological adjustments during gestation, including respiratory stimulation. Despite the fact that these hormones exert potent effects on neural development in the fetus, the hypothesis of a developmental control of the neural respiratory network by placental-derived steroids has been approached experimentally only recently. The objective of this review is to summarize the role and mode of action of placental steroids on respiratory control in adult mammals and highlight the potential pathways by which such steroids are supplied to the developing fetus. Additionally, we present recent results showing that the beta estradiol and progesterone receptors are expressed in the carotid body of newborn male rats, thus supporting the hypothesis of receptor-mediated effect of estradiol and progesterone on carotid bodies.     

Erythropoietin and respiratory control at adulthood and during early postnatal life

Erythropoietin (Epo) was originally discovered as a cytokine able to increase the production of red blood cells upon conditions of reduced oxygen availability. Now we know that Epo does far more than “only” augmenting the number of erythrocytes. Since the demonstration that Epo (and its receptor) is expressed in the mammalian brain, several elegant experiments were performed to reveal the function of this molecule in the neuronal tissue. Accordingly to its anti-apoptotic, neurotrophic and proliferative effects in the bone marrow, it was suitably suggested that upon pathological conditions Epo exerts neuroprotective functions (i.e. reducing the infarct volume of stroke, thus allowing better and faster recovery). We considered however, that Epo in brain might also exert a physiological function. Indeed, we found that Epo is an important modulator of the respiratory control system. By using adult mice we showed that Epo increases the hypoxic ventilatory response by interacting with both the central respiratory network (brainstem) as well as the main peripheral sensory organs detecting systemic hypoxia, the carotid bodies. More recently, our research turned to examine the exciting hypothesis that Epo is also implicated in the regulation of the neuronal control of ventilation during the postnatal development. The objective of this review is to summarize the role and mode of action of Epo on respiratory control in adult mammals and highlight the potential pathways by which this cytokine achieve this function. Additionally, we review recent evidences showing that Epo play a crucial role in setting the respiratory motor output (measured on the isolated brainstem spinal cord preparation, en bloc technique) during the early postnatal life.     

Light-dark discrimination and reversal learning in early postnatal kittens.

During the early postnatal period kittens were trained in a visual discrimination task involving light-dark stimuli in order to determine the age of onset of visual control of learned behavior. A Y water maze was used with escape from water as the reinforcer. The results indicate that kittens are able to master the discrimination within the 5th week of life. The relevance of this result to electrophysiological measures of maturation is discussed.     

The effects of undernutrition during early life on spatial learning

Recent research has shown that a lengthy period of undernutrition during early postnatal life can cause alterations in the morphological structure of the dentate gyrus. As this region is involved in the control of spatial memory, we decided to investigate whether undernourished rats also showed any deficits in this aspect of behaviour. Rats were undernourished from about birth until either 30 or 60 days of age and then nutritionally rehabilitated for a lengthy period before testing. There were significant differences in the body weight of control and undernourished rats in each experiment. The testing procedure involved rats being placed in a large pool of opaque water. They were required to swim to find a hidden platform located just below the water surface onto which they could escape. Each rat had to perform this test 20 times over a period of 3 days. The time taken and the total distance swum by each rat during each trial was measured. In Experiment 1, rats were familiarised with the water before testing took place, whereas in Experiment 2 they were not. There were no significant differences in the latency to find the platform or the distance swum between well-fed control and previously undernourished rats in either experiment. In conclusion, in our experiments we could not demonstrate that undernutrition during early life caused any deficits in spatial memory performance.     

The compensatory role of food-motivation in the maze learning performance of lactationally undernourished rats.

To test the hypothesis that the motivational effects of neonatal undernutrition might conceal the detrimental effects on learning, we tested previously undernourished and normally nourished Sprague-Dawley rats on learning of a novel maze pattern under either latent learning (nonappetitive) or food-motivated conditions. Under the nonappetitive conditions, the previously undernourished rats learned significantly less than the normal controls, but when motivated for food, the undernourished rats performed as well as the controls. When learning performance measures are sensitive to motivation, differential motivation between undernourished and normal subjects must be controlled or eliminated.     

