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Prenatal stress causes gender-dependent neuronal loss and oxidative stress in rat hippocampus
Abstract
Our purpose was to investigate the effects of prenatal stress on neuronal changes in the hippocampus and the possible involvement of oxidative stress in female and male rats. Female and male offspring (1-month-old), whose dams were restrained in middle or later pregnant stage (MS or LS), were studied to observe changes in the number of hippocampal neurons and the expression of neuronal nitric oxide synthase (nNOS) in the hippocampus. Both MS and LS induced an increase in the number of nNOS-positive expression in female and male offspring in the hippocampus; however, both MS and LS caused a significant decrease in the number of hippocampal neurons in the female, but not in the male offspring. In addition, significant increases in calcium content and oxidant generation were induced by LS in the hippocampal CA3 region in female rats. These data suggest that prenatal stress can cause oxidative stress and consequent damage to neurons, leading to neuronal loss in the brain of offspring during development.
... In the present study, following formalin injection, a higher MDA level in VPL was shown in S group compared to other groups suggesting an increased oxidative stress in this group of rats. Zhu et al (2004) reported that prenatal stress was associated with increased ROS and neuronal nitric oxide synthase expression in the hippocampus of rat offspring (41). Administration of Tualang honey in the pregnant dams was associated with reduced MDA level in VPL of prenatally stressed male rat offspring. ...
... In the present study, following formalin injection, a higher MDA level in VPL was shown in S group compared to other groups suggesting an increased oxidative stress in this group of rats. Zhu et al (2004) reported that prenatal stress was associated with increased ROS and neuronal nitric oxide synthase expression in the hippocampus of rat offspring (41). Administration of Tualang honey in the pregnant dams was associated with reduced MDA level in VPL of prenatally stressed male rat offspring. ...
... Therefore, these results suggest that prenatal stress was associated with structural changes in the VPL of the rats' offspring. Several studies have shown that oxidative tissue damage occur in various parts of the brain such as cerebral cortex, cerebellum, and hippocampus in the adult offspring exposed to prenatal stressed (41)(42)(43). ...
Introduction: Increased nociceptive responses were shown in the offspring of prenatally stressed rats. Reports have demonstrated the anti-nociceptive effects of Tualang honey in the rat offspring. The present study was done to determine whether the modulation of nociceptive behaviour by Tualang honey was mediated by modulating changes in the histology, oxidative stress parameters and N-methyl-D-aspartate (NMDA) receptors in the thalamus of the rat offspring. Methods: Eighteen Sprague Dawley pregnant rats were randomly assigned to control (C), stress (S) and stress-treated with Tualang honey (SH) groups. Stress was given in a form of restraint stress.Tualang honey was given to SH group from first day of pregnancy until delivery. Thirty-three adult male offspring were subjected to formalin test before they were sacrificed. Nociceptive behaviour score, number of neurons, level of oxidative stress parameters and NMDA receptors in the thalamus were analysed by using one-way ANOVA. Results: The study demonstrated a significant decrease in mean nociceptive behaviour score (p<0.05) with lower malondialdehyde (MDA, p<0.05) and higher superoxide dismutase SOD and catalase levels in the thalamus of SH group compared to S group (p<0.05). There was also increased Nissl positive neurons in the thalamus of SH group compared to S group. There was no significant difference in NMDA receptor level between S and SH groups. Conclusion: The modulation of nociceptive responses in the prenatally stressed rat offspring by Tualang honey was associated with improvement in oxidative stress parameters and histology of the thalamus in the rat offspring exposed to prenatal stress.
... Pregnant rats were separately exposed to restraint stress on days 14-20 of pregnancy three times daily for 45 min, as described previously (Cao et al., 2018;Zhu et al., 2004). To prevent the adaptation of animals to the daily procedure, restraint periods were shifted randomly within certain periods (08:00 AM-11:00 AM, 11:00 AM-2:00 PM, and 4:00 PM-7:00 PM). ...
... Sucrose preference was assessed in male PS offspring using a modified version of the sucrose preference test (Zhu et al., 2004). The sucrose consumption tests were performed using a two bottle test, with rats having free access to both water and a sucrose solution. ...
... We used the forced swimming test to assess depression-like behavior in male PS offspring. The forced swimming test procedure was conducted according to previous reports (Zhu et al., 2004). Rats were forced to swim in a cylindrical tank (height, 50 cm; diameter, 20 cm) filled with water (23-25°C) to a depth of 40 cm for 8 min. ...
... Pregnant rats were separately exposed to restraint stress on days 14-20 of pregnancy three times daily for 45 min, as described previously (Zhang et al., 2013;Zhu et al., 2004). To prevent the adaptation of animals to the daily procedure, restraint periods were shifted randomly within certain time periods (08:00 a.m.-11:00 a.m., 11:00 a.m.-2:00 p.m., and 4:00 p.m.-7:00 p.m.). ...
... Many studies have shown that the LTP of the hippocampus is a basic necessity for learning and memory formation (Popoli et al., 2012). Previous study have also demonstrated that the number of hippocampal neurons is decreased in offspring rats exposed to PS, and especially in female offspring (Zhu et al., 2004). During chronic stress, enhanced activity of the HPA axis results in elevated circulating glucocorticoid concentrations. ...
... The hippocampus is rich in GR and has been recognized as a primary target for brain effects of glucocorticoids. Indeed, chronic secretion of glucocorticoids induced by stress increases the incidence of hippocampal neuron loss in both rats and primates (Jia et al., 2009;Zhu et al., 2004). Moreover, evidence indicates that the response of the HPA axis to stress is sexually dimorphic; especially, basal and stressinduced increases in corticosterone levels in females were more remarkable than that in males exposed to PS (Harris & Seckl, 2011). ...
Prenatal stress (PS) can lead to impaired spatial learning and memory in offspring. Imperatorin (IMP) is a naturally occurring furanocoumarin with many pharmacological properties. However, the effects of IMP on cognitive impairment induced by PS and the underlying molecular mechanisms remain unclear. We investigated the protective effect of IMP treatment after PS on learning and memory deficits in female offspring at postnatal 60 days. After treating prenatally‐stressed offspring with IMP (15 and 30 mg/kg) for 28 days, we found that IMP increased body weight and ameliorated spatial learning and memory and working memory deficits in female offspring rats. Meanwhile, hippocampal Glu and serum corticosterone levels in prenatally‐stressed offspring were significantly decreased after IMP administration. Additionally, IMP treatment significantly increased BDNF, TrkB, CaMKII, and CREB mRNA expression in the hippocampus of offspring rats. Furthermore, PS‐mediated induction of RKIP protein and mRNA expression and glucocorticoid receptor protein expression in the hippocampus of offspring rats were significantly decreased by IMP treatment, and the protein expression of BDNF and TrkB and relative levels of p‐EKR/ERK, p‐CaMKIIα/CaMKIIα, and p‐CREB/CREB were remarkably increased after IMP treatment. Taken together, IMP can ameliorate PS‐induced learning and memory deficits through BDNF/TrkB and ERK/CaMKIIα/CREB signaling pathway and hypothalamic–pituitary–adrenal axis.
... Animals were sacrificed by cardiac perfusion with 4% paraformaldehyde under anesthesia. The whole brains were removed and processed to paraffin, sectioned at a thickness of 4 μm, and stained with toluidine blue, which is referred to the previous study [27]. For quantitative studies, neurons in the area of CA3 regions were counted using five equally spaced coronal sections passing through the hippocampus for each brain and quantified by Image-J software. ...
... Sections were washed with PBS for 5 min × 3 times, and blocked with 5% BSA for 30 min and incubated in anti-Ng and antic-fos (1:500) primary antibody diluted in 5% BSA overnight at 4°C, then further incubated with rat anti-rabbit IgG (30 min, 37°C). After staining with Mayer' hematoxylin for the nucleus, sections were mounted on poly-L-lysine-coated glass slides, dehydrated, and covered with coverslips by permount tm mounting medium, which can be referred to previous studies [27]. Imaging (400 ×) was performed using a Nikon Ti-U camera connected to a Nikon Eclipse Timicroscope. ...
... Moreover, disparate responses between males and females are observed not only in terms of basal levels of adrenocorticotropic hormone and corticosterone but more strikingly with respect to the hormonal response of offspring to stress. Researchers have demonstrated that the number of hippocampal neurons is decreased in offspring rats exposed to PS, especially in female offspring [27,32]. The levels of corticosterone in dams and offspring in response to prenatal stress were also found to be positively correlated [33]. ...
Background:
Prenatal stress (PS) leads to a wide variety of behavioral and emotional aberration observed in later life, particularly in the impairment of spatial learning and memory in offspring. Icariin (ICA) is a naturally occurring furanocoumarin and exhibits many pharmacological properties, including potent improvement on learning and memory.
Purpose:
We pretend to investigate the improvement of ICA on learning and memory impairment in PS.
Methods:
Female PS offspring rats were used to explore the effects of ICA on learning and memory impairment. After 28 days of ICA (20, 40 and 80 mg/kg/day) treatment, we measured Morris water maze and 8-Arm Maze, the HPA axis and the related pathway in the hippocampus.
Results:
We reported that ICA ameliorated the spatial learning and memory and working memory impairment in the female offspring rats. Correspondingly, ICA prevented adverse changes in the dendritic morphology of CA3 pyramidal neurons in the hippocampus. ICA significantly decreased the serum adrenocorticotropin, corticotropin-releasing hormone and corticosterone levels in offspring rats exposed to PS, associated with increased GR expression. Additionally, ICA treatment significantly increased the neurogranin (Ng) and c-fos protein expression of hippocampus in the offspring rats. Furthermore, the protein of relative content of p-EKR/ERK, p-CaMKIIα/CaMKIIα, p-CREB/CREB were remarkably increased after ICA treatment in the offspring rats.
