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Biochemical signaling pathways in living cells are often highly organized into spatially segregated volumes, membranes, scaffolds, subcellular compartments, and organelles comprising small numbers of interacting molecules. At this level of granularity stochastic behavior dominates, well-mixed continuum approximations based on concentrations break down and a particle-based approach is more accurate and more efficient. We describe and validate a new version of the open-source MCell simulation program (MCell4), which supports generalized 3D Monte Carlo modeling of diffusion and chemical reaction of discrete molecules and macromolecular complexes in solution, on surfaces representing membranes, and combinations thereof. The main improvements in MCell4 compared to the previous versions, MCell3 and MCell3-R, include a Python interface and native BioNetGen reaction language (BNGL) support. MCell4's Python interface opens up completely new possibilities for interfacing with external simulators to allow creation of sophisticated event-driven multiscale/multiphysics simulations. The native BNGL support, implemented through a new open-source library libBNG (also introduced in this paper), provides the capability to run a given BNGL model spatially resolved in MCell4 and, with appropriate simplifying assumptions, also in the BioNetGen simulation environment, greatly accelerating and simplifying model validation and comparison. [ABSTRACT FROM AUTHOR]

The effect of the synthetic analogue of leu-enkephalin (dalargin) on the level of corticosterone in the blood and the mass of the adrenal glands in rats with various typological features of behavior in the model of post-traumatic stress disorder (PTSD) was studied. Groups were formed: active low-anxiety (ALA) and high-anxiety (AHA), as well as passive low-anxiety (PLA) and high-anxiety (PHA) rats. Each of the four groups of rats was divided into three subgroups, where subgroup 1 is an intact control. Twenty days after the first stressful exposure, rats from subgroup 3 were injected intramuscularly with dalargin for seven days, and rats from subgroup 2 were injected with saline solution. It was found that the course of injections of dalargin into rats in the PTSD model had a positive effect on the studied indicators only in the group of active high-anxiety animals. [ABSTRACT FROM AUTHOR]

Morphological changes in the adrenal glands of male Wistar rats were studied after intramuscular injection of dalargin, a synthetic leu-enkephalin analog, in a model of post-traumatic stress disorders (PTSD). According to the results of testing in the T-maze and elevated plus maze (EPM), the rats were divided into four groups: active low-anxiety (ALA), active high-anxiety (AHA), passive low-anxiety (PLA), and passive high-anxiety (PHA) animals. In dalargin-injected ALA rats with a PTSD model, the thickness of the adrenal cortex zona fasciculata (zF) increased by 14% (p < 0.05), the area of zF cell nuclei by 9.5% (p < 0.001), and the area of the adrenal medulla by 21% (p < 0.05). With the development of a PTSD-like state in AHA rats, zF thickness increased by 10% (p < 0.05), while dalargin in a PTSD model prevented this increase. The development of a PTSD-like state in PLA rats was accompanied by an increase in zF thickness by 17% (p < 0.05) and a decrease in the area of zF cell nuclei, overall area of the adrenal medulla, and area of medullary cell nuclei by 10.5, 41 and 8%, respectively (p < 0.05). After dalargin injection in a PTSD model, the area of medullary cell nuclei decreased by another 7% (p < 0.05). In dalargin-injected PHA rats with a PTSD model, zF thickness increased by 23% (p < 0.01). It was concluded that the effects of dalargin on morphometric parameters of the rat adrenals in a PTSD model rely on individual typological features of rat behavior. [ABSTRACT FROM AUTHOR]

We report here a study examining the effects of acute normobaric hypoxia in the early postnatal period of development (postnatal day 2) on learning ability and the expression of GABAB receptors in the neocortex (medial prefrontal cortex) of adolescent rats (postnatal days 55–60) and also addressing the possibility of correcting identified disorders with the Russian-made drug salifen, a GABA derivative. Perinatal hypoxia has been shown to impair the formation and retention of memory traces in the novel object recognition and conditioned passive avoidance reflex tests and to reduce spatial learning ability in the Morris water maze test. Analysis of Western blot results revealed an increase in the quantity of GABAB receptor protein in the medial prefrontal area of the neocortex of rats exposed to perinatal hypoxia. Administration of salifen 15 mg/kg for 14 days after exposure to hypoxia improved the cognitive abilities of rats and normalized the level of GABAB receptor protein expression in the medial prefrontal cortex of rats. The results obtained here are of interest for solving an applied challenge in neonatology – the search for effective pharmacological correction of the sequelae of perinatal hypoxia. [ABSTRACT FROM AUTHOR]

Prenatal maternal stress disrupts offspring behavior and cognitive abilities not only in the first but also in subsequent generations. Various stress factors that affect fathers before conception can also exert a similar transgenerational effect on the offspring phenotype. The aim of the study was to reveal the transgenerational effect of prenatal stress on female Wistar rats during gestational days 15–19 on memory and insulin-like growth factor 2 (Igf2) gene expression in the brain of male and female offspring, as well as the effect of additional stress exposure within the stress–restress paradigm in prenatally stressed male rats prior to mating with intact females on memory and Igf2 expression in the brain of their offspring of both sexes. We demonstrated that prenatally stressed males and their F1 male descendants showed improved memory in the passive avoidance test and increased Igf2 expression in the hippocampus and cerebral cortex. F1 female descendants of prenatally stressed males, on the contrary, showed a decrease both in the duration of memory retention and in hippocampal and neocortical Igf2 expression. Additional stress exposure of prenatally stressed males prior to mating with intact females worsened memory and decreased the duration of its retention, as well as reduced Igf2 expression in the brain of the offspring of both sexes. We concluded that the transgenerational effects of prenatal stress on memory and Igf2 brain expression depend on the sex of the offspring, while prenatal stress per se contributes to memory impairment and a decrease in Igf2 expression in the offspring brain provided that such males were additionally stressed prior to mating. [ABSTRACT FROM AUTHOR]

