Prenatal Stress Rats Research Articles

Emotional dysregulation following prenatal stress is associated with altered prefrontal cortex responsiveness to an acute challenge in adolescence

Exposure to prenatal stress (PNS) has the potential to elicit multiple neurobiological alterations and increase the susceptibility to psychiatric disorders. Moreover, gestational stress may sensitize the brain toward an altered response to subsequent challenges. Here, we investigated the effects of PNS in rats and assessed whether these animals exhibit an altered brain responsiveness to an acute stress (AS) during adolescence. From gestational day 14 until delivery, Sprague Dawley dams were exposed to PNS or left undisturbed. During adolescence (PND38 to PND41), offspring were tested in the social interaction and splash test. At PND44 half of the animals were exposed to 5 min of forced swim stress. Males and Females exposed to PNS showed reduced sociability and increased anhedonic-like behavior. At the molecular level, exposure of adolescent rats to AS produced increased activation of the amygdala and ventral and dorsal hippocampus. Regarding the prefrontal cortex (PFC), we observed a pronounced activation in PNS males exposed to AS. Cell-type specific transcriptional analyses revealed a significant imbalance in the activation of PFC excitatory and inhibitory neurons in PNS males and females exposed to AS. Furthermore, stressed males exhibited disrupted HPA-axis function, while females showed impairments in the modulation of antioxidant genes. Our study shows that PNS induces emotional dysregulation and alters the responsiveness of the PFC to an acute stressor. Moreover, the disruption of excitatory and inhibitory balance during adolescence could influence the ability to respond to challenging events that may contribute to precipitate a full-blown pathologic condition.

Dissecting the Long-Term Effect of Stress Early in Life on FKBP5: The Role of miR-20b-5p and miR-29c-3p.

Exposure to early-life stress (ELS) has been related to an increased susceptibility to psychiatric disorders later in life. Although the molecular mechanisms underlying this association are still under investigation, glucocorticoid signaling has been proposed to be a key mediator. Here, we used two preclinical models, the prenatal stress (PNS) animal model and an in vitro model of hippocampal progenitor cells, to assess the long-term effect of ELS on FKBP5, NR3C1, NR3C2, and FoxO1, four stress-responsive genes involved in the effects of glucocorticoids. In the hippocampus of male PNS rats sacrificed at different time points during neurodevelopment (PND 21, 40, 62), we found a statistically significant up-regulation of FKBP5 at PND 40 and PND 62 and a significant increase in FoxO1 at PND 62. Interestingly, all four genes were significantly up-regulated in differentiated cells treated with cortisol during cell proliferation. As FKBP5 was consistently modulated by PNS at adolescence (PND 40) and adulthood (PND 62) and by cortisol treatment after cell differentiation, we measured a panel of miRNAs targeting FKBP5 in the same samples where FKBP5 expression levels were available. Interestingly, both miR-20b-5p and miR-29c-3p were significantly reduced in PNS-exposed animals (both at PND40 and 62) and also in the in vitro model after cortisol exposure. Our results highlight the key role of miR-20b-5p and miR-29c-3p in sustaining the long-term effects of ELS on the stress response system, representing a mechanistic link possibly contributing to the enhanced stress-related vulnerability to mental disorders.

Investigating the effects of antipsychotic drugs as a treatment for improving the activity of the unc-33 /Dpysl2 gene in C. elegans.

Prenatal stress is hypothesized to contribute to the development of schizophrenia. Lee and colleagues determined that prenatal stress in rats decreases levels of Dpysl2, which is found to be inactivated in schizophrenic patients. UNC-33 , the homolog to Dpysl2 in C. elegans , is important for axonal outgrowth and synapse formation. Herein, we study the effects of antipsychotic drugs on developing C.elegans exposed to stress through high temperatures. Results indicate that the unc-33 promoter was not impacted by antipsychotic drug treatment, but the lifespan was decreased.

Inhibition of FLT1 Attenuates Neurodevelopmental Abnormalities and Cognitive Impairment in Offspring Caused by Maternal Prenatal Stress.