Overexpression of the p75 neurotrophin receptor in the sensori-motor cortex of rats exposed to ethanol during early postnatal life

Foetal alcohol syndrome is a known cause of mental retardation. It has been suggested that the anatomical and functional alterations observed in the cerebral cortex could be mediated by an interference of ethanol with developmental processes modulated by neurotrophins and/or their receptors. We have studied by immunohistochemistry the expression of the p75 neurotrophin receptor (p75 NTR) in the sensori-motor cortex of P10 and P20 rats exposed to the inhalation of ethanol during the first week of postnatal life. At both the studied ages, the number of p75 NTR immunoreactive neurons was higher in ethanol treated animals compared to controls. The increase of immunoreactive elements was relatively more marked in the motor than in the somatosensory cortex. The involvement of p75 NTR in ethanol-induced apoptosis and neural plasticity is discussed.     

Influence of the inhibition of free-radical oxidation processes in early postnatal ontogenesis on learning in adult rats

The influence of the neonatal administration of the synthetic antioxidant mexidol on teaching rats an active avoidance conditioned reflex at the age of two months was studied. It was established that the inhibition of free-radical oxidation in the tissues of three to seven day old infant rats subsequently leads to facilitation of the learning process: to a decrease in the latent period of the avoidance reaction by a factor of 4–6, a two fold increase in the conditioned reflex response, and a decrease in total motoric activity at the stage of the stably developed reaction.Translated from Fiziologicheskii Zhurnal SSSR imeni I. M. Sechenova, Vol. 76, No. 10, pp. 1393–1396, October, 1990.     

Developmental delays in offspring of rats undernourished or zinc deprived during lactation

Offspring of rats who were zinc or calorie deprived during lactation were administered a battery of reflex and motor tests from postnatal Day 4 to Day 21. Compared to offspring of ad lib-fed control rats, both zinc deprived and undernourished offspring exhibited developmental delays in reflexes which appeared after the first postnatal week (auditory startle, air righting, and rope descent). As the deficiencies continued the delays appeared to be more pronounced. The zinc deficiency did not add to the deficits associated with calorie restriction alone because there were no significant differences between the zinc deficient and undernourished pups on any of the measures except eye opening. When rehabilitated offspring were tested at 45 and 60 days of age for motor deficits there were no significant impairments resulting from preweaning dietary conditions. However, the growth retardation of zinc deprived and undernourished rats persisted long after dietary rehabilitation was implemented.     

Electron microscopy of synaptic structures in olfactory cortex of early postnatal rats.

Layer 1 of the rat olfactory cortex has been studied with the electron microscope at birth and at several consecutive postnatal days up to 14 days of age. Special attention was directed towards synaptic structures and axons of the lateral olfactory tract (LOT). Numerous mature synapses are seen at birth and estimates were made of their subsequent increase in number. In addition, immature synapses are seen and mature postsynaptic sites occur with atypical, partial, multiple or no contact. The findings suggest: (1) considerable prenatal synaptogenesis in contrast to other cortical systems; (2) the maturation of the postsynaptic site may precede that of the presynaptic contact and vesicle accumulation; (3) there may be competition by more than one process for one postsynaptic specialization; (4) the non-innervated sites may result from deafferentation caused by prenatal cell death, although no degeneration was seen, and the atypical contacts may be a stage in the reinnervation of these sites; (5) the LOT develops in parallel with the synaptic neuropil and (6) by 14 days of age the area closely resembles adult tissue.     