It has been proved that paternal stress can affect the phenotype of offspring, inducing somatic, behavioral, hormonal, and molecular changes. One hypothetical mechanism responsible for the transmission of paternal effects to offspring is an altered spectrum of regulatory noncoding RNAs in spermatozoa. In the present work, we investigated the effect of paternal stress in models of posttraumatic stress disorder (PTSD) and depression on the spectrum of small RNA (micro- and piwiRNAs) in the sperm of stressed animals. Male Wistar rats were subjected to stress in two paradigms ("stress–restress" and "learned helplessness"), resulted in the development of PTSD- and depression-like states in model animals, respectively. Forty-eight days after the restress, RNA was isolated from obtained sperm preparations. The spectrum of small RNAs was examined by next-generation sequencing (NGS). In males with a PTSD-like state, altered expression of 27 piwiRNAs and 77 microRNAs was revealed compared with the control group. Among the targets of these microRNAs, one can distinguish genes the products of which may be involved in such mechanisms of transmission of paternal effects to offspring as changes in DNA methylation, histone modifications and RNA interference (Dnmt3a, Setd5, Hdac1, Mllt10, and Mtdh), as well as genes associated with the functioning of insulin-like growth factor 2, the expression of which is changed in the CNS in the offspring of males with a PTSD-like state (Igf2, Igf2bp2, and Igf2r). In males with a simulated depression-like state, no changes in the representation of small RNAs were registered. The results obtained demonstrate that paternal stress has a pronounced effect on the spectrum of short noncoding RNAs in spermatozoa in rats, however, this effect depends on the nature of the stress effect. [ABSTRACT FROM AUTHOR]

There are now a growing number of observations on the transgenerational impact of paternal stress on various offspring functions without involving direct interaction between offspring and father. In the offspring of parents who suffered from posttraumatic stress disorder (PTSD) have been observed an increase in PTSD-like symptoms. In experiments where a chronically elevated level of corticosterone was created in male mice during the entire period of spermatogenesis, a decrease in the stress reactivity of the hypothalamic–pituitary–adrenal (HPA) axis in the offspring of both sexes was shown. However, PTSD in patients creates a reduced level of glucocorticoids in the blood, and there are no experimental data on the effect of modeling PTSD in fathers on the activity of HPA axis of the offspring. The current study examined the relative influences of PTSD-like status ("stress–restress" paradigm) and depression-like status ("learned helplessness" paradigm) in male rats before mating on the HPA axis activity of their adult offspring. In addition to HPA axis activity, the expression of glucocorticoid receptors (GR) in the offspring was analyzed by quantitative immunocytochemistry in the hippocampus and medial prefrontal cortex (mPFC). We demonstrated that in female offspring of fathers with a PTSD-like or depressive-like status there is a decrease in basal and stress activity of the HPA axis in response to 30-min immobilization, which was accompanied by an increase in GR expression in the hippocampus and the 2nd layer mPFC. A similar profile of HPA axis activity was found in male offspring of fathers with modeling of PTSD. However, in male offspring of fathers with a depression-like status, the sensitivity of HPA axis to feedback signals decreased and was accompanied by a decrease in GR expression in the hippocampus and the 2nd layer of mPFC. We concluded that the PTSD- or depression-like status of male rats during the period of spermatogenesis has a differential effect on HPA axis activity and GR expression in the brain of their male offspring. [ABSTRACT FROM AUTHOR]

Abstract—We studied the effect of prenatal stress on the activity of glutathione-associated enzymes in subcellular fractions of neurons and neuroglia from the neocortex of 20-day-old male rats (during the period of intensive myelination). The following changes were observed in prenatally stressed animals compared to the control. The activity of glutathione peroxidase (EC 1.11.1.9) in the cytosol and the nuclear fraction of neurons and neuroglia increased, but decreased in the mitochondrial fraction. The activity of glutathione reductase (EC 1.8.1.7) increased in the cytosol and in the nuclear fraction of the neuroglia. The activity of glutathione transferase (EC 2.5.1.18) increased in the mitochondrial fraction of neurons and in the cytosol of neuroglia but decreased in the nuclear fraction of neurons and in the mitochondrial fraction of neuroglia. We believe that the changes in the activity of the studied enzymes in the subcellular fractions of neocortical neurons and neuroglia in prenatally stressed rats observed at the age of 20 days negatively affect the processes of myelination in the neocortex and may contribute to accelerated aging and the development of neurodegenerative diseases in later life. [ABSTRACT FROM AUTHOR]

Active and passive animals were selected from an overall population of Wistar rats using indexes of behavioral activity (IBA) and passivity (IBP) determined on testing in a T mazel; the elevated plus maze (EPM) was then used to divide animals into low-anxiety (active (ALA) and passive (PLA)) and high-anxiety (active (AHA) and passive (PHA)) groups. An experimental analog of PTSD was created using water immersion in the stress–restress paradigm. At 20 days after the first stress, experimental rats received intramuscular dalargin solution (0.1 mg/kg) for a week, while control rats received the same volume of physiological saline. All animals were tested in the EPM two days after one-week courses of injections. ALA rats with the PTSD model showed only a reduction in total motor-exploratory activity; the action of dalargin in the PTSD model was to promote increases in reactive anxiety in these animals. AHA rats with the PTSD model showed a decrease in total motor-exploratory activity and a simultaneous increase in their initially high anxiety; dalargin had an antistress action in these animals. PLA rats with the PTSD model showed decreased total motor-exploratory activity and increased reactive anxiety; injections of dalargin accelerated and enhanced the development of the PTSD-like state. PHA rats with the model of PTSD showed no notable changes in behavioral characteristics; dalargin injections had no visible effect on the behavior of these animals in the EPM. [ABSTRACT FROM AUTHOR]