Fms-like tyrosine kinase 1 (FLT1) has been shown to regulate processes such as angiogenesis, neurogenesis, and cognitive impairment. However, the role of FLT1 in prenatal stress (PS) is unclear. The purpose of this study was to investigate the role of FLT1 in PS mothers and their offspring. Wire mesh restrainers were used to construct PS rat model. The levels of FLT1, IL-1β, IL-6, and ROS in clinical samples and rat samples were detected by qRT-PCR, ELisa kit, and DCFH-DA fluorescence kit. Morris water maze assay and forced swimming assay were used to test the cognitive function of offspring young rats. The apoptosis level of hippocampal neurons and the expression of NMDARs were detected by MTT assay, TUNEL assay, and Western blot. The results showed that FLT1 was upregulated in PS mothers and positively correlated with PS degree. The level of FLT1 was elevated in PS model rats. Knockdown of FLT1 reduced maternal ROS and MDA levels and increased SOD levels in PS rats. Knockdown of FLT1 also reduced the secretion of IL-1β, IL-6, and cortisol in PS rats. Inhibition of FTL1 alleviated cognitive impairment in PS offspring pups. Inhibition of FTL1 reduced hippocampal neuronal apoptosis and increased the expression of NMDARs in PS progeny. In conclusions, we demonstrated that knockdown of FLT1 inhibits maternal oxidative stress, inflammation, and cortisol secretion in PS rats. In addition, knockdown of FLT1 also alleviated cognitive dysfunction and neurodevelopmental abnormalities in PS offspring pups.

Prenatal stress induces a depressive-like phenotype in adolescent rats: The key role of TGF-β1 pathway.

Stressful experiences early in life, especially in the prenatal period, can increase the risk to develop depression during adolescence. However, there may be important qualitative and quantitative differences in outcome of prenatal stress (PNS), where some individuals exposed to PNS are vulnerable and develop a depressive-like phenotype, while others appear to be resilient. PNS exposure, a well-established rat model of early life stress, is known to increase vulnerability to depression and a recent study demonstrated a strong interaction between transforming growth factor-β1 (TGF-β1) gene and PNS in the pathogenesis of depression. Moreover, it is well-known that the exposure to early life stress experiences induces brain oxidative damage by increasing nitric oxide levels and decreasing antioxidant factors. In the present work, we examined the role of TGF-β1 pathway in an animal model of adolescent depression induced by PNS obtained by exposing pregnant females to a stressful condition during the last week of gestation. We performed behavioral tests to identify vulnerable or resilient subjects in the obtained litters (postnatal day, PND > 35) and we carried out molecular analyses on hippocampus, a brain area with a key role in the pathogenesis of depression. We found that female, but not male, PNS adolescent rats exhibited a depressive-like behavior in forced swim test (FST), whereas both male and female PNS rats showed a deficit of recognition memory as assessed by novel object recognition test (NOR). Interestingly, we found an increased expression of type 2 TGF-β1 receptor (TGFβ-R2) in the hippocampus of both male and female resilient PNS rats, with higher plasma TGF-β1 levels in male, but not in female, PNS rats. Furthermore, PNS induced the activation of oxidative stress pathways by increasing inducible nitric oxide synthase (iNOS), NADPH oxidase 1 (NOX1) and NOX2 levels in the hippocampus of both male and female PNS adolescent rats. Our data suggest that high levels of TGF-β1 and its receptor TGFβ-R2 can significantly increase the resiliency of adolescent rats to PNS, suggesting that TGF-β1 pathway might represent a novel pharmacological target to prevent adolescent depression in rats.

Effects of RhoA on depression-like behavior in prenatally stressed offspring rats

Depression is a common mental disease that can lead to suicide when severe. Exposure to prenatal stress (PS) can lead to depression-like behavior in offspring, but the mechanism is unclear. RhoA (Ras homology family member A) plays an important role in stress-induced changes in synaptic plasticity, participating in the development of depression by activating the downstream effector ROCK (Rho-associated protein kinase). This study explored the influence in the expression of RhoA and downstream molecules ROCK1/2 in prenatally stressed rats, and the effect of RhoA inhibitor simvastatin on depression-like behavior induced by PS. Depression-like behavior in offspring was detected by sucrose preference test, forced swimming test, and open-field test. The mRNA and protein expression of RhoA and ROCK1/2 in the hippocampus and prefrontal cortex of offspring rats were detected by qRT-PCR and western blotting, respectively. Our results showed that PS causes depression-like behavior in offspring rats, associated with elevated expression of RhoA, ROCK1/2 in the hippocampus and prefrontal cortex. After administration of simvastatin to PS rats, the expression of RhoA and ROCK2 was significantly reduced, alleviating depression-like behavior. Our study demonstrated that RhoA participates in the depression-like behavior in prenatally stressed offspring rats, which may be a potential target for antidepressant therapy.