Conclusion:
Taken together, ICA may be an effective therapeutic for learning and memory dysfunction in female offspring exposed to PS, its neuroprotective effect was mediated in part by normalizing the HPA axis and up-regulating of ERK/CaMKIIα/CREB signaling, Ng and c-fos protein.
... There is no direct neural connection between the mother and fetus, the alterations of neuronal morphology induced by maternal stress are produced by the action of hormones at crucial periods of development. Prolonged GC exposure of the mother can reduce the number of hippocampal neurons of the offspring [10]. The hippocampus is particularly vulnerable to the effects of GCs because of the highest density of glucocorticoid receptor (GR) within the brain, which is intrinsically linked to both learning and memory and emotion. ...
... The hippocampus highly expresses GR, and is particularly vulnerable to GCs manipulations, especially in early life. Prolonged GCs may cause increased activation of excitatory amino acid receptors, including ionotropic glutamate receptors and metabotropic glutamate receptors, and unregulated increases in intracellular Ca 2+ concentrations, and consequently, increased generation of oxidants, oxidative and inflammatory damage in males [10]. In our study, the hippocampal nNOS expression in offspring rats was measured and found that the nNOS expression in offspring increased significantly in the PS group. ...
... Animals were sacrificed by cardiac perfusion with 4% paraforaldehyde under anesthesia. The whole brains were removed and processed in paraffin, sectioned at a thickness of 4 µm, and stained with toluidine blue, which are referred to the previous study [10]. For quantitative studies, neurons in the area of CA3 regions were counted using five equally spaced coronal sections passing through the hippocampus for each brain, and quantified by Image-J software. ...
Prenatal stress (PS) can increase the risk of nervous, endocrine and metabolic diseases, and immune dysfunction. Ferulic acid (FA) is a dietary phenolic acid that has pharmacological properties, including potent anti-inflammatory action. We used male, prenatally-stressed offspring rats to investigate the anti-depressive-like effects and possible anti-inflammatory mechanism of FA. We determined the animal behaviors, and the mRNA expression and concentration of inflammatory cytokines, and HPA axis. In addition, we assessed the modulation of hippocampal nuclear factor-κB (NF-κB) activation, neuronal nitric oxide synthase (nNOS) and glucocorticoid receptors (GR) expression via western blotting and immunohistochemistry. Administration of FA (12.5, 25, and 50 mg/kg/day, i.g.) for 28 days markedly increased sucrose intake, and decreased immobility time and total number of crossings, center crossings, rearing, and grooming in the male PS offspring. FA significantly reduced IL-6, IL-1β, and TNF-α concentration and increased IL-10 concentration in male, prenatally-stressed offspring, stimulated by the NF-κB pathway. In addition, FA inhibited interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), and increased interleukin-10 (IL-10) mRNA and protein expression. Furthermore, FA markedly decreased the serum adrenocorticotropin (ACTH) and corticosterone concentration by the increase of GR protein expression. Taken together, this study revealed that FA has anti-depressive-like effects in male, prenatally-stressed offspring, partially due to its anti-inflammatory activity and hypothalamic-pituitary-adrenal (HPA) axis.
... Disruptions in glutamate release have been found in the prefrontal cortex and hippocampus following acute stress (Musazzi et al., 2010); however, the study of glutamate transmission in animals exposed to chronic stress is still in its infancy. PS rats represent a model of stress-related disorders that demonstrates construct validity as it replicates the unfavorable environmental factors that occur in the etiology of depression and anxiety (Beneyto et al., 2007;Morley Fletcher et al., 2013;Sun et al., 2013a;Sun et al., 2013b;Zhu et al., 2004). In a previous work, we found that PS significantly increased glutamate concentration in the hippocampus, increased N-methyl-D-aspartate receptor protein levels (NMDAR), and excitatory amino acid transporters (EAATs) in the rat offspring (Jia et al., 2009). ...
... The pregnant rats were separately exposed to restraint stress on days 14-20 of pregnancy three times daily for 45 min, as described previously (Zhu et al., 2004). A transparent plastic tube (6.5 cm in diameter) with breathing holes was used as the restraint device. ...
... All rat offspring were tested using a modified version of the Forced swimming test (FST) as described previously (Zhu et al., 2004). All rat offspring were forced to swim in a cylindrical tank (20 cm in diameter; 50 cm in height; 40 cm in depth) filled with water (25 ± 2°C) for 8 min. ...
... Environmental enrichment or pharmacological strategies are other manipulations in pregnancy which is believed to positively affect the PS-induced neurological and behavioral complications (Darnaudéry & Maccari, 2008;Weinstock, 2002). Given that neuroinflammation and oxidative stress have been implicated as potential mediators of behavioral consequences of PS (Bernhardt et al., 2017;Calcia et al., 2016;Chen et al., 2020;Hantsoo et al., 2019;Zhu et al., 2004), maternal anti-inflammatory and antioxidant treatments thus may prevent the adverse effects of PS on the offspring's brain and behavior (Cao et al., 2014;Kwon et al., 2021;Lipton et al., 2017;Luft et al., 2021;Madhyastha et al., 2014;Scott et al., 2020;Ślusarczyk et al., 2016;Trojan et al., 2019). However, synthetic medications in current use for the complex etiopathogeneses of stress during pregnancy have slow responses as well as various unpleasant and severe side effects. ...
... Increased oxidative stress is a well-accepted mechanism in mediating the adverse effects of PS on the offspring's early development of brain and behavior (Dowell et al., 2019;Madhyastha et al., 2014;Zhu et al., 2004). Consistently, the present data support a role for oxidative stress in mediating the long-lasting effects of PS on anxiety-like and stresscoping behaviors and raise the possibility of treating oxidative stress to prevent neurodevelopmental programming by PS. ...
Prenatal manipulations can lead to neurobehavioral changes in the offspring. In this study, individual and combined effects of forced exercise and zinc supplementation during pregnancy on prenatally restraint stress (PRS)‐induced behavioral impairments, neuro‐inflammatory responses, and oxidative stress have been investigated in adolescent female rat offspring. Pregnant rats were divided into five groups: control; restraint stress (RS); RS + exercise stress (RS + ES), RS + zinc supplementation (RS + Zn); and RS + ES + Zn. All the pregnant rats (except control) were exposed to RS from gestational days 15 to 19. Pregnant rats in ES groups were subjected to forced treadmill exercise (30 min/daily), and in Zn groups to zinc sulfate (30 mg/kg/orally), throughout the pregnancy. At postnatal days 25–27, anxiety‐like and stress‐coping behaviors were recorded, and the gene expressions of interleukin‐1β (IL‐1β) and tumor necrosis factor‐α (TNF‐α) and the concentration of total antioxidant capacity were measured in the prefrontal cortex. PRS significantly enhanced anxiety, generated passive coping behaviors, increased IL‐1β and TNF‐α expression, and decreased the antioxidant capacity. ES potentiated while zinc reversed PRS‐induced behavioral impairments. Prenatal zinc also restored the anti‐inflammatory and antioxidant capacity but had no effect on additive responses imposed by the combination of RS and ES. Suppression of PRS‐induced behavioral and neurobiological impairments by zinc suggests the probable clinical importance of zinc on PRS‐induced changes on child temperament.
... In addition, both downregulation of components of the antioxidant synthesis and increases of reactive oxygen species (ROS) have been observed in patients with ischemic disease (28). So, administration the PFT in animals could decrease oxidative stress and improve antioxidant capacity, even for the short time (few hours). ...
... So, administration the PFT in animals could decrease oxidative stress and improve antioxidant capacity, even for the short time (few hours). Other authors also confirmed these results, such as reducing the production of free radicals and the number of pulmonary structural where changes resulting from cold ischemia (28,29). ...
The aim of this research was to examine the influence of the intraperitoneal application of PFT in different doses and regimen on systemic oxidative stress and activity of antioxidative enzymes in animals. Depending on whether the animals received only saline or PFT in different doses (8, 12, 16 ml/kg body weight), and time (1, 10, or 20 hours before sacrificing and blood sampling), all animals were divided into control or experimental groups. From plasma samples we measured following biomarkers of oxidative stress: superoxide anion radical (O2−), hydrogen peroxide (H2O2), nitrites (NO2−), index of lipid peroxidation measured as TBARS (thiobarbituric acid reactive substances), and from hemolysate samples activity of the next enzymes: catalase (CAT), superoxidedismutase (SOD) and reduced glutathione (GSH). All mentioned biochemical parameters of oxidative stress were determined spectrophotometrically (Shimadzu UV-1800UV-VIS spectrophotometer, Japan). Superoxide anion radical was a molecule very affected with the PFT administration. we observed the significantly higher activity of superoxide dismutase in all PFT treated groups in comparison with the CTRL group. The highest activity was observed in group treated with the 8 and 12 ml/kg of PFT nearly to sampling (1 hour). Catalase activity was significantly higher in PFT group in comparison with the CTRL, especially in PFT 16ml/kg group (1 hour). In comparison with the CTRL group, the total content of GSH was significantly lower in the groups treated PFT in dose of 16 ml/kg 1 hour and 10 hours before blood sampling. All these changes in oxidative stress markers seems to be very clear, but we can observe that almost all changes are induced in 1 hour after PFT administration. Probably, PFT solution has short-term protective effects on reducing oxidative stress, but no long term-effects. Maybe the chemical and biological instability of PFT solution could be a reason for that transient antioxidative effects, and developing the nano-formulation of PFT could be potential option for resolving the problem with poor pharmacodynamic of PFT.