Glucocorticoid hormones suppress testosterone production by Leydig cells, by interacting with glucocorticoid receptors located in these steroid-producing cells. In adult prenatally stressed males, increases in blood corticosterone were found to be accompanied by increased testosterone levels, which may be due to a decrease in the number of glucose receptors in Leydig cells. The present study sought to test this hypothesis. Glucocorticoid receptor levels in Leydig cells were estimated by quantitative immunohistochemistry. We also studied measures of spermatogenesis and sperm quality, as well as reproductive potential, which was analyzed in terms of the ability of males to fertilize females and produce offspring. These studies demonstrated decreases in the number of spermatogenic cells in the spermatogenic epithelium of the seminiferous tubules of prenatally stressed males, despite the increased blood testosterone level. Morphometric indicators of the seminiferous tubules, such as the thickness and area of the spermatogenic epithelium, in prenatally stressed males were increased, as were the number and area of Sertoli cells. We found statistically significant increases in the numbers of anomalous and immobile spermatozoids isolated from the epididymis of prenatally stressed males. The number of Leydig cells in the interstitial tissue of the testes of these males was reduced, though their area increased as compared with control males. Glucocorticoid receptor levels in Leydig cells were decreased in prenatally stressed males. Nonetheless, these changes did not influence the ability of prenatally stressed males to fertilize females and produce offspring. These results lead to the conclusion that increased blood testosterone levels in prenatally stressed males on the background of elevated glucocorticoid hormones lead to reductions in the sensitivity of Leydig cells to glucocorticoids. [ABSTRACT FROM AUTHOR]

The sequelae of stressing male rats using the "stress–restress" paradigm (a model of post-traumatic stress disorder, PTSD) on memory and the expression of the insulin-like growth factor 2 gene (Igf2) were studied in various brain structures in the adult offspring of both sexes. Expression of the Igf2 gene was also studied in neonatal offspring. Paternal stress was found to induce memory defi cit in the passive avoidance reaction and novel object recognition tests, predominantly in male offspring. Memory defi cit in female offspring was seen only in the novel object recognition test. Only male offspring showed reduced expression of the Igf2 gene in the hippocampus and neocortex in adulthood, though this was not seen in neonatal male offspring. These results provide evidence of the sex-specifi c effects of a PTSD-like state in paternal animals on memory and Igf2 gene expression in the brains of their adult offspring. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor 2 (IGF2) is conventionally regarded as the main growth factor acting in the fetal body during pregnancy. Recent studies have demonstrated an important role for IGF2 in the adult body. The Igf2 gene has been shown to be expressed at a high level in the central nervous system, where it plays an important role, particularly mediating the consolidation of hippocampus-dependent memory by means an interaction with the M6F/IGF2 receptor. This review discusses the place of IGF2 in the insulin superfamily, especially its expression as an imprinted gene, the receptor apparatus, and its involvement in embryonic development, as well as the function of IGF2 in the adult body. Particular attention is paid to the role of IGF2 in the pathogenesis of mental and neurological diseases characterized by memory impairments such as schizophrenia, depression, Alzheimer's disease, and post-traumatic stress disorder. Despite the fact that the question of the role of IGF2 in the pathogenesis of these diseases is still incompletely understood, further research in this area will allow new approaches to the treatment and diagnosis of these socially important nosologies to be developed. [ABSTRACT FROM AUTHOR]

Prenatal stress of any etiology is an integral factor of evolution. The activation of epigenetic processes by increased levels of maternal glucocorticoids changes the life path of newborns in unpredictable ways. Different stressors at different time points of embryogenesis will have different consequences, which also dynamically interact with each other. One dramatic result of such interacting processes is the growth of psychopathologies and neurological diseases. An increase in the level of maternal glucocorticoids causes a disruption of the redox balance in the fetus and, thus, oxidative stress, i.e., the process of shifting the pro- and antioxidant balance towards an increase in the formation of reactive oxygen species. Some epigenetic changes that can cause disorders of central nervous system are the result of oxidative stress. In additional, in normal and stressful conditions, the mother's reaction is mediated by the placenta. As a metabolically active organ, it also has its own system of redox balance, which is also subjected to oxidative stress. Placental epigenetic changes have both positive and negative effects on the fetus. The review examines the recent research on the complex analysis of the multicomponent problem of the causes and consequences of prenatal stress. [ABSTRACT FROM AUTHOR]

We report here studies of the effects of stressing male rats in the stress–restress paradigm, which is a model of post-traumatic stress disorder (PTSD), on the behavioral phenotype and the hypophyseal-adrenocortical system (HAS) in their adult offspring of both sexes. These experiments showed that only some proportion of males formed a PTSD-like state characterized by a reduced basal corticosterone level. The offspring of these rats had low body weight in the neonatal period of development and as adults were characterized by reduced movement activity and increased behavioral depressivity. Basal and stressed HAS activity in these animals was reduced and the sensitivity of this hormonal axis to negative feedback signals was increased. Behavioral changes were most marked in male offspring, while sequelae of the paternal PTSD-like state in female offspring were seen only in relation to activity levels and HAS activity. The offspring of males not forming a PTSD-like state displayed the smallest changes in behavior and HAS activity. It is suggested that the severity of the action of paternal stress on the offspring is determined by the individual stress resistance of fathers. [ABSTRACT FROM AUTHOR]

Prenatal stress is regarded as a risk factor for the development of diseases such as mental, cardiovascular, and metabolic disorders in later life. Dysregulation of the activity of the hypothalamo-hypophyseal-adrenocortical system (HHAS) is one of the mechanisms producing these disorders. Regulation of the HHAS is mediated by two types of receptor – mineralocorticoid (MR) and glucocorticoid receptors (GR) – in the corticolimbic structures of the brain. The link between prenatal stress, sex, and HHAS activity, as well as the role of central MR and GR in this interaction, has received insufficient study. We have investigated the effects of prenatal stress on HHAS activity in adult male and female rats and the expression of GR and MR in the hippocampus and medial prefrontal cortex (mPFC). Prenatal stress was modeled by subjecting pregnant female Wistar rats to 1-h restraint from days 15 to 19 of pregnancy. Basal HHAS activity and stress corticosterone levels in response to 30-min restraint were studied in their adult offspring. GR and MR expression was assessed by western blotting and also, in the hippocampus, by an immunohistochemical method. Prenatally stressed males displayed prolonged stress responses, while females showed increases in basal and stress reactivity, along with increases in the sensitivity of the HHAS to feedback signals. In males, changes in HHAS activity were accompanied by decreases in GR and MR content in the hippocampus and mPFC with an unaltered GR:MR ratio. Prenatally stressed females showed increased expression of GR protein and decreased quantities of MR protein in the hippocampus and an increased GR:MR ratio in both areas of the brain. The hippocampus of male and female animals showed changes in GR and MR content in field CA3 and the dentate gyrus. These data indicate that sex-dependent changes in GR and MR protein expression in the hippocampus and mPFC contribute to modifications of HHAS activity due to prenatal stress. [ABSTRACT FROM AUTHOR]

