L. A. Vataeva

Mild hypoxia preconditioning prevents impairment of passive avoidance learning and suppression of brain NGFI-A expression induced by severe hypoxia.

The aim of this work was to study effects of mild preconditioning hypobaric hypoxia (380 Torr for 2 h, repeated 3 or 6 times spaced at 24 h) on brain NGFI-A immunoreactivity and passive avoidance (PA) behavior in rats exposed to severe hypoxia (160 Torr for 3 h). Severe hypobaric hypoxia produced extensive neuronal loss in hippocampal CA1, while the preceding hypoxic preconditioning had clear protective effect on neuronal viability of vulnerable hippocampal cells. Besides, the hypoxic preconditioning prevented impairment of acquisition and retention of PA caused by severe hypoxia. The six-trial hypobaric preconditioning was more effective in protection against PA learning deficits in severe hypoxia exposed rats than the three-trial preconditioning. The preconditioning up-regulated severe hypoxia-suppressed neocortical and hippocampal expression of NGFI-A, suggesting a possible role for NGFI-A in the neuroprotective mechanisms activated by hypoxic preconditioning.

Antidepressant-like effects of mild hypoxia preconditioning in the learned helplessness model in rats.

The effects of preconditioning using mild repetitive hypobaric hypoxia (360 Torr for 2 h each of 3 days) have been studied in the learned helplessness model of depression in rats. Male Wistar rats displayed persistent depressive symptoms (depressive-like behaviour in open field, increased anxiety levels in elevated plus maze, ahedonia, elevated plasma glucocorticoids and impaired dexamethasone test) following the exposure to unpredictable and inescapable footshock in the learned helplessness paradigm. Antidepressant treatment (ludiomil, 5 mg/kg i.p.) augmented the development of the depressive state. The hypoxic preconditioning had a clear antidepressive action returning the behavioural and hormonal parameters to the control values and was equally effective in terms of our study as the antidepressant. The findings suggest hypoxic preconditioning as an effective tool for the prophylaxis of post-stress affective pathologies in humans.

The possible use of hypoxic preconditioning for the prophylaxis of post-stress depressive episodes.

The protective effects of hypoxic preconditioning on the development of depressive states in rat models were studied. Three episodes of intermittent preconditioning using hypobaric hypoxia (360 mmHg, 2 h) prevented the onset of depressive behavioral reactions, hyperfunction of the hypophyseal-adrenal system, and impairments in its suppression in the dexamethasone test in rats following unavoidable aversive stress in a model of endogenous depression. The anxiolytic and antidepressant actions of hypoxic preconditioning in experiments on rats were no less marked than those of the tetracyclic antidepressant ludiomil. The results obtained here provide evidence that preconditioning with intermittent hypobaric hypoxia increases resistance to psychoemotional stresses, has marked anxiolytic and antidepressant effects, and can be used for the prophylaxis of depressive episodes.

Behavioral alteration in the adult rats prenatally exposed to para-chlorophenylalanine

In the present work, effects of maternal administration of para-chlorophenylalanine (PCPA), a serotonin synthesis inhibitor, on behavior of adult offspring were studied. Pregnant rats were injected intraperitoneally with PCPA (200/100/100/50 mg/kg) either on the gestational days (GD) 8-11 or 14-17, or with vehicle at the same days. Behavioral parameters, in an open field, the Porsolt forced swim test and the Morris water maze test were evaluated at the age of 3-3.5 months in the male and female offspring. The prenatal PCPA increased activity in an open field in the offspring treated on either GD 8-11 or 14-17. The highest levels of the activity were revealed in the male and female offspring treated on GD 14-17. Besides, the PCPA treatment on GD 8-11 or 14-17 facilitated the intersession habituation of activity to repeated exposures to an open field in the male offspring. Both male and female offspring treated on GD 14-17 showed an increased immobility in the Porsolt forced swim test and a significant learning impairment in the Morris water maze. Thus, it has been shown that administration of PCPA to pregnant rats might cause significant changes in the adult offspring behavior. These results provide further evidence that unfavorable influence may have more adverse effects on the behavioral development of rats when exposed during the final trimester of pregnancy than during the second trimester.

Influence of severe hypoxia on rat emotional behavior: the modifying effect of preconditioning.

Convincing evidence has been obtained to date that the adverse effects of severe hypoxia/ischemia can be prevented by a preliminary mild stress. The latter procedure is often referred to as preconditioning and regarded as a form of brain cell adaptation to insufficient oxygen and blood supply [1–3]. Moderate hypoxia is successfully used as a preconditioning factor. The data on the protective effect of preconditioning have mainly been obtained by analysis of destructive changes in various brain regions caused by severe hypoxia/ischemia. The destructive changes proved to be the most pronounced in the hippocampus. These data agree with the results of behavioral experiments, which testify to the altering effect of hypoxia/ischemia on learning and memory [4]. In this study, the abnormal behavioral reactions connected with the motivation–emotion sphere and the correcting effect of preconditioning were primarily analyzed.