Exploratory behavior, learning ability, and thyroid hormonal responses to stress in female rats rehabilitating from postnatal hypothyroidism

Newborn female Long-Evans rats were divided into groups of normal, hypothyroid [0.1% propylthiouracil (PTU) a reversible antithyroid goitrogen in the litter's drinking water], and hypothyroid rehabilitated (PTU water from birth to day 25, normal water thereafter). The rats were tested for several adaptive behavioral tasks between 40 and 90 days of age. At day 50, serum concentration of TSH and thyroid hormones revealed no detectable amounts of T4 and a 10-fold increase in TSH in the hypothyroid rats. At the same age in the rehabilitated animals, TSH levels were still below normal, a deficit fully normalized by day 90. Normal 50-day-old rats responded to pain stress (electric footshocks) by a significant depression of serum T4 and elevation of T3 levels within 10 min of treatment, whereas the rehabilitated animals exhibited an opposite pattern of response, i.e., an increase in the circulating T4 and a decrease in T3. At 50 days of age, both hypothyroid and rehabilitated rats showed decreased exploratory activity and no habituation in the hole-board test, whereas the locomotor activity of the rehabilitated females was significantly higher than that of the normals. No differences were found in the scores of passive avoidance learning (one trial step-through) among the three groups. Similarly, the rate of acquisition of the active one-way conditioned avoidance response (CAR) of the hypothyroid and rehabilitated rats did not differ significantly from that of the controls. However, the hypothyroid rats required significantly more unconditioned stimuli (footshocks) to acquire CAR and showed longer response latency and less intertrial responses. Although the hypothyroid rats showed no extinction of CAR, the rehabilitated rats were capable of extinction to an extent indistinguishable from normal rats. But compared with the normal animals, the rehabilitated rats showed significantly higher intertrial activity during both the acquisition and extinction phases of CAR.     

Blood ethanol concentration from early postnatal exposure: effects on memory-based learning and hippocampal neuroanatomy in infant and adult rats.

Early postnatal exposure to ethanol (EtOH) that results in daily high-peak blood ethanol concentration (BEC) retarded the acquisition of single-patterned alteration (PA), a kind of memory-based discrimination learning, and was related to reduced brain weight, hippocampal cell number, and CA1 area in infant rats. These behavioral and neuroanatomical effects survived into young adulthood. On the PA discrimination, in both pups and young adults, postnatal exposure to high-peak EtOH condition, in relation to low-peak and control conditions, impaired the acquisition of PA at 60-s but not at 30-s intertrial intervals. These results provide further evidence of hippocampal involvement in intermediate-term memory and indicate that early postnatal EtOH is a behavioral and neuroanatomical teratogen, particularly when the BEC is relatively high.     

Effect of ambient temperature on rectal temperature in normal and malnourished rats during early postnatal development

Information on body temperature is frequently lacking in metabolic studies on normal and malnourished suckling rats although differences in their thermoregulatory efficiency may be expected. The aim of the present study was to evaluate the effect of different ambient temperatures on the rectal temperature of litters of normal and protein deprived rats to establish the ambient temperatures at which a normal rectal temperature can be expected at various postnatal ages. The offspring of normal rats and rats subjected to a dietary reduction of 50% of the protein intake were examined 10 days to 30 days postnatally. The pups were transferred from the nest cage to an incubator: the rectal temperature was measured immediately after transfer to the incubator and 30 and 60 min later at ambient temperatures of 35, 30 and 25 degrees C. Up to 15 days of age control pups showed a fall in rectal temperature after the short exposure to room temperature (22 degrees C) needed for transfer. A similar fall of rectal temperature was recorded in the malnourished pups up to 25 days age. The effects of the ambient temperatures on the malnourished pups indicated a delay in the control of body temperature of some 10 days. This is in agreement with a previous report on semi-starved rats (Heim & Szelenyi 1965). The conditions for the maintenance of a normal rectal temperature in litters of normal and malnourished suckling rats separated from their mother are out-lined.     