Calmodulin-dependent kinase II (CaMKII) has long been known to play an important role in learning and memory as well as long term potentiation (LTP). More recently it has been suggested that it might be involved in the time averaging of synaptic signals, which can then lead to the high precision of information stored at a single synapse. However, the role of the scaffolding molecule, neurogranin (Ng), in governing the dynamics of CaMKII is not yet fully understood. In this work, we adopt a rule-based modeling approach through the Monte Carlo method to study the effect of Ca2+ signals on the dynamics of CaMKII phosphorylation in the postsynaptic density (PSD). Calcium surges are observed in synaptic spines during an EPSP and back-propagating action potential due to the opening of NMDA receptors and voltage dependent calcium channels. Using agent-based models, we computationally investigate the dynamics of phosphorylation of CaMKII monomers and dodecameric holoenzymes. The scaffolding molecule, Ng, when present in significant concentration, limits the availability of free calmodulin (CaM), the protein which activates CaMKII in the presence of calcium. We show that Ng plays an important modulatory role in CaMKII phosphorylation following a surge of high calcium concentration. We find a non-intuitive dependence of this effect on CaM concentration that results from the different affinities of CaM for CaMKII depending on the number of calcium ions bound to the former. It has been shown previously that in the absence of phosphatase, CaMKII monomers integrate over Ca2+ signals of certain frequencies through autophosphorylation (Pepke et al, Plos Comp. Bio., 2010). We also study the effect of multiple calcium spikes on CaMKII holoenzyme autophosphorylation, and show that in the presence of phosphatase, CaMKII behaves as a leaky integrator of calcium signals, a result that has been recently observed in vivo. Our models predict that the parameters of this leaky integrator are finely tuned through the interactions of Ng, CaM, CaMKII, and PP1, providing a mechanism to precisely control the sensitivity of synapses to calcium signals. Author Summary not valid for PLOS ONE submissions. Author summary: Neurons communicate with each other through synapses. The strength of a particular synapse is effectively the level of sensitivity of the postsynaptic neuron in response to firing of the presynaptic neuron. The process of changing synaptic strength is dubbed synaptic plasticity, a foundational aspect of learning and memory. In this work, we create a computational model of a calcium signaling pathway that sets off a chain reaction in CaMKII phosphorylation, eventually leading to synaptic plasticity. Computational modeling provides a unique way to tease apart and understand the non-intuitive results of interactions between the molecules involved. Our model successfully predicts the experimentally observed activation dynamics of this crucially important enzyme which is necessary for learning. These dynamics, along with other pathways, regulate the size of the synapse, which is known to be highly correlated with synaptic strength. In this work, we reveal quantitative characteristics of CaMKII activation for various stimuli, leading to important insights regarding the potential role of Neurogranin, a scaffolding protein in this pathway. [ABSTRACT FROM AUTHOR]

Abstract—We studied the capability to learn in a passive avoidance task and the rate of its extinction in male rats whose fathers were subjected to stress during the period of spermatogenesis using the "stress–restress" paradigm (a model of post-traumatic stress disorder). In the brain of trained and untrained rats, we studied the expression of genes encoding insulin-like growth factor II and H19, the expression of which is imprinted at the early stages of ontogeny. Experimental males exhibited impaired memory consolidation and accelerated extinction of a passive avoidance response. The expression of Igf2 was decreased in the hippocampus and neocortex of untrained male offspring of stressed fathers. The increased expression of the Igf2 and H19 genes was revealed in the hippocampus of male offspring of control fathers 20 h after training, whereas in the experimental rats, the expression of these genes did not alter. Our data show that the impairment of memory in male offspring of stressed fathers may be mediated by decreased expression of the Igf2 gene. [ABSTRACT FROM AUTHOR]

Abstract—We studied the effect of prenatal stress on the activity of glutathione-bound enzymes in the subcellular fractions of neurons and neuroglia of rat neocortex. The results of the study showed that prenatal stress causes changes in the activity of these enzymes in both neurons and neocortical neuroglia. These changes differ in the subcellular fractions of the studied cell populations. In the nuclei of neurons and neuroglia fraction, the activity of glutathione peroxidase increases. In the cytosol of neurons fraction, the activity of glutathione peroxidase decreases, while in the cytosol of neuroglia it grows. In neuronal mitochondria, the activity of glutathione peroxidase and glutathione transferase increases, while in the neuroglial mitochondria fraction, the activity of glutathione peroxidase decreases. It has been suggested that a change in the activity of these enzymes in the subcellular fractions of neurons and neuroglia is one of the causes for the resistance of the neocortex to the effects of prenatal stress. [ABSTRACT FROM AUTHOR]

Changes in behavior and hypothalamo-hypophyseal-adrenal system (HHAC) activity were studied in adult prenatally stressed female rats in an experimental model of depression, i.e., learned helplessness. Females born to intact mothers were found not to form depression-like behavior, as evidenced by the absence of changes in HHAC activity, despite reductions in locomotor activity in the open field and increases in the duration of immobility in the forced swimming test. At the same time, females born to mothers stressed during the last weeks of pregnancy showed changes in behavior and HHAC activity analogous to those found in our previous studies of these animals in the stress-restress paradigm. These results lead to the conclusion that prenatal stress modifies animals' sensitivity to intense stressors. This is apparent in the specific pattern of HHAC activity after stressing, independently of the type of stress. [ABSTRACT FROM AUTHOR]

—We studied the role of vascular endothelial growth factor (VEGF) in post-hypoxic damage of the rat brain and in the effect of saliphene, a GABA derivative that is considered as a potential neuroprotector. The method of quantitative immunohistochemistry was used to evaluate the expression of VEGF in the rat brain (neocortex and hippocampus) at the early and late periods after perinatal hypoxia and the subsequent administration of saliphene. Hypoxia resulted in an increase in the expression of vascular endothelial growth factor in the developing rat brain, and injections of saliphene prevented an increase in VEGF expression, leaving this index at the level of the control values. Thus, the changes the expression of vascular endothelial growth factor (VEGF) in the rat brain after perinatal hypoxia may be considered as a marker of the neuroprotective effect of saliphene. [ABSTRACT FROM AUTHOR]