Effects of high-fat diet on growth and depression-like behavior of prenatal stress offspring rats

To investigate effects of high-fat diet (HFD) on body length, weight and depression-like behavior of prenatal stress (PS) offspring rats. PS rat model was established by restraint stress. Sucrose preference and forced swimming tests were performed. Moreover, the effects of HFD on the growth and depression-like behavior in offspring rats were observed. Length of male and female HF group was significantly longer than that control, but length of male PS+HF group was significantly shorter than HF group. Body weight of male and female HF group was significantly higher than control, and body weight of male PS+HF group was significantly lower than HF group. No significant differences were observed in length between female PS +HF and HF groups. Compared with male PS+HF group, growth rate of male HF group was significantly higher. Moreover, HFD could reduce sucrose preference, and prolong immobility time of PS offspring rats. HFD can promote weight gain of male and female normal offspring rats. PS can partially inhibit effects of HFD on weight gain of PS male offspring rats, but exert no significant effects on PS female offspring rats. HFD can aggravate PS-induced depression-like behavior in offspring rats.

Chronic Piromelatine Treatment Alleviates Anxiety, Depressive Responses and Abnormal Hypothalamic-Pituitary-Adrenal Axis Activity in Prenatally Stressed Male and Female Rats.

The prenatal stress (PNS) model in rodents can induce different abnormal responses that replicate the pathophysiology of depression. We applied this model to evaluate the efficacy of piromelatine (Pir), a novel melatonin analog developed for the treatment of insomnia, in male and female offspring. Adult PNS rats from both sexes showed comparable disturbance associated with high levels of anxiety and depressive responses. Both males and females with PNS demonstrated impaired feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis compared to the intact offspring and increased glucocorticoid receptors in the hippocampus. However, opposite to female offspring, the male PNS rats showed an increased expression of mineralocorticoid receptors in the hippocampus. Piromelatine (20 mg/kg, i.p., for 21 days injected from postnatal day 60) attenuated the high anxiety level tested in the open field, elevated plus-maze and light-dark test, and depressive-like behavior in the sucrose preference and the forced swimming tests in a sex-specific manner. The drug reversed to control level stress-induced increase of plasma corticosterone 120 min later in both sexes. Piromelatine also corrected to control level the PNS-induced alterations of corticosteroid receptors only in male offspring. Our findings suggest that the piromelatine treatment exerts beneficial effects on impaired behavioral responses and dysregulated HPA axis in both sexes, while it corrects the PNS-induced changes in the hippocampal corticosteroid receptors only in male offspring.

Effects of prenatal stress on neuroactive steroid responses to acute stress in adult male and female rats.

Acute swim stress results in the robust production of several neuroactive steroids, which act as mediators of the stress response. These steroids include glucocorticoids, and positive GABAA receptor modulatory steroids such as allopregnanolone and tetrahydrocorticosterone (THDOC), which potentiate inhibitory GABA signalling, thereby playing a role in the negative control of the hypothalamic‐pituitary‐adrenal (HPA) axis. Prenatally stressed (PNS) offspring exhibit increased vulnerability to stress‐related disorders and frequently display exaggerated HPA axis responses to stressors during adulthood, which may be a result of reduced neuroactive steroid production and consequently inhibitory signalling. Here, we investigated whether exposure of rats to prenatal social stress from gestational day 16‐20 altered neuroactive steroid production under non‐stress conditions and in response to an acute stressor (swim stress) in adulthood. Using liquid chromatography‐mass spectrometry, nine neuroactive steroids were quantified (corticosterone, deoxycorticosterone [DOC], dihydrodeoxycorticosterone, THDOC, progesterone, dihydroprogesterone, allopregnanolone, pregnenolone, testosterone) in plasma and in five brain regions (frontal cortex, hypothalamus, amygdala, hippocampus, brainstem) of male and female control and PNS rats. There was no difference in the neuroactive steroid profile between control and PNS rats under basal conditions. The increase in circulating corticosterone induced by acute swim stress was similar in control and PNS offspring. However, greater stress‐induced corticosterone and DOC concentrations were observed in the brainstem of male PNS offspring, whereas DOC concentrations were lower in the hippocampus of PNS females compared to controls, following acute stress. Although PNS rats did not show deficits in allopregnanolone responses to acute stress, there were modest deficits in the production of THDOC in the brainstem, amygdala, and frontal cortex of PNS males and in the frontal cortex of PNS females. The data suggest that neuroactive steroid modulation of GABAergic signalling following stress exposure may be affected in a sex‐ and region‐specific manner in PNS offspring.

Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats.

Prenatal stress (PS) can lead to neuroendocrine and emotional disorders later in adolescence. Sexual dimorphism in these neurodevelopmental outcomes have been observed; however, the underlying mechanisms are not fully understood. To address this issue, we investigated whether there are sex differences in epigenetic reprogramming in rats exposed to PS. Pregnant female rats were subjected to chronic restraint stress from gestational day (G)12 to G18. From postnatal day (P)38 to P45, subgroups of offspring including both males and females were subjected to behavioral testing and brain tissue specimens were analyzed by DNA pyrosequencing, western blotting, and Golgi staining to assess changes in methylation pattern of glucocorticoid receptor (GR) gene, expression of DNA methyltransferase (DNMT) and DNA demethylase, and dendrite morphology, respectively. The DNA methyltransferase inhibitor decitabine was administered to rats prior to PS to further evaluate the role of methylation in the sexually dimorphic effects of PS. The results showed that PS increased anxiety-like behavior in offspring, especially in females, while depression-like behavior was increased in male offspring compared to control littermates. The methylation pattern in the promoter region of the GR gene differed between males and females. Sex-specific changes in the expression of DNMTs (DNMT1 and DNMT3a) and DNA demethylase (Tet methylcytosine dioxygenase 2) were also observed. Interestingly, decitabine alleviated the behavioral disorder caused by PS and restored dendrite density and morphology in female but not male rats. These findings suggest that different change patterns of DNMT and demethylase in the two sexes after PS are responsible for the sexually dimorphism, which could have implications for the clinical management of stress-related disorders.

Combination of Stressors in the Critical Periods of Development Increases Resistance to Inflammatory Pain Stress in Adult Rats

We report here studies of the long-term effects of combined stress in the prenatal and prepubertal periods of development on measures of tonic inflammatory pain in the formalin test and the severity of depression-like behavior, and also the stress reactivity of the hormonal response in adult rats. In addition, the effects of the serotonin (5-HT) reuptake inhibitor fluoxetine and the 5-HT1A receptor agonist buspirone, given chronically to stressed mothers during pregnancy, on various types of adaptive behavior impaired by prenatal stress were assessed in rats of both sexes. The results showed that in rats of both sexes prenatal stress increased the pain response organized at the spinal and supraspinal levels of the central nervous system and that fluoxetine and buspirone normalized responses. Stress during the prepuberal period of development eliminated the effects of prenatal stress on the inflammatory pain responses integrated at the supraspinal level in adult rats; in these conditions, fluoxetine and buspirone had no effects, in contrast to their antinociceptive actions on the pain response integrated at the spinal level. Stress at prepubertal age eliminated sex-related differences seen in depression-like behavior in prenatally unstressed and prenatally stressed rats given physiological saline. Control adult females and adult females exposed to prenatal stress in the prepubertal period showed increases in the plasma corticosterone level after forced swimming as compared with the basal hormone level, though there were no significant differences in the level of stress reactivity of the hormonal response after forced swimming. Thus, the conditions for stress actions increasing stress resistance in adult rats were identified. Stress in the critical period of development formed a phenotype with increased stress resistance to inflammatory pain, which was seen in responses organized at the supraspinal level in adult individuals.