... The interaction observed for the hippocampusis consistent with preclinical observations of alterations in hippocampal structure in female but not male offspring after prenatal stress (e.g. Zhu et al., 2004;Behan et al., 2011;Bock et al., 2011). These studies reported neuronal loss, glial deficits and loss of dendritic complexity in prepubertal female rodents. ...
... These studies reported neuronal loss, glial deficits and loss of dendritic complexity in prepubertal female rodents. However, neuronal loss is a gradual process (Zhu et al., 2004), and it remains unclear to what extent such structural deficits in the hippocampus occur in the newborn period (Weinstock, 2011). More basic and clinical research is needed to gain insight into the developmental trajectories of amygdala and hippocampus volumes in male and female children exposed to AMD, and their association with the subsequent onset of child psychopathology. ...
Background
Several studies have reported enlarged amygdala and smaller hippocampus volumes in children and adolescents exposed to maternal depression. It is unclear whether similar volumetric differences are detectable in the infants’ first weeks of life, following exposure in utero. We investigated subcortical volumes in 2-to-6 week old infants exposed to antenatal maternal depression (AMD) from a South African birth cohort.
Methods
AMD was measured with the Beck Depression Inventory 2nd edition (BDI-II) at 28-32 weeks gestation. T2-weighted structural images were acquired during natural sleep on a 3T Siemens Allegra scanner. Subcortical regions were segmented based on the University of North Carolina neonatal brain atlas. Volumetric estimates were compared between AMD-exposed (BDI-II⩾20) and unexposed (BDI-II<14) infants, adjusted for age, sex and total intracranial volume using analysis of covariance.
Results
Larger volumes were observed in AMD-exposed (N=49) compared to unexposed infants (N=75) for the right amygdala (1.93% difference, p=0.039) and bilateral caudate nucleus (left: 5.79% difference, p=0.001; right: 6.09% difference, p<0.001). A significant AMD-by-sex interaction was found for the hippocampus (left: F(1,118)=4.80, p=0.030; right: F(1,118)=5.16, p=0.025), reflecting greater volume in AMD-exposed females (left: 5.09% difference, p=0.001, right: 3.54% difference, p=0.010), but not males.
Conclusions
Volumetric differences in subcortical regions can be detected in AMD-exposed infants soon after birth, suggesting structural changes may occur in utero. Female infants might exhibit volumetric changes that are not observed in male infants. The potential mechanisms underlying these early volumetric differences, and their significance for long-term child mental health, require further investigation.
... Therefore, protection during this period of gestation needs ample attention, which requires understanding of probable mechanisms involved during late stages of gestation in inducing neurobehavioral deficits. An increased level of circulating glucocorticoids and its extensive impact on the developing brain [45] as well as altered expression of brain derived neurotrophic factor and brain monoamines [7], the possible involvement of oxidants and the relation to glucocorticoid hormones in stress have been proposed [46]. An enhanced glucocorticoid effect can compromise mitochondrial respiration and, Figure 4. Effect of prenatal stress and NAC on whole brain homogenate serotonin levels (nmol/mL) at PND 36 in rat offspring. ...
... Therefore, protection during this period of gestation needs ample attention, which requires understanding of probable mechanisms involved during late stages of gestation in inducing neurobehavioral deficits. An increased level of circulating glucocorticoids and its extensive impact on the developing brain [45] as well as altered expression of brain derived neurotrophic factor and brain monoamines [7], the possible involvement of oxidants and the relation to glucocorticoid hormones in stress have been proposed [46]. An enhanced glucocorticoid effect can compromise mitochondrial respiration and, thereby, contribute to ROS production. ...
Prenatal adversaries like stress are known to harm the progeny and oxidative stress, which is known to be one of the causative factors. N-acetyl cysteine (NAC), which is a potent antioxidant, has been shown to play a neuroprotective role in humans and experimental animals. This study examines the benefits of NAC on the prenatal stress-induced learning and memory deficits and alteration in brain neurotransmitter in rat pups. Pregnant dams were restrained (45 min; 3 times/day) during the early or late gestational period. Other groups received early or late gestational restrain stress combined with NAC treatment throughout the gestational period. At postnatal day (PND) 28, offspring were tested in a shuttle box for assessing learning and memory, which was followed by a brain neurotransmitter (dopamine, norepinephrine, and serotonin) estimation on PND 36. Late gestational stress resulted in learning deficits, the inability to retain the memory, and reduced brain dopamine content while not affecting norepinephrine and serotonin. NAC treatment in prenatally stressed rats reversed learning and memory deficits as well as brain dopamine content in offspring. These findings suggest that NAC protect the progeny from an undesirable cognitive sequel associated with prenatal stress.
... Hormones and Behavior 94 (2017) 135-144 glucocorticoids (Lupien et al., 2009). The negative association observed in girls, but not in boys, between evening salivary cortisol levels and long-term declarative memory is in line with previous studies that describe greater hippocampal stress-related sensitivity in females, both human and non-human (Buss et al., 2007;Zhu et al., 2004). Across the brain as a whole, the highest GR concentration is found in the hippocampus (De Kloet et al., 1998), and the GR system is differentially affected by stress in males and females, with the latter possibly being more prone to dysregulation (Bourke et al., 2012). ...
... However, a study conducted in young adolescents did report negative long-term associations between high evening salivary cortisol levels and declarative memory (Vaillancourt et al., 2011). Our results are also consistent with animal studies that have reported a negative effect of stress hormones on hippocampus structure and function (Liu et al., 2000;Zhu et al., 2004). ...
Stress system activity in early life can have long-term effects on neurodevelopment. The main aim of this study was to assess the association of child evening salivary cortisol and alpha-amylase basal levels at 14 months of age with longer-term neuropsychological development at 4 years in a low-risk population-based birth cohort derived from the INMA (Environment and Childhood) project in Spain. We included 186 parent-children pairs with information on both stress system activity and neurodevelopment. Both stress markers at 14 months of age showed an association with neuropsychological development at 4 years. Salivary cortisol showed a sex-specific pattern of association. In girls, cortisol levels at 14 months were negatively associated with cognitive development [long-term declarative memory (β = − 17.8, p = 0.028; 95% CI = − 33.2 to − 2.5); executive function (β = − 9.8, p = 0.08; 95% CI = − 21 to 1)] and gross motor development (β = − 13; p = 0.022; 95% CI = − 24 to − 2), whereas in boys cortisol levels were negatively associated with socioemotional development [autistic-like behaviours: Incidence Rate Ratio (IRR) = 1.6, p = 0.039; 95% CI = 1.01 to 2.41]. Salivary alpha-amylase was positively associated with socioemotional development in boys only [social competence (β = 2.11, p = 0.013; 95% CI = 0.47 to 3.72), autistic-like behaviours (IRR = 0.93, p = 0.042; 95% CI = 0.87 to 0.99) and hyperactivity symptoms (IRR = 0.81, p = 0.021; 95% CI = 0.69 to 0.97)]. These results suggest that stress system activity in early life is associated with longer-term neurodevelopment and that sex is an important factor in this relationship.
... However, when the stressor occurred in the middle or late stages of pregnancy (MS and LS), it caused a significant decrease in the number of hippocampal neurons in the female, but not in the male offspring. LS significantly increased the oxidant factors in the CA3 region in PS female, which was suggested to cause oxidative stress and consequently, damage to hippocampal neurons(V'Iushina et al., 2012;Zhu et al., 2004). Another mechanism proposed to induce hippocampal pyramidal neuronal damage and cognitive dysfunction in PS involved oxidative mitochondrial DNA damage based on increases noted in the level of 8-hydroxy-2′-deoxyguanosine (8-OH-dG; the major end-product of damaged DNA caused by ROS). ...
Distressing events during pregnancy that engage activity of the body's endocrine stress response have been linked with later life cognitive deficits in offspring and associated with developmental changes in cognitive‐controlling neural regions. Interestingly, prenatal stress (PS)‐induced alterations have shown some sex specificity. Here, we review the literature of animal studies examining sex‐specific effect of physical PS on the function and structure of the hippocampus as hippocampal impairments likely underlie PS‐associated deficits in learning and memory. Furthermore, the connectivity between the hypothalamic–pituitary–adrenal (HPA) axis and the hippocampus as well as the heavy presence of glucocorticoid receptors (GRs) in the hippocampus suggests this structure plays an important role in modulation of activity within stress circuitry in a sex‐specific pattern. We hope that better understanding of sex‐specific, PS‐related hippocampal impairment will assist in uncovering the molecular mechanisms behind sex‐based risk factors in PS populations across development, and perhaps contribute to greater precision in management of cognitive disturbances in this vulnerable population.
... However, few study elucidated the underlying mechanism. A growing number of literatures suggested the possible involvement of oxidative stress in the association between maternal psychological stress and fetal hearing impairment [42,43]. Oxidative damage was one of the most widely accepted pathogenic mechanism underlying diverse birth deficits or disorder, and played a key role in hearing impairment caused by heavy metal and noises [44,45]. ...
Background
Newborn hearing screening results indicated that more than 40% of the detected infants had no recognized risk factors. To determine whether maternal exposure to ambient air pollutants and experience of stressful life event, as well as lack of fresh fruit and vegetable during pregnancy are associated with the abnormal hearing development among newborns.
Methods
A total of 1193 newborns and their mothers were recruited in this study. Personal information and covariates were collected by face to face interview. Medical examination results of newborns and their mothers were extracted from medical record. We estimated personal air pollutant exposure level through inverse distance weighted method based on data from air quality monitoring stations and assessed the auditory development of newborns via distortion product otoacoustic emission (DPOAE). Unconditional logistic regression model was used to estimate the relationship between DPOAE screening result and the potential influential factors as well as the combined effect.