The negative long-term effects of hypoxic exposure on postnatal day 2 (human incomplete pregnancy model) on behavior (open field test) and activity of the hypothalamic-pituitary-adrenal (HPA) axis were studied in pubertal rats together with the possibility of their correction by post-hypoxic administration of a GABA derivative salifen (an adduct of γ-amino-β-phenylbutyric acid and salicylic acid). It was shown that perinatal hypoxic exposure impairs the inhibitory mechanisms in the CNS as manifested in the absence of motor activity inhibition in the open field as well as in the enhanced and prolonged stress response of the HPA axis. Post-hypoxic administration of salifen (15 mg/kg) for 14 days restored efficiently the inhibitory processes except for persistently increased hormonal stress reactivity of the HPA axis. Possible mechanisms underlying the therapeutic effects of salifen are discussed. [ABSTRACT FROM AUTHOR]

A mechanism of nucleation and formation of Ti-Cr coatings on synthetic diamond powders of grade HSD 90 has been revealed and investigated. The metal deposition has been found to occur selectively and heal surface defects (microcracks, steps, etc.). Ti is the matrix metal that forms the coating as a whole, while Cr is the alloying element. Thermal stability of metal-coated diamond powders has been studied by derivatography. It has been found out that in comparison to non-coated powders the coated ones have the oxidation resistance increased by 40°C and feature an interdiffusion at the coating-bond interface. [ABSTRACT FROM AUTHOR]

We studied the effects of acute normobaric hypoxia on postnatal day 2 (model of preterm pregnancy) on reflex activity and behavior of juvenile male Wistar rats and the possibility of correction of behavioral deficit by administration of GABA derivative Salifen after hypoxia. It is shown, that perinatal hypoxia impaired righting reflex and forelimb grip strength and increased motor activity in juvenile male rats. Administration of Salifen for 14 days in a dose of 15 mg/kg improved reflex activity and behavior of rats, which indicates the prospect of further study of the therapeutic efficacy of this drug on models of neonatal encephalopathy. [ABSTRACT FROM AUTHOR]

We report here our studies of the neuroendocrine mechanisms underlying the development of an anxiety-like state in female rats at different phases of the estrous cycle (blood estradiol level) in a stress-restress post-traumatic stress disorder (PTSD) model. Quantitative immunocytochemical methods were used to demonstrate an increase in corticoliberin expression in the paraventricular nucleus (PVN) of the hypothalamus in female rats 10 days after restress in all experimental groups. On post-restress day 30, the level of corticoliberin expression in the PVN of the hypothalamus decreased to the level seen in the control group. A significant increase in vasopressin immunoreactivity during development of the anxiety-like state was seen only in the PVN of the hypothalamus in female rats in the estrus phase (low estradiol level) at the moment of severe combined stress in the stress-restress model. Thus, the most significant changes in the neuroendocrine system of the hypothalamus was seen in female rats subjected to stress in the estrus phase, this consisting of a sharp decrease in the endogenous plasma estradiol level. Hyperactivity of the hypothalamic component of the vasopressinergic system can evidently be regarded as one of the mechanisms forming the experimental anxious PTSD-like state in female rats in the stress-restress model. [ABSTRACT FROM AUTHOR]

This study elucidated the potential antidepressant-like effect of prolonged Ropren® administration (8.6 mg/kg, orally, once daily for 28 days) using a β-amyloid (25-35) rat model of Alzheimer's disease following gonadectomy. The experimental model was created by intracerebroventricular injection of β-amyloid (25-35) into gonadectomized (GDX) rats and GDX rats with testosterone propionate (TP, 0.5 mg/kg, subcutaneous, once daily, 28 days) supplementation. Ropren® was administered to the GDX rats and GDX rats treated with TP. Depression-like behavior was assessed in the forced swimming test, and the spontaneous locomotor activity was assessed using the open-field test. The corticosterone and testosterone levels in the blood serum before and after FST were measured in all experimental groups. Treatment with Ropren® significantly decreased the immobility time of GDX rats with β-amyloid (25-35) in the forced swimming test. Coadministration of Ropren® with TP exerted a markedly synergistic antidepressant-like effect in the GDX rats with β-amyloid (25-35 on the same model of depression-like behavior testing. Ropren® administered alone or together with TP significantly enhanced crossing, frequency of rearing, and grooming of the GDX rats with β-amyloid (25-35) in the open-field test. Moreover, Ropren® administered alone or together with TP significantly decreased the elevated corticosterone levels in the blood serum of GDX rats with β-amyloid (25-35) following the forced swimming test. These results indicate that Ropren® has a marked antidepressant-like effect in the experimental model of Alzheimer's disease in male rats with altered levels of androgens. [ABSTRACT FROM AUTHOR]

Changes in the activity of the hypothalamo-hypophyseal-adrenocortical system (HHAS) were studied in adult prenatally stressed female rats in an experimental model of post-traumatic stress disorder (PTSD) in which the animals were subjected to combined treatment consisting of restraint for 2 h, swimming for 20 min, and ether stress, with subsequent restress seven days later (the stress-restress paradigm). An increase in the HHAS stress response was seen after combined stress in prenatally stressed females, apparent at the time of restress. Both control and prenatally stressed animals showed increases in the sensitivity of the hormonal axis to negative feedback signals, which supported accelerated inhibition of the HHAS after its activation by stress. Only prenatally stressed females showed a decrease in the basal corticosterone level and persistence of increased HHAS sensitivity to feedback signals one month after stress and restress. Control females were found to form the PTSD-like state after stress-restress mainly via corticotropin-releasing hormone, while vasopressin was involved in this process in prenatally stressed females. [ABSTRACT FROM AUTHOR]