Prenatal stress impairs memory function in the early development of male-offspring associated with the gaba function

Prenatal stress (PS) induces cognitive deficits, abnormal behavior patterns and physical impairments in offspring, which disturbs the developmental process. GABA systems play a key role in the brain development. The developmental trajectories are less understood although PS increases the expression of GABAAR in young offspring. In the present study, we aimed to examine if the long-lasting effects on memory function and hippocampal synaptic plasticity induced by PS were associated with the GABA function throughout developmental process. Thus, a PS rat model was established by using restraint stress three 45-min periods per day from gestational day 15 until delivery. PS-exposed offspring exhibited the memory function deficits, LTP and depotentiation inhibitions in young and puberty offspring, but the disorder resolved at adult offspring. Meanwhile, the hippocampal spine density was decreased by PS in offspring. Additionally, we found that the balance of excitatory and inhibitory receptors was significantly disturbed after PS. The immunostaining of parvalbumin level was increased in the PS group. Overall, these all results suggest that the PS induces negative effects in memory and hippocampal synaptic plasticity in the early developmental stage, which could be an underlying mechanism of the disturbed GABA function.

Alterations in ‘inflammatory’ pathways in the rat prefrontal cortex as early biological predictors of the long-term negative consequences of exposure to stress early in life

Early life stress, especially when experienced during the first period of life, affects the brain developmental trajectories leading to an enhanced vulnerability for stress-related psychiatric disorders later in life. Although both clinical and preclinical studies clearly support this association, the biological pathways deregulated by such exposure, and the effects in shaping the neurodevelopmental trajectories, have so far been poorly investigated.By using the prenatal stress (PNS) model, a well-established rat model of early life stress, we performed transcriptomic analyses in the prefrontal cortex of rats exposed or not to PNS and sacrificed at different postnatal days (PNDs 21, 40, 62). We first investigated the long-lasting mechanisms and pathways affected in the PFC. We have decided to focus on the prefrontal cortex because we have previously shown that this brain region is highly sensitive to PNS exposure. We found that adult animals exposed to PNS show alterations in 389 genes, mainly involved in stress and inflammatory signalling. We then wanted to establish whether PNS exposure could also affect the neurodevelopmental trajectories in order to identify the most critical temporal window.We found that PNS rats show the most significant changes during adolescence (between PND 40 versus PND 21), with alterations of several pathways related to stress, inflammation and metabolism, which were maintained until adulthood.

Effects of Prenatal Stress on the Formation of the Orexinergic System of the Hypothalamus in Rats

The effects of prenatal stress (PNS) on the formation of the orexinergic and dopaminergic systems of the brain were studied in 14- and 30-day-old rat pups born to females subjected to sleep deprivation (6 h/day) using the “small areas” method from day 13 to day 19 of pregnancy. The open fi eld test showed impairments to motor development in 14-day-old PNS rat pups. Immunohistochemical studies of brain sections showed that the hypothalamus contained a signifi cantly larger quantity of orexin A in neurons in the periforniceal area, while high-performance liquid chromatography demonstrated increases in the dopamine level and its rate of metabolism as compared with control rat pups born to intact females. Western blotting results provided evidence of a decrease in the striatal level of the GABA-sythesizing enzyme (GAD65) and an increase in the level of tyrosine hydroxylase (an enzyme involved in dopamine synthesis) phosphorylated at serine-40 as compared with controls. By day 30 of life measures of motor activity in PNS rat pups were no different from those in controls, though PNS rat pups had higher levels of anxiety and lower levels of exploratory activity. The results of morphological and biochemical studies also provided evidence that there were no differences between the study parameters in the hypothalamus and striatum in 30-day-old rat pups as compared with controls, which was confi rmed by results from electrophysiological studies indicating that there were no differences in the organization of the sleep-waking cycle in 30-day-old PNS and control rat pups. We discuss here the morphofunctional interactions of the orexinergic and dopaminergic systems of the brain in the early postnatal period of development of the body and the role of orexins in the compensatory mechanisms of the brain.

The Long-Term Effects of Early Life Stress on the Modulation of miR-19 Levels.