Results
The results indicated that PM 10 exposure during the second trimester and stressful life event during the third trimester could increase the risk of not passing DPOAE test among newborns. However, frequent intakes of fruit and vegetable significantly reduced the risk. There was a synergetic interaction between PM 10 exposure and stressful life event on neonatal hearing development.
Conclusions
To alleviate abnormal auditory development among fetus, pregnant woman should decrease the exposures to ambient air pollutant and negative life event and at the same time, intake sufficient fresh fruit and vegetable.
... However, prolonged inflammation and disturbance in immune homeostasis can lead to an oxidative stress condition and more severe damage of cellular and tissue structures. Restraint stress at late-stage of pregnancy in rats caused increased intracellular ROS, loss of hippocampal neurons and activation of NF-kB signaling (Zhu et al., 2004;Cai et al., 2007). In the same animal model, oxidative damage in mitochondrial DNA in hippocampal neurons only in females rat offspring was reported (Song et al., 2009). ...
A growing body of evidence highlights that several insults during pregnancy impact the vascular function and immune response of the male and female offspring. Overactivation of the immune system negatively influences cardiovascular function and contributes to cardiovascular disease. In this review, we propose that modulation of the immune system is a potential link between prenatal stress and offspring vascular dysfunction. Glucocorticoids are key mediators of stress and modulate the inflammatory response. The potential mechanisms whereby prenatal stress negatively impacts vascular function in the offspring, including poor hypothalamic–pituitary–adrenal axis regulation of inflammatory response, activation of Th17 cells, renin–angiotensin–aldosterone system hyperactivation, reactive oxygen species imbalance, generation of neoantigens and TLR4 activation, are discussed. Alterations in the immune system by maternal stress during pregnancy have broad relevance for vascular dysfunction and immune-mediated diseases, such as cardiovascular disease.
... This study demonstrated that supplementation with Tualang honey during pregnancy has increased the offspring's pain threshold to phasic as well as tonic pain. Prenatal stress has been shown to result in hypercortisolemia, leading to alterations in the brain including changes in endocannabinoid levels in the hippocampus and production of oxidative stress [76]. These changes contribute to neuronal loss in the brain of offspring during fetal development [77]. ...
Tualang honey has been shown to protect against neurodegeneration, leading to improved memory/learning as well as mood. In addition, studies have also demonstrated its anti-inflammatory and antioxidant properties. However, a substantial part of this research lacks systematization, and there seems to be a tendency to start anew with every study. This review presents a decade of research on Tualang honey with a particular interest in the underlying mechanisms related to its effects on the central nervous system. A total of 28 original articles published between 2011 and 2020 addressing the central nervous system (CNS) effects of Tualang honey were analysed. We identified five main categories, namely nootropic, antinociceptive, stress-relieving, antidepressant, and anxiolytic effects of Tualang honey, and proposed the underlying mechanisms. The findings from this review may potentially be beneficial towards developing new therapeutic roles for Tualang honey and help in determining how best to benefit from this brain supplement.
... Preclinical studies have already identified an important relationship between prenatal stress and the brain activation of the immune system (Enayati et al., 2020;Sowa et al., 2017;Zhang et al., 2016) and oxidative stress response (Song et al., 2009;Zhu et al., 2004), contributing to the development of neurological diseases throughout life. The activation of an immunosuppressive phenotype is characterized by the increased exposure to glucocorticoids, promoting an imbalance in the levels of inflammatory pathways, lipid peroxidation and antioxidant defenses (Coutinho and Chapman, 2011). ...
Maternal stress has been described as an important component in the offspring's cerebral development, altering the susceptibility to diseases in later life. Moreover, the postnatal period is essential for the development and integration of several peripheral and central systems related to the control of homeostasis. Thus, this study aimed to evaluate the effects of prenatal stress on the activation of cortical neurons, by performing experiments both under basal conditions and after KCl-induced depolarization. Female mice were divided in two groups: control and prenatal restraint stress. Cortical neurons from the offspring were obtained at gestational day 18. The effects of prenatal stress and KCl stimulations on cellular mortality, autophagy, gene expression, oxidative stress, and inflammation were evaluated. We found that neurons from PNS mice have decreased necrosis and autophagy after depolarization. Moreover, prenatal stress modulated the HPA axis, as observed by the increased GR and decreased 5HTr1 mRNA expression. The BDNF is an important factor for neuronal function and results demonstrated that KCl-induced depolarization increased the gene expression of BDNF I, BDNF IV, and TRκB. Furthermore, prenatal stress and KCl treatment induced significant alterations in oxidative and inflammatory markers. In conclusion, prenatal stress and stimulation with KCl may influence several markers related to neurodevelopment in cortical neurons from neonate mice, supporting the well-known long-term effects of maternal stress.
... High levels of glucocorticoids as a physiological response to PS stimulate postsynaptic excitatory receptors by over-releasing glutamate. Consequently, increased intracellular Ca+2 concentration leads to seizure susceptibility and oxidative stress which may cause neuronal loss in the developing hippocampus [11,12]. However, the long-term effects of PS and early acute seizure on the oxidative stress markers, synaptic transmission and neuronal denstiy of hippocampus need to be clarified. ...
Objectives: This study aimed to investigate the effects of prenatal stress (PS) on hippocampus of early acute pentylenetetrazole (PTZ)-kindled offspring in adolescence. Recognition memory, morphological changes and synaptophysin levels in hippocampus were evaluated. Methods: Restraint stress was induced to a group of pregnant dams and non-stressed (NA) group remained undisturbed. Next, male and female offspring were divided as 1. PS-PTZ, 2. PS-control, 3. NA-PTZ and 4. NA-control (n = 12 in each group). The object recognition test was performed following PTZ injection (45 mg/kg) on postnatal day 10 (P10). Brains were collected on postnatal day 35 (P35) to determine neuronal density and synaptophysin expression by immuno/-histological studies. Further, oxidative stress products in hippocampus were analyzed with different biochemical assays. Results: PS impaired recognition memory in PTZ group significantly (p = 0.03); however, the impairment of PS was reversible in control group compared to PTZ (p = 0.04). Furthermore, PS caused neuronal loss in CA1 (p = 0.01) and decreased synaptophysin expression in the CA3 area of hippocampus in PTZ group (p = 0.03). PS also increased the oxidative stress markers in PTZ group significantly (p < 0.05). Conclusions: These results suggest that PS causes neurodevelopmental deficits in adolescent hippocampus and recognition memory after early-life seizures prominently. However, the damage of only PS in adolescence can be reversible. Therefore, the effects of PS in the adult hippocampus and other regions of brain need to be further studied
... Early life adversity, for instance, maternal separation, favors oxidative stress in parvalbumin-(PV-) positive neurons [119] (more on the role of parvalbumin-expressing neurons is discussed further). Prenatal stress also supports oxidative stress and neuronal loss in the rat hippocampus [120]. At the same time, human epidemiological studies confirm that prenatal stress due to grief, famine, and major disasters has effects on vulnerability to schizophrenia [121]. ...
Schizophrenia is recognized to be a highly heterogeneous disease at various levels, from genetics to clinical manifestations and treatment sensitivity. This heterogeneity is also reflected in the variety of oxidative stress-related mechanisms contributing to the phenotypic realization and manifestation of schizophrenia. At the molecular level, these mechanisms are supposed to include genetic causes that increase the susceptibility of individuals to oxidative stress and lead to gene expression dysregulation caused by abnormal regulation of redox-sensitive transcriptional factors, noncoding RNAs, and epigenetic mechanisms favored by environmental insults. These changes form the basis of the prooxidant state and lead to altered redox signaling related to glutathione deficiency and impaired expression and function of redox-sensitive transcriptional factors (Nrf2, NF-κB, FoxO, etc.). At the cellular level, these changes lead to mitochondrial dysfunction and metabolic abnormalities that contribute to aberrant neuronal development, abnormal myelination, neurotransmitter anomalies, and dysfunction of parvalbumin-positive interneurons. Immune dysfunction also contributes to redox imbalance. At the whole-organism level, all these mechanisms ultimately contribute to the manifestation and development of schizophrenia. In this review, we consider oxidative stress-related mechanisms and new treatment perspectives associated with the correction of redox imbalance in schizophrenia. We suggest that not only antioxidants but also redox-regulated transcription factor-targeting drugs (including Nrf2 and FoxO activators or NF-κB inhibitors) have great promise in schizophrenia. But it is necessary to develop the stratification criteria of schizophrenia patients based on oxidative stress-related markers for the administration of redox-correcting treatment.
... 5,6 The oxidative stress may contribute to damage of the neurons in the hippocampus of offspring and impairment of memory function. 7 Another report has shown that stress-induced elevation of N-methyl-D-aspartate (NMDA) receptors and corticosterone might mediate reduced learning ability, impaired memory, and other stress-induced neurologic disorders. 8 Studies have demonstrated that the hippocampus of prenatally stressed animals, e.g. ...
Objectives:
This study investigated whether the alterations in memory and hippocampus morphology and levels of malondialdehyde (MDA) and N-methyl-D-aspartate (NMDA) receptor in the hippocampus of adult rats after prenatal stress could be prevented by administration of Tualang honey (TH).
Materials and methods:
Twenty-four pregnant rats were randomly grouped into a control group (C), a stress group (S), and a stress group treated with TH. Eight male pups from each group were randomly chosen and they were sacrificed at eight or ten weeks of age following the novel object recognition test. Their brains were removed and histological changes and levels of MDA and NMDA receptors in the hippocampus were determined.