The aim of the present work was to compare the effects of blockade of 5-HT or 5-HT serotonin receptors on depression-like behavior in adult female rats with experimental estrogen deficiency whose mothers had been subjected to prenatal stress during pregnancy. Two weeks after removal of the ovaries, ovariectomized (OE) prenatally stressed female rats received chronic administration of the 5-HT serotonin receptor antagonist NAN-190 (0.1 mg/kg, i.p.) or the 5-HT serotonin receptor antagonist ketanserin (0.1 mg/kg, i.p.) alone or in combination with a low dose of 17β-estradiol (0.5 μg/rat, s.c.) for 14 days before behavior tests started and then until tests were completed. The behavioral methods used were the Porsolt test and the open field test. The results showed that chronic administration of NAN-190 to OE prenatally stressed females led to a prodepressive effect, while the combination of NAN-190 with low-dose 17β-estradiol, conversely, had an antidepressant effect in the Porsolt test. In the open field test, these two experimental groups of rats showed decreases in the amounts of grooming reactions, vertical motor activity, and exploratory activity. Administration of ketanserin to OE prenatally stressed females produced an antidepressant effect, as compared with control animals. However, combined administration of ketanserin and low-dose 17β-estradiol to OE prenatally stressed females had no positive effect on the behavior of the animals in the Porsolt test. [ABSTRACT FROM AUTHOR]

Using the experimental model of post-traumatic stress disorder (stress-restress paradigm), we studied the dynamics of activity of the hypothalamic-pituitary-adrenal system (HPAS) in adult male rats, whose mothers were daily subjected to restraint stress on days 15-19 of pregnancy. Prenatally stressed males that were subjected to combined stress and subsequent restress exhibited not only increased sensitivity of HPAS to negative feedback signals (manifested under restress conditions), but also enhanced stress system reactivity. These changes persisted to the 30th day after restress. Under basal conditions, the number of cells in the hypothalamic paraventricular nucleus of these animals expressing corticotropin-releasing hormone and vasopressin was shown to decrease progressively on days 1-30. By contrast, combined stress and restress in control animals were followed by an increase in the count of CRH-immunopositive cells in the magnocellular and parvocellular parts of the paraventricular nucleus and number of vasopressin-immunopositive cells in the magnocellular part of the nucleus (to the 10th day after restress). Our results indicate a peculiar level of functional activity of HPAS in prenatally stressed males in the stress-restress paradigm: decreased activity under basal conditions and enhanced reactivity during stress. [ABSTRACT FROM AUTHOR]

Changes in activity of the hypothalamic-pituitary-adrenal (HPA) axis were examined in adult, prenatally stressed male rats in the experimental depression model of 'learned helplessness'. It was shown that in males descending from intact mothers a depressive-like state was accompanied by an increase in activity of the entire HPA axis. Namely, expression of corticotropin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN) increased coupled to a rise in plasma levels of ACTH and corticosterone as well as in adrenal weight. At the same time, in males born to mothers who suffered stress during the last week of pregnancy a decrease was detected in activity both of the central (hypothalamus) and peripheral (adrenal cortex) parts of this regulatory hormonal axis, analogous to that we revealed previously in the 'stress-restress' experimental model. It is concluded that prenatal stress modifies the sensitivity of animals to inescapable intense stress impacts, as manifested in the specific pattern of HPA axis activity after stressing. [ABSTRACT FROM AUTHOR]

We report here studies of the actions of 17β-estradiol in relation to regulation of the level of anxiety and depression-like behavior in experimental estrogen deficit in female rats born to mothers subjected to restraint stress for 1 h with increased illumination from day 15 to day 19 of pregnancy. Adult control and prenatally stressed ovariectomized females received 17β-estradiol (0.5 μg/animal) for 14 days. Ovariectomy was found to eliminate the differences between control and prenatally stressed females in terms of the level of anxiety in the elevated plus maze and the duration of immobility in the forced swimming test. Administration of 17β-estradiol at this dose had no significant effect on the behavior of control ovariectomized females, while hormone injections in prenatally stressed animals led to significant reductions in the levels of anxiety and behavioral depressivity. These data provide evidence that prenatally stressed females are more sensitive to 17β-estradiol replacement therapy. [ABSTRACT FROM AUTHOR]

The formation of the anxious-depressive state in a 'stress-restress' model was studied in adult prenatally stressed male rats, this being an experimental analog of human post-traumatic stress disorder. Male rats born to control females and to females subjected, on days 15-19 of pregnancy, to daily 1-h restraint stress were subjected to severe combined stress with subsequent restress after seven days. Both control and prenatally stressed males formed a pathological state 10 days after restress, with increases in the levels of anxiety and depressive behavior, as well as inhibition of the stress-related activity of the hypothalamohypophyseal-adrenocortical system due to activation of pathological negative feedback. However, the signs of post-stress pathology were longer-lasting in prenatally stressed animals, as evidenced by a decrease in the basal corticosterone level and an increase in anxiety still present 20 days after restress. These results lead to the conclusion that prenatal stress promotes the development of major behavioral and hormonal pathology in the stress-restress paradigm in adult animals. [ABSTRACT FROM AUTHOR]

By the method of quantitative immunohistochemistry there has been studied expression of corticotrophin-releasing hormone (CRH) and vasopressin in hypothalamic paraventricular nucleus (PVN) of prenatally stressed rats in the experimental model of the posttraumatic stress disorder-the paradigm 'stress-restress'. The prenatal stress was modeled by immobilization of pregnant female rats for 1 h from the 15th to the 19th day of pregnancy. It has been shown that in sexually mature males-descendants of stressed mothers-a decrease in immunoreactivity to CRH and vasopressin is observed in the parvocellular and magnocellular PVN areas 10 days after the restress. In the control group males born by intact mothers the level of immunoreactivity to CRH was increased in both PVN areas, whereas with respect to vasopressin-in the magnocellular area. Only in the prenatally stressed males there is detected a decrease in the corticosterone level in the blood plasma 10 days after the restress. It is concluded that in the control group males the manifestation of the pathological state in the paradigm 'stress-restress' consists in hyperactivation of the hypothalamic chain of regulation of the hypothalamus-pituitary-adrenocortical system, whereas in the prenatally stressed animals, on the contrary, there is observed a decrease in activity both of the central (PVN) and of the peripheral (adrenal cortex) chain of this hormonal axis. [ABSTRACT FROM AUTHOR]