Spatial conditional discrimination learning in developing rats

The present study established an effective procedure for studying spatial conditional discrimination learning in juvenile rats using a T-maze. Wire mesh located on the floor of the maze as well as a second, identical T-maze apparatus served as conditional cues which signaled whether a left or a right response would be rewarded. In Experiment 1, conditional discrimination was evident on Postnatal Day (PND) 30 when mesh+maze or maze-alone were the conditional cues, but not when mesh-alone was the cue. Experiment 2 confirmed that mesh-alone was sufficiently salient to support learning of a simple (nonconditional) discrimination. Its failure to serve as a conditional cue in Experiment 1 does not reflect its general ineffectiveness as a stimulus. Experiment 3 confirmed that the learning shown in Experiment 1 was indeed conditional in nature by comparing performance on conditional versus nonconditional versions of the task. Experiment 4 showed that PND19 and PND23 pups also were capable of performing the task when maze+mesh was the cue; however, the findings indicate that PND19 subjects do not use a conditional strategy to learn this task. The findings suggest postnatal ontogeny of conditional discrimination learning and underscore the importance of conditional cue salience, and of identifying task strategies, in developmental studies of conditional discrimination learning.     

Body temperature and 5-hydroxytryptamine during early postnatal maturation in mice.

A relationship between the maturational increases in body temperature and brain indoleamines has been explored through altering brain 5-hydroxytryptamine (5-HT) content. Effects on body temperature at approximately constant ambient temperature (about 24 degrees C) have been studied following pharmacological manipulations in mice up to 16 days postpartum. Administration of 5-hydroxytryptophan (5-HTP) to increase 5-HT levels was associated with decreased body temperature throughout the maturational period. Depletion of 5-HT with p-chlorophenylalanine (p-CPA) was associated with increased body temperature at all ages studied, although 5-HT depletion was less effective in young animals than in older animals. The drug NSD-1034 acts at a different enzymatic step, and is effective in both central and peripheral tissues to reduce 5-HT and norepinephrine (NE) levels. NSD-1034 decreased body temperature up to 10 days of age; however, the effect was reversed at about 14 days, and the drug increased body temperature significantly in 16-day-old animals. These results suggest a role for 5-HT in the mechanisms of heat production in early postnatal life.     

Social behaviour of rats following pre- and early postnatal undernutrition

The social behaviour of adult male rats which had been undernourished at some stage before weaning was investigated. Litters were cross-fostered at birth between well fed and underfed dams. Thus, some were undernourished only during gestation, others only during the suckling period and others throughout both periods. After weaning all animals had free access to food and were grouped with two or three littermates. Each adult previously undernourished rat was allocated its own control partner which had been well fed throughout life. Four measures of social interaction were recorded during five 10 min tests. Postnatal undernutrition increased the frequency of allogroom and walk over and pre with postnatal undernutrition had a similar effect. Rearing and mount were unaffected by either treatment. Prenatally growth restricted rats did not differ from controls on any measure. Thus, adult social behaviour was more affected by the postnatal than by the prenatal experience. In another experiment smaller control rats were found not to differ in their social behaviour from larger control rats, indicating that size is not an important factor in these studies.     

Differences between rats and undernourished preweaning, and controls in learning about a redundant stimulus during acquisition of a conditioned emotional response

Male rats were undernourished during the first three weeks of life by restricting maternal food consumption. Following nutritional rehabilitation, previously undernourished (PU) and control (C) rats were trained to operate a lever to obtain food reward on a variable interval schedule. When rates of responding had stabilised, the rats were tested for suppression of lever-pressing during the illumination of a light which preceded footshock. There were not differences between PU and C groups in the acquisition of this conditioned emotional response, nor were there differences in suppression when a redundant, tone stimulus was presented contemporaneously with the light to predict shock. When the tone was subsequently tested alone for its ability to suppress lever-pressing it was found to have acquired this property in C, but not in PU animals. In a second experiment, PU and C rats were found not to differ in their response to the tone when it was presented as a novel stimulus, nor in suppression to the tone when it was made the sole predictor of footshock. It was concluded that PU and C rats differed in learning about a stimulus predicting footshock, only when that stimulus was redundant. Among the possible explanations for this behavioural difference between PU and control rats are differences in motivation, curiosity, or strength of conditioning. These possibilities are evaluated within the context of current formal theories of conditioning.