MicroRNAs (miRNAs), one of the major small non-coding RNA classes, have been proposed as regulatory molecules in neurodevelopment and stress response. Although alterations in miRNAs profiles have been implicated in several psychiatric and neurodevelopmental disorders, the contribution of individual miRNAs in brain development and function is still unknown. Recent studies have identified miR-19 as a key regulator of brain trajectories, since it drives the differentiation of neural stem cells into mature neurons. However, no findings are available on how vulnerability factors for these disorders, such as early life stress (ELS), can modulate the expression of miR-19 and its target genes. To reach our aim, we investigated miR-19 modulation in human hippocampal progenitor stem cells (HPCs) treated with cortisol during 3 days of proliferation and harvested immediately after the end of the treatment or after 20 days of differentiation into mature neurons. We also analyzed the long-term expression changes of miR-19 and of its validated target genes, involved in neurodevelopment and inflammation, in the hippocampus of adult rats exposed or not to prenatal stress (PNS). Interestingly, we observed a significant downregulation of miR-19 levels both in proliferating (FC = −1.59, p-value = 0.022 for miR-19a; FC = −1.79, p-value = 0.016 for miR-19b) as well as differentiated HPCs (FC = −1.28, p-value = 0.065 for miR-19a; FC = −1.75, p-value = 0.047 for miR-19b) treated with cortisol. Similarly, we found a long-term decrease of miR-19 levels in the hippocampus of adult PNS rats (FC = −1.35, p-value = 0.025 for miR-19a; FC = −1.43, p-value = 0.032 for miR-19b). Among all the validated target genes, we observed a significant increase of NRCAM (FC = 1.20, p-value = 0.027), IL4R (FC = 1.26, p-value = 0.046), and RAPGEF2 (FC = 1.23, p-value = 0.020).We suggest that ELS can cause a long-term downregulation of miR-19 levels, which may be responsible of alterations in neurodevelopmental pathways and in immune/inflammatory processes, leading to an enhanced risk for mental disorders later in life. Intervention strategies targeting miR-19 may prevent alterations in these pathways, reducing the ELS-related effects.

RTMS Ameliorates Prenatal Stress–Induced Cognitive Deficits in Male-Offspring Rats Associated With BDNF/TrkB Signaling Pathway

Background. Growing evidences suggest that brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) plays a key role in the regulation of hippocampal synaptic plasticity in a prenatal stress (PNS) rat model. Repetitive transcranial magnetic stimulation (rTMS) is currently being acknowledged to affect attention and memory in both preclinical and clinical studies, although the mechanism is still unclear. Objective. The current study aimed to explore whether a whole brain rTMS (5 Hz, 14 days) could ameliorate cognitive dysfunction–induced PNS in male offspring, and examine if the positive effect of rTMS was associated with the BDNF/TrkB signaling in the hippocampus. Methods. The rats were randomly divided into 5 groups: CON, PNS, PNS + rTMS, PNS + rTMS + DMSO (dimethyl sulfoxide), and PNS + rTMS + K252a. Spatial cognition was evaluated by using Morris water maze test. Following behavioral assessment, both paired-pulse facilitation and long-term potentiation were recorded from Schaffer collaterals to CA1 region in the hippocampus. Synaptic, apoptotic, and BDNF/TrkB signaling proteins were measured by Western blot. Results. PNS-exposed offspring exhibited cognitive deficits, long-term potentiation inhibition in the hippocampus, the decrease of synaptic and BDNF/TrkB signaling proteins expression, apoptosis, and reduced number of cells in the CA1 region. Five-hertz rTMS significantly alleviated the PNS-induced abnormalities. However, the effect of rTMS was antagonized by intracerebroventricular infusion of K252a (a TrkB inhibitor). Conclusions. The findings suggest that 5-Hz rTMS significantly improves the impairment of spatial cognition and hippocampal synaptic plasticity, which is possibly associated with the activation of BDNF/TrkB signaling.