The dynamics of changes in behavioral and hormonal manifestations of a pathological state in mature female rats born by mothers exposed to daily restraint stress on days 15-19 of pregnancy were studied in the experimental model of posttraumatic stress disorder (stress-restress paradigm). Experiments demonstrated increased anxiety in control and prenatally stressed female rats after combined stress followed by restress. This parameter remained enhanced until day 10 after restress in control rats and day 30 in prenatally stressed animals. The severity of depression increased on days 1 and 10 after restress in prenatally stressed female rats. Basal activity of the pituitary-adrenocortical axis increased only in prenatally stressed female rats under these conditions. This parameter increased 1 day after restress and decreased after day 30. It was concluded that prenatal stress could increase the predisposition to post-stress mental pathologies in experimental animals, which are manifested in increased severity and duration of behavioral and hormonal impairments. [ABSTRACT FROM AUTHOR]

The characteristics of the formation of a pathological state in an experimental model of post-traumatic stress disorder (PTSD) in adult female rats born to mothers subjected to daily restraint stress during the last third of pregnancy were studied. Both control and prenatally stressed female rats developed a pathological state after severe combined stress and subsequent restress, with long-lasting increases in anxiety and enhanced fast feedback inhibition of stress-related hypophyseal-adrenocortical system (HAS) activity. However, while development of the pathological state in control animals progressed to the anxiety type, prenatally stressed animals developed not only anxiety, but also increased depression-like behavior, i.e., an anxiety-depression disorder developed. These data are interpreted in the light of the interaction between the characteristics of HAS activity in prenatally stressed females and the predisposition of these animals to developing poststress pathology. [ABSTRACT FROM AUTHOR]

Using the immunohistochemical method, we studied the expression of glucocorticoid receptors (GRs) in the hippocampus during the postnatal period of development of male rats that were born to dams that were subjected to immobilization stress from the 15th to 19th day of pregnancy. In addition, we used Western blotting to study changes in the expression of the transcription factor NGFI-A in the hippocampus of prenatally stressed animals. We found that prenatal stress induces a considerable decrease in the number of GR-positive cells in the CA1 area of the hippocampus and dentate gyrus during the 1st week of life, an increase in their number and the number of strongly immunopositive cells during the 2nd week, and a decrease in the number of GR-expressing cells in the 3rd week of life. The expression of NGFI-A in the hip-pocampus of prenatally stressed males increased during the 1st and 2nd weeks of life but did not change during the 3rd week as compared to the control animals. We conclude that the destructive effects of prenatal stress on the developing hippocampus may be determined by alteration of the number of GRs in the early postnatal period, whereas induction of NGFI-A in the hippocampus of prenatally stressed males in the early neonatal period possibly has an adaptive character. [ABSTRACT FROM AUTHOR]

We compared the effects of an antagonist of 5-HT receptors, NAN-190 (0.1 mg/kg intraperitoneally), and an antagonist of 5-HT receptors, ketanserin (0.1 mg/kg intraperitoneally), which were chronically injected for 14 days, on the anxiety level in prenatally stressed female rats with an ovariectomyinduced experimental deficiency of estrogens. Chronic administration of ketanserin to ovariectomized prenatally stressed females had an anxiolytic effect and corrected disturbed levels of follitropin, lutropin, and estradiol. Administration of NAN-190 to ovariectomized prenatally stressed rats increased the anxiety level and decreased the ratio between the levels of tropic and peripheral sex hormones. [ABSTRACT FROM AUTHOR]

The effects of dehydroepiandrosterone sulfate (DHEA-S) on changes in the levels of anxiety induced by administration of the stress neurohormone corticoliberin were studied. A T maze was used to select Wistar rats with active and passive strategies of adaptive behavior. Testing of the active group in an elevated plus maze was used to select low- and high-anxiety individuals. Intranasal administration of corticoliberin to low-anxiety active rats resulted in decreases in total activity and increases in the level of anxiety, while high-anxiety animals had low sensitivity to this neurohormone. Prior administration of DHEA-S at a dose of 3 mg/100 g had antistress effects in low-anxiety rats and anxiolytic effects in high-anxiety rats. In passive animals, which were characterized by initially high levels of anxiety and were resistant to corticoliberin, administration of DHEA-S also had antistress actions. These results led to the conclusion that the effects of DHEA-S depended on the initial psychoemotional state and behavioral sensitivity to corticoliberin. [ABSTRACT FROM AUTHOR]

The experiments reported here addressed comparative analysis of the role of 5-HT serotonin receptors in the mechanisms mediating cognitive processes during natural cyclical changes in sex hormone levels in adult female rats. The effects of chronic (14 days) administration of the 5-HT serotonin receptor agonist 8-OH-DPAT (0.05 mg/kg, s.c.) and the 5-HT serotonin receptor antagonist NAN-190 (0.1 mg/kg, i.p.) to females at different phases of the ovarian cycle on conditioned reflex responses were studied. A conditioned passive avoidance reaction and the Morris water maze were used as behavioral tests. Chronic administration of NAN-190 to females led to the appearance of the conditioned passive avoidance response in the proestrus and estrus phases, in contrast to control females, but had no effects on the dynamics of spatial learning in the Morris water test. Chronic administration of 8-OH-DPAT consistently impaired the processes of non-spatial and spatial learning in females regardless of the phase of the ovarian cycle. The results obtained in these experiments evidenced the modulatory role of 5-HT serotonin receptors in learning processes in rats in key phases of the ovarian cycle. [ABSTRACT FROM AUTHOR]

We studied the effects of immobilization of female rat during days 15-18 of pregnancy on the behavior in novel environment (open field test) and blood level of steroid hormones in their female offspring depending on the cycle phase and age. The rats were tested at the age of 3, 12, and 24 months. Locomotor and exploratory activity and anxiety of control rats depended on the phase of estrous cycle. Age-related changes in the studied parameters were noted: locomotor and exploratory activity decreased and anxiety increased against the background of reduced secretion of the main ovarian hormones with age. In addition, blood estradiol level and behavior in novel environment virtually did not depend on age and estrous cycle phase in prenatally stressed females. Our fi ndings suggest that maternal stress has a modulatory effect on relationship between behavioral type and estrous cycle stage, as well as on age-related pattern of behavioral reactions. [ABSTRACT FROM AUTHOR]