Results:
The offspring from TH group showed significantly increased preference index (p<0.05) with higher neuronal number compared to S group. A significantly lower level of MDA and NMDA receptors were shown in TH group (P<0.01; P<0.05 respectively) compared to S group. The parameters investigated were not significantly different between C and TH groups.
Conclusion:
The study has shown that memory alteration, changes in hippocampus histology, MDA and NMDA receptor levels could be prevented by TH administration during prenatal stress. The results suggest the beneficial effects of Tualang honey in prenatally stressed rat offspring.
... Immersion in cold water induces very high (more than 200%) concentrations of maternal glucocorticoids (Guerrero et al, 2016;García-Vargas et al., 2019). High concentrations of maternal corticosterone cause neuronal degeneration in the hippocampus (Sousa et al., 2000) and induce the loss of hippocampal neurons (Zhu et al., 2004), disrupt fetal hippocampus development as well as neurogenesis in adult life in males and females (Guerrero et al., 2016), retraction and atrophy of dendrites in the CA3 pyramidal neurons of the hippocampus (Conrad, 2006;Hosseini-Sharifabad and Hadinedoushan, 2007), leading to cognitive deficiencies in adulthood (Luine et al., 1994;Sunanda et al, 2000). In addition to the above evidence, the results of the present study show that prenatal stress also alters 5-HT and NA during cognitive processes. ...
Prenatal stress causes learning and spatial memory deficits in adulthood by modifying hippocampal function. The dorsal hippocampus contains serotonergic and noradrenergic neuron terminals, which are related to cognitive processes. It is currently unknown whether prenatal stress modifies serotonin (5-HT) and noradrenaline (NA) content and their release in the hippocampus during cognitive performance. Therefore, we measured these variables in the dorsal hippocampus of prenatally stressed males during spatial learning and memory tests. Cognitive tests were performed in 3-month-old control and prenatally stressed male rats in the Morris Water Maze (MWM). After cognitive tests, the dorsal hippocampus was dissected to quantify 5-HT and NA content. In other males, 5-HT and NA release in the dorsal hippocampus was assessed by microdialysis, before and after cognitive tests. Prenatally stressed males showed longer latencies to reach the platform, compared to control animals. Hippocampal 5-HT content decreased during learning and memory tasks in both groups, while NA content was not modified in prenatally stressed males neither before, nor after learning and memory tests. 5-HT and NA release were significantly lower in prenatally stressed animals during spatial learning and memory tasks. Corticosterone response was greater in prenatally stressed animals compared to controls. These results show that cognitive disruption caused by prenatal stress is related to decreased 5-HT and NA release, and to higher adrenal axis response in prenatally stressed animals.
... Experimental models of early-life stress have already been associated with alterations on oxidative status and, thus, reported associations between altered mitochondrial respiratory chain, increased neuronal damage, decreased neuronal population in the hippocampus and impairments in spatial memory (Marković et al. 2017;Noschang et al. 2010;Zhu et al. 2004). These impairments can be associated with the fact that the hippocampus is a susceptible region to both behavioral early life alterations and the effects of oxidative stress (Huang 2014;Salim 2017;Wang and Michaelis 2010;Youssef et al. 2019). ...
Early life stress (ELS) exposure is a well-known risk factor for the development of psychiatric conditions, including anxiety disorder. Preclinical studies show that maternal separation (MS), a classical model of ELS, causes hypothalamic–pituitary–adrenal (HPA) axis alterations, a key contributor to the stress response modulation. Given that HPA axis activation has been shown to induce oxidative stress, it is possible to hypothesize that oxidative stress mediates the relationship between chronic ELS exposure and the development of several disorders. Here, we investigate the effects of MS in the oxidative status [plasma and brain reduced glutathione, catalase and thiobarbituric acid reactive substances (TBARS)], metabolism (glucose, triglycerides and cholesterol) and anxiety-like behaviors in adult Balb/cJ mice. In short, we found that MS increased anxiety-like behaviors in the open field, light/dark test but not in the elevated-plus maze. Animals also presented increased circulating cholesterol, increased TBARS in the plasma and decreased catalase in the hippocampus. Our findings suggest that MS induces long-term alterations in oxidative stress and increased anxiety-like behaviors.
... Maternal stress during pregnancy can affect fetal brain development and exert profound neurobiological effects on postnatal motor and affective development (Wadhwa et al., 2001;Huizink et al., 2003). Studies have shown that dams suffering stress during pregnancy exhibit hippocampal neuronal loss and reduced neurogenesis (Zhu et al., 2004;Lucassen et al., 2009), while prenatal stress in the rat causes long-term spatial memory deficits and hippocampal abnormalities as detected by magnetic resonance imaging (Liu et al., 2011). These studies on animals demonstrate the importance of exploring whether stress in adolescence accelerates the AISLM induced by prenatal exposure to inflammation. ...
Age-associated impairment of spatial learning and memory (AISLM) presents substantial challenges to our health and society. Increasing evidence has indicated that embryonic exposure to inflammation accelerates the AISLM, and this can be attributable, at least partly, to changed synaptic plasticity associated with the activities of various proteins. However, it is still uncertain whether social psychological factors affect this AISLM and/or the expression of synaptic protein-associated genes. Synaptotagmin-1 (Syt1) and activity-regulated cytoskeleton-associated protein (Arc) are two synaptic proteins closely related to cognitive functions. In this study, pregnant CD-1 mice received daily intraperitoneal injections of lipopolysaccharide (LPS) (50 μg/kg) or normal saline at days 15–17 of gestation, and half of the offspring of each group were then subjected to stress for 28 days in adolescence. The Morris water maze (MWM) test was used to separately evaluate spatial learning and memory at 3 and 15 months of age, while western blotting and RNAscope assays were used to measure the protein and mRNA levels of Arc and Syt1 in the hippocampus. The results showed that, at 15 months of age, control mice had worse cognitive ability and higher protein and mRNA levels of Arc and Syt1 than their younger counterparts. Embryonic exposure to inflammation or exposure to stress in adolescence aggravated the AISLM, as well as the age-related increase in Arc and Syt1 expression. Moreover, the hippocampal protein and mRNA levels of Arc and Syt1 were significantly correlated with the performance in the learning and memory periods of the MWM test, especially in the mice that had suffered adverse insults in early life. Our findings indicated that prenatal exposure to inflammation or stress exposure in adolescence exacerbated the AISLM and age-related upregulation of Arc and Syt1 expression, and these effects were linked to cognitive impairments in CD-1 mice exposed to adverse factors in early life.
... Sex differences in oxidative stress have previously been implicated in the study of cardiovascular diseases, which also have a sex/ gender bias in disease prevalence [93] and are often comorbid with PTSD [6,7]. Sex differences in response to oxidative stress have also been reported in the brain, notably in the hippocampus, in response to ethanol withdrawal [94] and prenatal stress [95]. Moreover, these sex differences appear to be evolutionarily conserved with reports of sex-specific adaptation to oxidative stress even reported in fruit flies [96]. ...
Background:
While post-traumatic stress disorder (PTSD) is defined by behavioral/cognitive symptoms most directly relevant to brain function, it can be considered a systemic disorder characterized by a distinct inability to reinstate homeostasis after trauma.
Methods:
In this study, we conducted a secondary analysis of gene expression profiles in key PTSD-relevant tissues, namely blood, amygdala, and hippocampus, from a rat model of PTSD, to identify sex-specific and shared processes associated with individual differences in response to recent trauma exposure.
Results:
Our findings suggest both shared and sex-specific mechanisms underlying individual differences associated with vulnerability and resilience to trauma in hippocampus, amygdala, and blood. By disentangling cell composition from transcriptional changes, we found higher proportions of hippocampal oligodendrocytes in the PTSD-like, extreme behavioral response (EBR) group for both sexes and also identified modules for transcriptional activity associated with group differences (i.e., response to trauma) in the hippocampus that appeared to be sex-specific. By contrast, we found prominent sex differences, but no group differences, in amygdalar cell composition, and both shared and sex-specific modules representing PTSD-relevant transcriptional activity in the amygdala. Across amygdala and hippocampus, both sex-specific and shared processes were relevant to an overarching framework for EBR implicating disrupted TNFα/NFκΒ signaling and excitatory/inhibitory imbalance in dysregulated synaptic/structural plasticity with important implications for fear learning and memory. Our main finding in peripheral blood was consistent with the human literature and identified wound healing processes and hemostasis to be upregulated in the resilient, minimal behavioral response (MBR) group across sexes, but disrupted in a sexually dimorphic manner in the EBR group.
Conclusion:
In contrast to the varied characterization of the PTSD-like EBR group, characterization of MBR across blood, amygdala, and hippocampus suggests a common theme of upregulated wound healing and extracellular matrix (ECM) remodeling shared between sexes. In all, we identified differential oligodendrocyte proportions in hippocampus between PTSD-like EBR and resilient MBR, and identified processes and pathways that characterize the EBR and MBR-associated transcriptional changes across hippocampus, amygdala, and blood. The sex-specific mechanisms involved in EBR may contribute to the pronounced disparity in risk for PTSD, with women much more likely to develop PTSD.
... It is a hippocampal proper parcellation with no head/body subdivisions. Although twelve subfield volumes are generated by FreeSurfer 6.0, we only included subfields that have been shown to be preferentially affected by prenatal exposures (i.e., gestational diabetes, prenatal stress) including the CA1, CA2/3, CA4, DG (granule cell layer), and subiculum (Florian & Nunes, 2011;Golalipour, Kafshgiri, & Ghafari, 2012;Graf et al., 2014;Lotfi et al., 2016;Niculescu & Lupu, 2009a;Tozuka et al., 2009;Wang et al., 2015;Zhou et al., 2018;Zhu et al., 2004). ...