The Effect of Compulsory Sports Activities on Substantia Nigra Tissue and Behavioral Tests Induction Parkinsons Model with 6-Hydroxydopamine in Prenatal Stress Rats

The Effect of Compulsory Sports Activities on Substantia Nigra Tissue and Behavioral Tests Induction Parkinsons Model with 6-Hydroxydopamine in Prenatal Stress Rats

EXPERIMENTAL MODEL OF SCHIZOPHRENIA AND MORPHOLOGICAL CHANGES IN BRAIN

Schizophrenia is a complex psychiatric mental disorder often characterized by abnormal social behavior and failure to recognize what is real. Common symptoms include false beliefs, unclear or confused thinking, auditory hallucinations, reduced social engagement and emotional expression, and inactivity. Neuroontogenetic theory explains the occurrence of disease events taken place during intrauterine period. Gutamatergic signaling interferes with ethion-pathogenic mechanisms of schizophrenia. The disease is associated with N-methyl-D-aspartate NMDA receptor hypofunction and a number of genes suspected in respect of schizophrenia influence on a NMDA receptor signaling. NRG1 and ErbB4 its receptor involved in the glutamatergic signaling by regulating the NMDA receptor complex. Neuregulins are signaling proteins structurally related to the epidermal growth factor (EGF). The mechanisms underlying the contribution of NRG1/ErbB4 system to schizophrenia pathophysiology remain insignificant, but they reveal only after the complete maturation of the brain. Prenatal stress in rats simulates many of the cognitive and sensory deficits manifest in the disease. Identified in this experimental model deficits in immunochistochemical expression of Neuroregulin1- ErbB4- system directed changes at the molecular level in the hippocampus, a brain structure with a role in the regulation of stress.

Hypothalamic insulin and glucagon-like peptide-1 levels in an animal model of depression and their effect on corticotropin-releasing hormone promoter gene activity in a hypothalamic cell line.

In depression, excessive glucocorticoid action may cause maladaptive brain changes, including in the pathways controlling energy metabolism. Insulin and glucagon-like peptide-1 (GLP-1), besides regulation of glucose homeostasis, also possess neurotrophic properties. Current study was aimed at investigating the influence of prenatal stress (PS) on insulin, GLP-1 and their receptor (IR and GLP-1R) levels in the hypothalamus. GLP-1 and GLP-1R were assayed also in the hippocampus and frontal cortex - brain regions mainly affected in depression. The second objective was to determine the influence of exendin-4 and insulin on CRH promoter gene activity in in vitro conditions. Adult male PS rats were subjected to acute stress and/or received orally glucose. Levels of hormones and their receptors were assayed with ELISA method. In vitro studies were performed on mHypoA-2/12 hypothalamic cell line, stably transfected with CRH promoter coupled with luciferase. PS has reduced GLP-1 and GLP-1R levels, attenuated glucose-induced increase in insulin concentration and increased the amount of phosphorylated IR in the hypothalamus of animals subjected to additional stress stimuli, and also decreased the GLP-1R level in the hippocampus. In vitro studies demonstrated that insulin is capable of increasing CRH promoter activity in the condition of stimulation of the cAMP/PKA pathway in the applied cellular model. Prenatal stress may act as a preconditioning factor, affecting the concentrations of hormones such as insulin and GLP-1 in the hypothalamus in response to adverse stimuli. The decreased GLP-1R level in the hippocampus could be linked with the disturbances in neuronal plasticity.

Effect of prenatal stress on neural oscillations in developing hippocampal formation

The effect of prenatal stress (PS) on offspring's behavior was reported previously. Several studies attempted to reveal the mechanisms of PS on synaptic and molecular levels. However, the influences of PS on neural oscillations and their interaction in hippocampus are still unknown. In the present study, a PS rat model was established by using restraint stress. The local-field potentials (LFPs) were simultaneously recorded from the hippocampal CA3 and CA1 regions in young, adolescent and early-adult offspring rats. After that, LFPs were analyzed by analytic algorithms for estimating power spectrum, coherence, phase synchronization and cross-frequency coupling. The results showed that there was a significant influence of PS on power distribution from 1 to 100 Hz during different developmental stages. The identical-frequency synchronizations between CA3 and CA1 regions, including coherence and phase synchronization, were significantly reduced in PS rats compared to that in normal rats. Meanwhile, PS significantly impaired the cross-frequency coupling strength between theta and gamma rhythms. These data show that PS alters the neural oscillations and their interaction on the hippocampal CA3-CA1 pathway, which may be associated with the behavior outcomes and synaptic impairments previously reported in PS offspring rats. Moreover, the significant PS × age interactions between the effects of PS and age have been only found in the cross-frequency coupling, implying that the cross-frequency coupling more appropriately reflects the differences of the behavioral effects of PS in different postnatal ages.