The effects of treatment of rats with hydrocortisone (1 mg/100 g) or the glucocorticoid receptor blocker RU38486 (1 mg/100 g) from day 1 to day 5 of life on changes in the dynamics of the stress response of the hypophyseal-adrenocortical system (HAS), orientational-investigative activity, and anxiety in immature and adult male rats were studied. Excess glucocorticoid hormones during the early neonatal period was found to increase orientational-investigative activity and the level of anxiety in immature males without altering the functional activity of the HAS or behavior in adult rats. Conversely, impairment of glucocorticoid receptor mechanisms in brain structures in neonatal rats led to decreased feedback efficiency in the regulation of the HAS, decreases in motor activity, and increases in anxiety levels in conditions of contextual novelty, which was most clearly apparent at adult age. It is suggested that rearrangement of glucocorticoid reception during the neonatal period of development is among the causes of the various hormonal and behavioral impairments in adult individuals. [ABSTRACT FROM AUTHOR]

We studied effects of the selective inhibitors of serotonin reuptake fluoxetine and paroxetine, which were orally administered at a dose of 5.0 mg/kg from the 1st to 14th days of postnatal life, on the anxiety behavior and hormonal stress reactivity of mature prenatally stressed male rats. We found that prenatal stress decreased the anxiety level in mature male rats. Chronic treatment with paroxetine did not the alter the anxiety behavior of prenatally stressed males. In contrast, treatment with fluoxetine had an anxiogenic effect on their behavior, canceling the effect of prenatal stress on the anxiety behavior of male rats. Prenatal stress considerably affected the dynamics of the stress response of the pituitary-adrenal system, which was seen as disturbances in the regulation of system feedback under conditions of stress-induced activation. Chronic administration of paroxetine or fluoxetine corrected the dynamics of stress-induced levels of corticosterone in the blood of prenatally stressed males. [ABSTRACT FROM AUTHOR]

The effects of immobilization (1 h/day) of female rats from days 15 to 18 of pregnancy on the secretion of sex steroid hormones depending on the stage of the estrous cycle, functional activity of the hypophyseal-adrenocortical system (HAS), and its sensitivity to regulatory signals were studied in their female offspring at different stages of ontogeny. Prenatal stress was found to lead to significant impairments to the activity of the sexual system depending on the animals' age. Older females showed a significant decrease in HAS sensitivity to feedback signals. These data provide evidence that maternal stress has a modifying effect on changes in the reproductive functions of female rats with age and on the significant decrease in the efficacy of the feedback functions of the HAS. [ABSTRACT FROM AUTHOR]

In this study, we performed a comparative analysis of the effects of chronic administration of an agonist of 5-HT receptors, 8-OH-DPAT, (0.05 mg/kg, subcutaneously) and an antagonist of 5-HT receptors, NAN-190, (0.1 mg/kg, intraperitoneally) for 14 days on the anxiety behavior, monoamine metabolism in the hippocampus and amygdala, and the level of sex hormones in the blood of adult female rats during the estrus cycle. Anxiety behavior was tested in an elevated X-maze. The level of monoamines and their metabolites was evaluated using HPLC with an electrochemical detector; the content of sex hormones in the blood was measured using an enzyme immunoassay. We found that chronic administration of 8-OH-DPAT has an anxiolytic effect in rats in estrus and proestrus. After treatment with NAN-190, we found clear modulation of anxiety behavior that depended on the phase of the estrus cycle, an anxiolytic effect at a high level of endogenous estrogens and an anxiogenic effect at a low level of estrogens. The anxiolytic effect of 8-OH-DPAT in female rats was accompanied by its suppressive influence on the pituitary-ovarian and noradrenergic systems and by its activating effect on the dopaminergic system of the brain. In contrast, the behavioral effects of NAN-190 in female rats during key phases of the estrus cycle corresponded to its stimulating effect of the pituitary-ovarian system and the absence of any effect on the monoaminergic systems of the brain. These data suggest that the mechanisms of anxiety include tight interaction between the ovarian hormonal system and the serotonergic brain system. [ABSTRACT FROM AUTHOR]

Abstract  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. [ABSTRACT FROM AUTHOR]

Expression of glucocorticoid receptor protein in the hippocampus and frontal cortex of male and female rats during the 1st, 2nd, and 3rd weeks of life was studied by Western blot hybridization. In the frontal cortex, the concentration of receptor protein progressively increased from the 1st to the 3rd week of life; in females, expression of 94-kDa protein significantly surpassed that in males during the 1st week of life. In the hippocampus, expression of 94-kDa and 82-kDa proteins during the 1st week of life was higher in males. Moreover, expression of the major glucocorticoid receptor isoform (94 kDa) in this structure remained unchanged in all periods of the study in males, whereas in females it was low over the first 2 weeks of life and increased by the 3rd week. Variations in the expression of glucocorticoid receptors in the hippocampus of male and female rats coincide with changes in plasma corticosterone concentration during the early postnatal ontogeny. [ABSTRACT FROM AUTHOR]

Abstract  We report here studies on the delayed effects of exogenous progesterone on the formation of anxiety in female mice. Ovariectomized female mice were given seven days of replacement therapy either with the two main ovarian hormones-progesterone and estradiol benzoate-or with progesterone only; levels of anxiety were measured six hours later in the elevated plus-maze. The role of nuclear progesterone receptors in controlling the level of anxiety was assessed by giving some mice injections of the synthetic progesterone receptor blocker mifepristone 2 h before the last dose of hormones. An immunohistochemical method was used to study changes in the number of nuclear progesterone receptors in different areas of the brains of experimental animals. These studies showed that progesterone has a delayed enhancing effect on anxiety in female mice. The role of nuclear progesterone receptors in forming this behavioral characteristic was supported by a strong correlation between changes in the numbers of progesterone receptor-immunopositive cells in several brain structures and the level of anxiety. Prior blockade of progesterone receptors using mifepristone led to a maximal reduction in the level of anxiety, which was also evidence for a role for the genomic mechanisms of action of progesterone in controlling anxiety in females. [ABSTRACT FROM AUTHOR]