Maternal para-chlorophenylalanine exposure modifies central monoamines and behaviors in the adult offspring

We reported a perspective animal model of neurodevelopmental disorders using rats prenatally exposed to an inhibitor of serotonin (5HT) synthesis, para-chlorophenylalanine (PCPA). Earlier, we demonstrated that prenatal exposure to PCPA caused fetal 5HT depletion and changes both in open field activity and in depression-related behavior, as well as impairments in spatial learning in the adult offspring (Vataeva et al., 2007). The present study revealed that prenatal PCPA treatment resulted in the offsprings significantly reduced anxiety-related behavior in the elevated plus-maze and reduced neophobia to intake fluids in a novel environment. These effects are accompanied by hedonic changes in the form of an appropriate increase in saccharin preference. We confirmed our earlier finding that prenatal PCPA exposure affected the open field locomotor activity. In the present study we have shown that the selective 5HT reuptake inhibitor (SSRI) paroxetine decreases locomotor activity in the prenatally PCPA-treated offspring. It was also found that in the PCPA-treated fetal brain, 5HT depletion was associated with a significant decrease in the level of dopamine (DA) metabolite dihydroxyphenylacetic acid (DOPAC) and with a reduction of DOPAC/DA and homovanillic acid (HVA)/DA ratios. An assay of adult offspring brain revealed that the prenatal PCPA produced different effects on monoamines in the studied brain structures. The relationships between behavioral abnormalities and alterations in brain monoamine levels consequent on the prenatal PCPA treatment are discussed.

Hypobaric Hypoxia Affects Rat Behavior and Immediate Early Gene Expression in the Brain: the Corrective Effect of Preconditioning

Molecular and cellular mechanisms of the brain responses to hypoxia have been extensively studied in the past decades. It has been shown that the cellular genome is involved in these reactions. A rapid expression of immediate early gene superfamilies ( c-fos , c-jun , junB , NGFIA, etc.) in response to different types of hypoxia has been reported [1–3]. However, the role that hypoxia-induced changes in the immediate early gene expression play in the mechanisms of neuronal damage and survival, as well as in the behavioral status alterations, is still unclear [3, 4].

Effects of prenatal hypoxia on expression of thioredoxin-1 in the rat hippocampus at different stages of postnatal ontogeny

We studied the expression of the antioxidant protein thioredoxin-1 in the hippocampus of rat pups that were subjected to hypoxia at prenatal days 14–16, at the 3rd and 14th days after their birth, and at 80–90 days when the pups became mature. In spite of the specific features of certain hippocampal regions and the presence of exceptions related to them, 3 days after birth we observed a general trend to a decrease in thioredoxin-1 expression in rats subjected to hypoxia, as compared to the control animals of the same age. Then, thioredoxin-1 expression was substantially increased on the 14th day of postnatal life. In adult rats, thioredoxin-1 expression decreased again. These changes were very prominent in the CA1 field of the hippocampus. A decrease in the activity of the physiological antioxidant system is an important index of cell-membrane homeostasis, whose impairment under hypoxic conditions can result in the development of neurodegenerative diseases.

Training in the Morris Water Maze of Female and Male Rats Exposed to Hypoxia at Various Periods of Prenatal Development

Capability for learning was studied in the offspring of rats exposed to hyporbaric hypoxia on the days 11–13, 14–16 or 18–20 of pregnancy. Training in the Morris water maze has been shown to lead to consequences of effect of prenatal hypoxia evident in males, but not in females. The most pronounced changes are found at training in the male rats whose mothers were exposed to hypoxia on the days 14–16 of pregnancy. The revealed differences in the character of learning depend on experimental conditions. Under “severe” stress conditions (at the water temperature of 16–17°C), prenatal hypoxia leads to an improvement of learning parameters as compared with control, while under more favorable conditions (at the water temperature of 23–24°C), to their deterioration.

Long-Term Consequences of Hypoxia During the Perinatal Period of Development on the Structural-Functional Characteristics of the Brain in Rats

The experiments reported here showed that acute hypoxia during the perinatal period of development leads to structural changes in the motor and visual areas of the neocortex, detectable by postnatal day 20 as impairments to the structural organization of the layers of the neocortex. We report the first data showing that different hippocampal fields respond differently to hypoxia during the postnatal period and present evidence for the existence of long-term sequelae of perinatal hypoxia in the structure of the hippocampus. Acute hypoxia was followed by cell death in all fields and thinning of the pyramidal neuron layers. The greatest levels of cell death occurred in fields CA4 and CA3. As postnatal age increased, cell death remained significant in field CA4, decreased in field CA3, and was not seen in field CA1, though granule neuron death in the dentate fascia increased with increasing age. In addition, there were decreases in the sizes of pyramidal neuron cell bodies in all hippocampal fields. All hippocampal fields showed activation of astrocyte reactions, more marked in field CA4, where gliosis persisted to prepubertal age. Hypoxia in the early postnatal period could have effects on synaptogenesis, particularly on the formation of giant synapses in the dentate fascia. Studies of the functional characteristics of the nervous system in such animals showed that hypoxia could induce significant impairments in behavioral reactions. Rats of the experimental group showed impairments to the inhibitory functions of the cerebral cortex, increased anxiety, and disturbances to spatial learning and working memory.