[Prenatal hypoxia modifies working memory and the activity of hippocampal polyphosphoinositide system in rats].

The present study was aimed at the analysis of spatial learning abilities in the Morris water maze (working memory) as well as hippocampal levels of phosphatidylinositol 4,5-diphosphates (TPI), phosphatidylinositol 4-phosphates (DPI), phosphotidylinositols (MPI), and expression of the type 1 inositol 1,4,5-trisphosphate receptor (IR3R1) in rats exposed to severe hypobaric hypoxia (ascent to 11 km, 3 h) on prenatal days 14-16 (group 1) or 17-19 (group 2). Exposure to severe hypoxia led to significant elevation of TP 1 and DPI hippocampal levels in juvenile and adult rats in the group 1, however these changes were more pronounced in juvenile rats than in adults. In the group 2, hypoxia up-regulated TPI and DPI hippocampal levels in juvenile rats, but in adult animals of this group just a small TPI level up-regulation was detected. Activation of IR3R1 expression was found to occur in the hippocampus both of juvenile and adult rats in the groups 1 and 2. These finding are consistent with the impaired spatial learning ability we revealed in the Morris water maze, indicative of a working memory deficit in the rat offspring exposed to hypobaric hypoxia during the first half of the last week of pregnancy.

[Effects of the prenatal hypoxia on the hypothalamic-pituitary-adrenal axis function and working memory in rats].

A comparative analysis of the effects of severe hypobaric hypoxia in different prenatal periods on expression profiles of glucocorticoid receptors (GR) in dorsal (CA1) and ventral (dental gyrus) hippocampus and neocortex of rats, their stress reactivity and working memory has been performed in the present study for the first time. According to the data obtained, severe hypoxia in the prenatal period induces remarkable disturbances of GR expression in the neurons of neocortex of adult males but not females, that correlates to the disruption of working memory in adult males exposed to hypoxia on the prenatal 14-16th days. Elevation of stress plasma corticosterone levels have been observed only in the females subjected to hypoxia on the prenatal 17-19th days. Hypoxia in the females and males results in the differential changes in functions of hippocampus, as well as of other brain areas involved in learning.

[Effect of hypoxia in early perinatal ontogenesis on behavior and structural characteristics of the rat brain].

The study has shown the acute hypoxia in newborn rat pups to lead to disturbances of processes of formation of brain structures, behavior reactions, and learning in the subsequent ontogenesis. The single normobaric hypoxia at the 2nd day of life causes retardation of such integrative parameter or genera development and growth as body mass at the period of feeding. In such animals, essential disturbances of the sensorimotor development were revealed in forms of delay of reflex reactions of turning on a plane, negative geotaxis, and avoidance of edge. Also detected was action of hypoxia on hanging on a rope by using front legs (a symptom of muscle weakness). Morphological study has shown stereotypic reaction to the early postnatal action of hypoxia in all studies of all studied functional zones of neocortex - motor, sensomotor, auditory, visual. The death of nerve cells is predominant in the II-III associative layers, the sizes and number of pyramidal neurons are sharply decreased. Different hippocampus fields maturing in mammals show a characteristic response to hypoxia. In individual hippocampus fields there was detected different degree of death of neurons, predominant in the CA3 and CA4 fields. A possibility of modeling of perinatal encephalopathy with minimal brain dysfunctions in children is discussed.

Effect of prenatal hypobaric hypoxia on glutamatergic signal transduction in rat brain.

Ca(2+)-mediated signal transduction of group I metabotropic glutamate receptors (ImGluR) was studied in the brain of young (15 days) and old rats (90 days) exposed to severe hypobaric hypoxia on gestation days 14-16. Changes in the concentration of bound intracellular Ca(2+) (Ca(2+) response) were evaluated after repeated application of a selective ImGluR agonist 3,5-dihydroxyphenylglycine (DHPG) to cultured brain slices. Primary application of DHPG for 2 min induced a negative Ca(2+) response in slices from 15-day-old intact animals, while repeated application caused a positive response. In slices from 90-day-old control animals, both responses were negative. In slices from rats of both age groups subjected to severe prenatal hypobaric hypoxia, both responses were mainly positive, but short-term negative components were present in adult animals. Our results suggest that severe hypobaric hypoxia changes the balance between the two constitutive signal pathways triggered by ImGluR (inosine triphosphate and diacylglycerol pathways). This procedure is followed by the increased influx of extracellular Ca(2+) (as compared to Ca(2+) release from the intracellular stores). This imbalance is particularly pronounced at the early stage of ontogeny.

[The remote consequences of hypoxia influence in perinatal development period on structurally functional characteristics of the rat brain].

The study has shown that influence of acute hypoxia in perinatal period leads to structural changes in motor and visual of the neocortex for 20 postnatal days in the form of disturbance of the structural organisation of the neocortex layers. Different fields of hippocampus in perinatal period differently react to hypoxia, and evidence of existence of a long-term perinatal hypoxia was obtained. It is established that after action of acute hypoxia in all the fields there is a cellular destruction, and thinning of pyramidal neurones layers. The most expressed cellular destruction takes place in fields CA4 and CA3. In process of augmentation, the destruction of cells remains appreciable in the field CA4, reduced in the field CA3 and not found in the field CA1; however, in fascia dentate, the destruction of granular neurones with age augmentation increases. Along with in reduction of the dimensions of cellular bodies pyramidal neurones in all fields of hippocampus takes place. Also in all fields of hippocampus, activation of astrocytic reaction occurs, more expressed in the field CA4. The hypoxia influence in the early postnatal period can affect synaptogenes, particularly the formation of giant synapses in a dentate fascia. Study of functional features of the excitatory system of such animals has shown that hypoxia can induce appreciable disturbances of behavioural responses. In rats, disturbances of inhibiting functions of the cerebral cortex, raised anxiety, and spatial learning and working memory disturbances have been noted.