... These free radicals can cause lipid peroxidation, damage to cell membranes and mitochondria, and trigger DNA damage; all of which can cause an increase in osteoblast apoptosis and a decrease in bone density. 4,5 Malondialdehyde (MDA) is a secondary product of lipid peroxidation due to exposure to reactive oxygen species (ROS) and other free radicals; is one of the biomarkers of cell damage due to oxidative stress 6,7 . This can disrupt the balance of levels of free radicals and antioxidants in the body. ...
... 5,6 The oxidative stress may contribute to damage of the neurons in the hippocampus of offspring and impairment of memory function. 7 Another report has shown that stressinduced elevation of N-methyl-D-aspartate (NMDA) receptors and corticosterone might mediate the reduced learning ability, impaired memory and other stress-induced neurologic disorders. 8 Studies have demonstrated that the hippocampus of prenatally stressed animals e.g. ...
... It is a hippocampal proper parcellation with no head/body subdivisions. Although twelve subfield volumes are generated by FreeSurfer 6.0, we only included subfields that have been shown to be preferentially affected by prenatal exposures (i.e., gestational diabetes, prenatal stress) including the CA1, CA2/3, CA4, DG (granule cell layer), and subiculum (Florian & Nunes, 2011;Golalipour, Kafshgiri, & Ghafari, 2012;Graf et al., 2014;Lotfi et al., 2016;Niculescu & Lupu, 2009a;Tozuka et al., 2009;Wang et al., 2015;Zhou et al., 2018;Zhu et al., 2004). ...
Introduction:
Animal studies have shown that male but not female offspring exposed to maternal obesity have abnormal hippocampal development. Similar sex differences were observed in animal models of developmental programming by prenatal stress or maternal diabetes. We aimed to translate this work into humans by examining sex-specific effects of exposure to maternal obesity on hippocampal volume in children.
Methods:
Eighty-eight children (37 boys and 51 girls) aged 7-11 years completed the study. Maternal prepregnancy body mass index (BMI) was obtained from electronic medical records. A high-resolution anatomical scan was performed using a 3-Tesla magnetic resonance imaging (MRI) scanner. Total hippocampal volume and hippocampal subfield volumes were analyzed using FreeSurfer 6.0. Linear regression was used to investigate sex differences in relationships between maternal prepregnancy BMI and child hippocampal volume.
Results:
Maternal prepregnancy BMI ranged from 19.0 to 50.4 kg/m2 . We observed a significant interaction between maternal prepregnancy BMI and sex on total hippocampal volume (p < .001) such that boys (r = -.39, p = .018) but not girls (r = .11, p = .45) had a significant negative relationship between maternal prepregnancy BMI and total hippocampal volume. This relationship in boys remained significant after adjusting for child and maternal covariates (β = -126.98, p = .012). The sex interactions with prepregnancy BMI were consistently observed in hippocampal subfields CA1 (p = .008), CA2/3 (p = .016), CA4 (p = .002), dentate gyrus (p < .001), and subiculum (p < .001).
Conclusions:
Our results support findings in animal models and suggest that boys may be more vulnerable to the adverse effects of exposure to maternal obesity on hippocampal development than girls.
... These waves are nearly abolished in prenatally stressed rats with subsequent impairment of dentate gyrus granule cell maturation (Seki and others 2012). Oxidative stress, the involvement of which has been amply demonstrated in various CNS disorders including schizophrenia, autism, Down syndrome, epilepsy and Alzheimer disease (Iannello and others 1999;Markesbery 1997;Ng and others 2008;Waldbaum and Patel 2010), is elevated in the dentate gyrus of prenatally stressed rats (Zhu and others 2004). In the context of the general literature, our data raise the possibility that astrocyte dysfunction and/or oxidative stress accruing, for example, from overexpression of HO-1 in astrocytes may impair the generation of spontaneous neural oscillations necessary for maturational events. ...
Hippocampal abnormalities have been heavily implicated in the pathophysiology of schizophrenia. The dentate gyrus of the hippocampus was shown to manifest an immature molecular profile in schizophrenia subjects, as well as in various animal models of the disorder. In this position paper, we advance a hypothesis that this immature molecular profile is accompanied by an identifiable immature morphology of the dentate gyrus granule cell layer. We adduce evidence for arrested maturation of the dentate gyrus in the human schizophrenia-affected brain, as well as multiple rodent models of the disease. Implications of this neurohistopathological signature for current theory regarding the development of schizophrenia are discussed.
... The number of neurons was significantly higher with administration of Tualang honey to the pregnant dams. Other reports have shown that neuronal damage in the brain of offspring was associated with increased glucocorticoids and oxidative stress [35][36][37]. Glucocorticoid has an important role in intrauterine programming and it exerts its effects by altering the expression of various proteins including receptors, enzymes, ion channels, transporters and growth factors [38]. The hormone is required to initiate the terminal neuronal maturation and the remodelling of axons and dendrites during development of the central nervous system. ...
Objective:
This study was done to determine whether Tualang honey could prevent the altered nociceptive behaviour, with its associated changes of oxidative stress markers and morphology of the spinal cord, among the offspring of prenatally stressed rats.
Methods:
Pregnant rats were divided into three groups: control, stress, and stress treated with Tualang honey. The stress and stress treated with Tualang honey groups were subjected to restraint stress from day 11 of pregnancy until delivery. Ten week old male offspring (n = 9 from each group) were given formalin injection and their nociceptive behaviours were recorded. After 2 h, the rats were sacrificed, and their spinal cords were removed to assess oxidative stress activity and morphology. Nociceptive behaviour was analysed using repeated measures analysis of variance (ANOVA), while the levels of oxidative stress parameters and number of Nissl-stained neurons were analysed using a one-way ANOVA.
Results:
This study demonstrated that prenatal stress was associated with increased nociceptive behaviour, changes in the oxidative stress parameters and morphology of the spinal cord of offspring exposed to prenatal stress; administration of Tualang honey reduced the alteration of these parameters.
Conclusion:
This study provides a preliminary understanding of the beneficial effects of Tualang honey against the changes in oxidative stress and neuronal damage in the spinal cord of the offspring of prenatally stressed rats.
... The involvement of oxidants in the stress response has been hypothesized some 20 years ago (McIntosh and Sapolsky, 1996;Liu and Mori, 1999); still, it was not before 2004 when Zhu et al. (2004) explored their role in ELS using a model of restraint stress treatment of rat dams (Table 1). At 1-month age, hippocampi from prenatally stressed offspring showed a loss of neuronal cells and increased ROS production in the hippocampal CA3 region. ...
Mitochondria play a central role in cellular energy-generating processes and are master regulators of cell life. They provide the energy necessary to reinstate and sustain homeostasis in response to stress, and to launch energy intensive adaptation programs to ensure an organism’s survival and future well-being. By this means, mitochondria are particularly apt to mediate brain programming by early-life stress (ELS) and to serve at the same time as subcellular substrate in the programming process. With a focus on mitochondria’s integrated role in metabolism, steroidogenesis and oxidative stress, we review current findings on altered mitochondrial function in the brain, the placenta and peripheral blood cells following ELS-dependent programming in rodents and recent insights from humans exposed to early life adversity (ELA). Concluding, we propose a role of the mitochondrion as subcellular intersection point connecting ELS, brain programming and mental well-being, and a role as a potential site for therapeutic interventions in individuals exposed to severe ELS.
... The number of neurons was significantly higher with administration of Tualang honey to the pregnant dams. Other reports have shown that neuronal damage in the brain of offspring was associated with increased glucocorticoids and oxidative stress [35][36][37]. Glucocorti- coid has an important role in intrauterine programming and it exerts its effects by altering the expression of various proteins including receptors, enzymes, ion channels, transporters and growth factors [38]. The hormone is required to initiate the termi- nal neuronal maturation and the remodelling of axons and den- drites during development of the central nervous system. ...
Background
Tualang honey (TH) has been shown to exert beneficial effects on learning and memory function in various animal models. However, its learning and memory effects in lipopolysaccharide (LPS) rat model have not been elucidated.
Objective
The present study aimed to investigate the cognitive-enhancing effects of TH and its methanolic fraction in comparison to the clinically approved N-methyl-D-aspartate (NMDA) receptor antagonist (memantine) using LPS rat model.
Methods
A total of ninety male Sprague Dawley rats were divided into 5 groups: (i) control, (ii) untreated LPS (iii) LPS treated with 200 mg/kg TH, (iv) LPS treated with 150 mg/kg methanol fraction of TH (MTH) and (v) LPS treated with 10 mg/kg memantine. All treatments were administered intraperitoneally once daily for 14 days. Morris water maze (MWM) and novel object recognition (NOR) tests were performed to assess spatial and recognition memory function.
Results
The present study confirmed that LPS significantly impairs spatial and recognition memory and alone treatment with TH or MTH improved spatial and recognition memory comparable to memantine.
Conclusion
Both TH and its methanolic fraction improved spatial and recognition memory of LPS rat model comparable to memantine. Thus, TH and its methanolic fraction have potential preventivetherapeutic effects for neurodegenerative diseases involving neuroinflammation.
... It is a hippocampal proper parcellation with no head/body subdivisions. Although twelve subfield volumes are generated by FreeSurfer 6.0, we only included subfields that have been shown to be preferentially affected by prenatal exposures (i.e., gestational diabetes, prenatal stress) including the CA1, CA2/3, CA4, DG (granule cell layer), and subiculum (Florian & Nunes, 2011;Golalipour, Kafshgiri, & Ghafari, 2012;Graf et al., 2014;Lotfi et al., 2016;Niculescu & Lupu, 2009a;Tozuka et al., 2009;Wang et al., 2015;Zhou et al., 2018;Zhu et al., 2004). ...
Offspring exposed to maternal obesity in utero are at increased risk for the development of metabolic disorders. Recent evidence also links exposure to maternal obesity with impaired cognition during childhood. While the underlying mechanisms are unclear, studies in animals have shown that fetal exposure to maternal obesity causes decreased neurogenesis in the dentate gyrus and impaired hippocampal learning. The hippocampus is important for memory, and its development is sensitive to the in utero metabolic environment. We tested the hypothesis that in utero exposure to maternal obesity would be associated with reduced hippocampal volume in children. Sixty-seven children (41 girls, 26 boys) ages 7 to 11 years participated in the study. Children were born at Kaiser Permanente Southern California. Maternal pre-pregnancy BMI was obtained from electronic medical records. Children’s height and weight were measured, and a high-resolution anatomical scan was performed using a 3 Tesla MRI. Total hippocampus volume and hippocampus subfield volumes were analyzed using FreeSurfer 6.0. Linear regression was used to investigate relationships between maternal pre-pregnancy BMI and child hippocampus volume. Maternal pre-pregnancy BMIs ranged from 19.0 to 50.4 kg/m2. Children’s BMI z-scores ranged from -1.8 to 2.6. Maternal pre-pregnancy BMI was negatively correlated with total hippocampus volume, adjusting for child age, sex, BMI-z score, intracranial volume (P=0.05). Results remained after further adjusting for maternal diabetes exposure (P=0.04). A 5-unit increase in maternal pre-pregnancy BMI was associated with 78 mm3 (95% CI:3.3-152.8 mm3) reductions in total hippocampus volume. The inverse correlation was also observed in CA3 (P=.04), CA4 (P=.03), dentate gyrus (P=.03) and subiculum (P=.01) subfields, adjusting for the same covariates. Our results suggest that exposure to maternal obesity adversely impacts hippocampus volume in children, and this impact is uniform across subfields.
Disclosure
K.A. Page: None. S. Luo: None. X. Wang: None. J. Alves: None. M.P. Martinez: None. A. Xiang: None.
... Intriguingly, our results demonstrating alterations of embryonic microglia with IL-1β also support redox mechanisms, based on the importance of reactive oxygen species for IL-1β's activation of microglia [30,31]. These convergent findings support the importance of redox dysregulation in the effects of prenatal stress [32,33]. ...
Maternal stress during pregnancy is associated with an increased risk of psychopathology in offspring. Resident immune cells of the brain, microglia, may be mediators of prenatal stress and altered neurodevelopment. Here, we demonstrate that neither the exogenous pro-inflammatory cytokine, interleukin-1β (IL-1β), nor the glucocorticoid hormone, corticosterone, recapitulated the full effects of prenatal stress on the morphology of microglial cells in the cortical plate of embryonic mice; IL-1β effects showed greater similarity to prenatal stress effects on microglia. Unexpectedly, oil vehicle alone, which has antioxidant properties, moderated the effects of prenatal stress on microglia. Microglia changes with prenatal stress were also sensitive to the antioxidant, N-acetylcysteine, suggesting redox dysregulation as a mechanism of prenatal stress.
... Exposure to prenatal insults, such as maternal cold stress, has been reported to increase the rates of unhealthy newborn animals, and leads to growth retardation, immune dysfunction and an increase in disease susceptibility. Because there is no direct neural connection between the mother and fetus, these effects may be caused by the hormones which are produced by maternal stress [5], such as glucocorticoids. Prenatal insults lead to the overproduction of glucocorticoids by the HPA axis, which can pass through the placental barrier and reach the fetus [6]. ...
In mammals, environmental factors including cold stress exert dramatic effects on adult health during late gestation, the cold stress response refers to an organism's response to cold. Indeed, cells and organs, including the hippocampus, are coordinated to respond to prevent hypothermia. The hippocampus act as an important brain structure that regulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and suppress the stress reaction through feedback regulation of the HPA axis. To evaluate the response of the hippocampus during prenatal cold stress, we established a prenatal cold stress rat model. The molecular and signaling pathways responsible for the hippocampus cold exposure response were investigated. We assessed the glucocorticoid receptor, mineralocorticoid receptor, brain-derived neurotrophic factor (BDNF), RNA-binding motif protein 3 (RBM3), heat shock protein 70, protein expression, and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and nuclear factor-kappa B pathways. Male and female offspring behavior were evaluated. Cold stress reduced the BDNF level in the maternal hippocampus in contrast to the increase in RBM3. BDNF has been shown to induce and RBM3 inhibits ERK phosphorylation. We measured p-ERK1/2 and showed low-level phosphorylation in the hippocampus after cold stress. Furthermore, we demonstrated that cold stress enhanced phosphorylation of P65 on Ser536, and led to apoptosis of the hippocampus in a caspase 3-independent manner. Behavioral tests were performed on pubescent male and female offspring, both of which showed evidence of reduced anxiety-like behavior. In summary, a more thorough understanding of these mechanisms may lead to maternal intervention that can reverse the damage of prenatal stressors or prevent the damage altogether and improve the physical quality of neonatal rats.
... kinase C (PKC) and extracellular signal-regulated kinase (ERK) are able to induce Nrf2 dissociation from Kelchlike ECH-associated protein 1 (Keap1) and subsequent translocation to the nucleus by phosphorylating Nrf2 at serine and threonine residues [11,12]. Our previous study has demonstrated that prenatally-stressed offspring rats showed more depression-like behaviors and lower level of ERK2 mRNA in the hippocampus and prefrontal cortex compared with the control rats [13,14], accompanied with high levels of CORT in hippocampus, excessive intracellular reactive oxygen species (ROS) in hippocampal CA3 area and hippocampal neurons loss [15,16]. These data strongly suggest that the decline of ERK is involved in oxidative damage in the hippocampus of prenatally-stressed rats accompany with high levels of plasma CORT. ...
Substantial evidence has shown that elevated circulating corticosteroids or chronic stress contributes to neuronal cell death, cognitive and mental disorders. However, the underlying mechanism is still unclear. Taurine is considered to protect neuronal cells from apoptotic cell death in neurodegenerative diseases and neuropsychiatric disorders. In the present study, the protective effects of taurine against corticosterone (CORT)-induced oxidative damage in SK-N-SH neuronal cells were investigated. The results showed that CORT significantly induced cell death, which was blocked by pretreatment with taurine. Similarly, pretreatment with taurine suppressed CORT-induced apoptotic cell death decreasing the levels of intracellular reactive oxygen species and improving mitochondrial function. Pretreatment with taurine increased the expression of phosphorylated extracellular regulated protein kinases (ERK) as well as the nuclear translocation of nuclear factor (erythroid 2-derived)-like 2 (Nrf2) in the CORT rich environment. Furthermore, administration of the ERK inhibitor U0126 or transient (siRNA) silencing of Nrf2 blocked the protective effects of taurine on cell viability and expression levels of Nrf2 and heme oxygenase-1 (HO-1) in the CORT model of neuronal damage. These results suggest that the Nrf2 signaling pathway may play a role in the protection mechanism of taurine against CORT-induced neuronal oxidative damage.
... It has been identified as one of the mechanisms of stress or corticosterone mediated neurotoxicity as well. Several previous studies reported that exogenous corticosterone directly increased oxidative mediators and decreased brain SOD and CAT activities ( Zafir and Banu, 2009;Zhu et al., 2004). Additionally, accumulating levels of ROS can oxidize proteins, lipids and DNA (Scherz Shouval and Elazar, 2011). ...
Depression is a psychiatric disorder and chronic stress, leading to altered glucocorticoid secretion patterns, is one of the factors that induce depression. Our previous study showed that amantadine significantly attenuated the impairments of synaptic plasticity and cognitive function a rat model of CUS. However, little is known regarding the underlying mechanism. In the present study, the whole-cell patch-clamp technique was applied to examine the protection effect of amantadine on the hippocampus CA3-CA1 pathway. Evoked excitatory postsynaptic currents (eEPSCs), miniature excitatory postsynaptic currents (mEPSCs), paired-pulse ratio (PPR) and the action potentials of CA3 neurons were recorded. Our data showed that corticosterone increased the amplitude of eEPSCs and decreased the value of paired-pulse ratio (PPR), but both of them were significantly reversed by amantadine. In addition, the frequency of mEPSC was considerably increased by corticosterone, but it was reduced by amantadine. Moreover, we used the Fluo-3/AM image to detect the Ca²⁺ influx in primary cultured hippocampal neurons. The results showed that the intracellular calcium levels were significantly decreased by amantadine in the corticosterone treated neurons. Additionally, the superoxide dismutase (SOD) and catalase (CAT) activities were reduced by corticosterone, while they were enhanced by either amantadine or low-calcium artificial cerebral spinal fluid (ACSF). These results suggest that amantadine significantly improves corticosterone-induced abnormal glutamatergic synaptic transmission of CA3-CA1 synapses presynaptically and alleviates the activities of antioxidant enzymes via regulating the calcium influx. This article is protected by copyright. All rights reserved.
... Several previous studies reported that there were a reduced neurogenesis, an increased cell death and an enhanced oxidative stress of hippocampal neurons in PS offspring rats (Lemaire et al., 2000;Mandyam et al., 2008;Zhu et al., 2004). In the present study, there were evident damages including irregular cellular alignments and the reduction of cell number in the hippocampus in the PS group ( Fig. 5a & b), which was in line with previous findings. ...