[Effect of prenatal hypobaric hypoxia on activity of the rat brain phosphoinositide system].

Activity of the phosphoinositide system of the intracellular signalization was studied in offspring of rats exposed to severe hypobaric hypoxia at the 14-16th (group 1) or the 18-20th day (group 2) of prenatal development. At the age of 15 days, in animals of both experimental groups the basal level of triphosphoinositides in the brain cortex was shown to be elevated as compared with control. In the group 1 this parameters also remains elevated in adult animals. Application of glutamate produces a more pronounced increase of the inositephosphates in brain sections of the 15-day old rats of the group 1 than in sections of animals of the control group. In the 15-day old rats of the group 2, as compared with control, the phosphoinositide response to glutamate application was reduced. No changes in the inositephosphate levels were revealed after application of glutamate upon sections of adult (the 90-day old) control animals and of adult rats of the group 2. In sections of adult rats of the group 1, on the contrary, the glutamate application produced an increase of the inositephosphate content. The obtained data indicate essential changes of the phosphoinositide metabolism in the brain of rats exposed to action of hypoxia at the period of prenatal development. The character and the degree of these changes depend on the period of development when the action of hypoxia occurs.

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.

[Effect of serotonin deficit at different stages of prenatal ontogenesis on behavior of adult male and female rats].

Effects of maternal parachlorophenilalanine (PCPA) administration on the offspring behavior were studied in the open field, Porsolt forced swimming, and Morris water maze tests. PCPA was administered in two different gestational periods: on gestational days (GD) 8-11 or GD 14-17, at doses 200/100/100/50 mg/kg. It was found that prenatal exposure to PCPA results in fetal serotonin (5-HT) depletion and changes in both open field activity and depression-related behavior, as well as impairments in spatial learning in the adult offspring. The most pronounced effects on behavior were observed in the male and female offspring whose mothers were depleted of serotonin by PCPA during the third trimester of pregnancy. These results provide further evidence that adverse factors have the most severe effects on the development of rat brain function when exposed during the final trimester of pregnancy than during the second trimester.

[Behavior of female and male mice submitted to action of p-chlorophenylalanine in prenatal ontogenesis].

Effect of serotonin (5-HT) deficit produced by administration ofp-chlorophenylalanine at a dose of 400 mg/kg to pregnant female mice on the day 8 of gestation and on the subsequent behavior of their offspring (hybrids F1 (C57BL/CBA)) was studied. The 5-HT deficit in prenatal ontogenesis leads to the following changes of behavior: 1) females and males of the experimental group show a higher level of the explorative activity in the "open field" than control animals; 2) in females of the experimental group at the age of 90 days, unlike control females and males of experimental and control groups, the explorative activity is extinguished at the threefold testing in the "open field"; 3) females of the experimental group have a decreased level of anxiety in tests "elevated plus-maze" and the "dark-light chamber". Males of the experimental group, on the contrary, have an elevated level of anxiety. The obtained data show that the 5-HT deficit at the prenatal period affects various aspects of behavior. The degree of the changes produced by the prenatal 5-HT deficit can have different manifestation depending on sex of the animals.

[The effect of preceding mild hypoxia on the alteration of acquisition and retention of the conditioned passive avoidance behavior caused by severe hypobaric hypoxia in rats]. / Vliianie predvaritel'nogo vozdeistviia umerennoi gipoksii na narusheniia vyrabotki i vosproizvedeniia uslovnoi reaktsii passivnogo izbeganiia, vyzyvaemye tiazheloi giperbaricheskoi gipoksiei u krys.

The purpose of this study was to determine whether mild hypobaric hypoxic preconditioning provides protection against learning deficit caused by subsequent more severe hypoxia insult. Learning was examined using a passive avoidance task. Three groups of Wistar male rats: the intact and exposed to either severe hypoxia (160 Torr, exposition 3 h) or mild hypobaric hypoxic preconditioning (360 Torr, exposition 2 h, repeated three or six times daily) followed by severe hypoxia, were included in this study. In experiment 1 a passive avoidance response was acquired in 15 min immediately after hypoxia. In experiment 2 rats were exposed to hypoxia in 60 min after the acquisition of passive avoidance response. The mild hypobaric hypoxic preconditioning significantly attenuated the hypoxia-induced learning deficit in rats in Experiments 1 and 2. In experiment 1 the mild hypobaric hypoxic preconditioning repeated six times was more effective in protection against learning deficit in hypoxia exposed rats than in the case of triple mild hypobaric hypoxic preconditioning. The amount of rats suffered irreversible respiratory arrest was also assessed in this study. It was found that 50% of rats exposed to severe hypoxia died in consequence of this pathology, whereas in rats preconditioned before the severe hypoxia only 15% died for this reason. The overall results indicate that the mild hypobaric hypoxic preconditioning significantly increases CNS resistance to severe hypoxia in rats.