Prenatal stress (PS) brings numerous outcomes on offspring, including anxiety, depression-like behavior and other cognitive disorder. In this study, a rat model of PS was established by using restraint stress for 45min three times per day from the 15th to 21st day of pregnancy. Behavioral tests, including open field test (OPT), elevated plus-maze (EPM) and Morris water-maze (MWM), were performed in adolescent male-offspring. The bidirectional synaptic plasticity, including long-term potential (LTP) and depotentiation (DEP), from the hippocampal Schaffer collaterals to CA1 region was subsequently measured. Furthermore, Western blot assay, immunofluorescence staining and hematoxylin-eosin (HE) staining were employed. The MWM test showed that the cognitive flexibility was remarkably damaged in PS offspring. Meanwhile, PS considerably aggravated the anxiety and depression-like behavior in OPT and EPM. Both LTP and DEP were significantly inhibited by PS. Furthermore, PS considerably altered the expression of synaptic-related proteins NR2A, NR2B and PSD-95 in adolescent male-offspring. Interestingly, PS significantly elevated the autophagy level in the hippocampus of male-offspring. In order to investigate the role of autophagy on the negative impacts of PS in adolescent male-offspring, both in vitro and in vivo studies were performed. It was found that autophagy inhibitors significantly eliminated the alterations in gene expression induced by corticosterone. The results suggest that regulating autophagy may become a new targeted therapy to relieve the damage induced by PS in adolescent male-offspring.
... 6 Other environmental factors associated with redox imbalance and SZ are prenatal malnutrition and maternal stress during pregnancy. [7][8][9][10][11][12] For example, low protein intake during pregnancy has been shown to induce mitochondrial dysfunction and a decrease in endogenous antioxidants, resulting in higher ROS production. 13 In addition, obstetric events, such as hypoxia, and environmental insults later in life, such as social stress, are associated with oxidative stress and represent risk factors for SZ. ...
Schizophrenia (SZ) is a neurodevelopmental disorder with a broad symptomatology, including cognitive symptoms that are thought to arise from the prefrontal cortex (PFC). The neurobiological aetiology of these symptoms remains elusive, yet both impaired redox control and PFC dysconnectivity have been recently implicated. PFC dysconnectivity has been linked to white matter, oligodendrocyte (OL) and myelin abnormalities in SZ patients. Myelin is produced by mature OLs, and OL precursor cells (OPCs) are exceptionally susceptible to oxidative stress. Here we propose a hypothesis for the aetiology of cognitive symptomatology in SZ: the redox-induced prefrontal OPC-dysfunctioning hypothesis. We pose that the combination of genetic and environmental factors causes oxidative stress marked by a build-up of reactive oxygen species that, during late adolescence, impair OPC signal transduction processes that are necessary for OPC proliferation and differentiation, and involve AMP-activated protein kinase, Akt-mTOR-P70S6K and peroxisome proliferator receptor alpha signalling. OPC dysfunctioning coincides with the relatively late onset of PFC myelination, causing hypomyelination and disruption of connectivity in this brain area. The resulting cognitive deficits arise in parallel with SZ onset. Hence, our hypothesis provides a novel neurobiological framework for the aetiology of SZ cognitive symptoms. Future research addressing our hypothesis could have important implications for the development of new (combined) antioxidant- and promyelination-based strategies to treat the cognitive symptoms in SZ.
... Prenatal stress-induc ed suppression of neuronal proliferation involving brain antioxidant systems was reported by Kawamura et al. [16]. Prenatal stress-induced oxidative damage to mitochondrial DNA and damage to hippocampal neurons in neonates is reported by Zhu et al. [43]. Hence the cellular damage in the developing brain could be attributed to overproduction of antioxidants. ...
Prenatal stress-induced neurobehavioral deficits observed in offspring are multifactorial, including oxidative stress in the developing brain. The time by which the developing brain acquires self-defense against oxidative stress is not clear. Hence in the present study we aimed to evaluate the brain antioxidant status during different developing periods. Further the study also evaluates the role of the glutathione precursor, N-Acetyl cysteine (NAC) on the brain antioxidant status. Pregnant rats were subjected to restraint stress during an early or late gestational period. Another set of rats received NAC during the entire gestational period along with early or late gestational stress. The study parameters included several antioxidant studies directly from rat brain homogenate on postnatal day 24 or 48. Early or late gestational stress has caused severe oxidative stress in the developing brain on postnatal day 24 in all the parameters studied. However, brain reduced glutathione (GSH), superoxide dismutase (SOD) and total antioxidant activity (TAO) were not affected by either early or late gestational stress on postnatal day 48, but the brain malondialdehyde (MDA) level remained high and brain glutathione reductase (GSS-Rd) level remained low on postnatal day 48. Prenatal NAC treatment has reversed the oxidative damage in all the parameters on postnatal day 24 and also the brain MDA level and GSS-Rd level on postnatal day 48. This study confirms that the growing brain acquires antioxidant capacity over time but during early postnatal development it is vulnerable to oxidative stress and related neurological consequences. N-Acetyl cysteine treatment during the prenatal period as an antioxidant supplement exerted a beneficiary effect in this study. Hence glutathione supplement in the nutritional source would be an idealistic approach to prenatal stress-induced neurological comorbidities in children.
... The pregnant rats were separately exposed to restraint stress on days 14-20 of pregnancy three times daily for 45 min [21]. To prevent habituation of animals to the daily procedure, restraint periods were randomly shifted within certain time periods (08:00-10:00, 11:00-13:00, and 15:00-17:00). ...
Adolescence is a time of continued brain maturation, particularly in limbic and cortical regions, which undoubtedly plays a role in the physiological and emotional changes. Prenatally stressed offspring rats were used to investigate the potential antidepressive-like effects of imperatorin (IMP) extracted from the root of radix angelica. After 4 weeks of treatment of IMP, behavioral tests (sucrose-preference test, forced-swimming test, and open-field test) were measured. 5-hydroxytryptamine (5-HT) concentration in the hippocampus and frontal cortex was measured using an enzyme-linked immunosorbent assay. Serotonin transporters (5-HTT) and 5-HT1A receptor (5-HT1AR) mRNA expression in the hippocampus and frontal cortex were also determined by real-time PCR. Administration with IMP (15 and 30 mg/kg/day, intragastrically) for 28 days markedly increased the percentage of sucrose (anhedonia), decreased the immobility time, and increased the number of total crossings, center crossings, rearing, and grooming in the male prenatally stressed offspring. Meanwhile, we found that 5-HT concentration in the hippocampus and frontal cortex was significantly increased in the IMP-treated group. Subsequently, we found significantly decreased 5-HTT and increased 5-HT1AR mRNA expressions in the hippocampus and frontal cortex after IMP treatment in the prenatally stressed male offspring. IMP showed antidepressive-like effects and increased 5-HT concentration in male prenatally stressed offspring, suggesting that IMP could be of therapeutic use in preventing depressive-like behavior in adolescence.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.
Sex differences in neuropsychiatric disorders are well reported although the mechanisms remain poorly understood. The prevalence of major depressive disorders and anxiety disorders are substantially higher in women as compared to men. Moreover, sex differences also exist in terms of symptom severity as well as comorbidities of such ailments with other neurological disorders. Nitric oxide containing neurons are widely distributed within the brain and nitric oxide synthase may co-localize with gonadal hormones’ receptors. Estrogen as well as other gonadal hormones may influence nitric oxide synthase expression. Neuronal nitric oxide synthase (nNOS), is abundant in multiple regions of the brain closely associated with the pathophysiology of affective disorders including the prefrontal cortex, hippocampus, amygdala, and the hypothalamus. This review article critically examines the clinical and basic research findings on sex differences in stress-related neuropsychiatric diseases with a particular focus on the role of nitric oxide action in the pathophysiology of such disorders. The interplay between gonadal hormones and NO signaling in the brain, as well as how such interactions affect mood disorders, are also discussed. Recent advances in therapeutic approaches for developing appropriate NO modulators and targeting NO signaling pathways for stress related disorders have been briefly covered, as well as priorities for future research.
Schizophrenia (SZ) is a severe psychiatric disorder and its cognitive symptoms arise from prefrontal cortex (PFC) dysfunctioning and involve altered myelination and interneuron abnormalities. In Chapters 1 and 2 of this thesis, I have introduced the hypothesis that the myelination of parvalbumin interneurons is affected in SZ and that that high levels of oxidative stress interfere with the differentiation of oligodendrocytes (OLs) and as such hinder proper myelination. Using the APO-SUS rat model, in Chapter 3, I showed that PFC-dependent cognitive behaviour is impaired, there is an OL differentiation defect and parvalbumin interneuron hypomyelination in the APO-SUS PFC, and that environmental enrichment (EE) can restore OL differentiation, myelination and cognitive behaviour in APO-SUS rats. In Chapter 4, I show that there is oxidative stress in APO-SUS mPFC, and that this partially underlies the APO-SUS OL differentiation defect. Notably, antioxidant treatment rescued oxidative stress, interneuron myelination as well as cognitive defects in APO-SUS rats. Myelin membranes consist mainly of lipids, accordingly in Chapter 5 I show altered expression of lipid-related genes in SZ PFC, I identified shared genetic etiology between SZ and lipids, and showed that reduced cognitive performance of SZ patients was correlated with a decreased lipid content in the PFC.
Prenatal stress is associated with the release of stress hormones including catecholamines and glucocorticoids. High levels of glucocorticoids can pass through the placenta and enter fetal circulation. The hormone may alter the metabolism in the fetus and lead to oxidative stress. Oxidative stress of the structures involved in processing pain information in prenatally stressed offspring may result in cell damage, gene alteration, and increased pain responses in humans and animals. Increased pain responses in rats could be reduced by giving antioxidants to the pregnant dams induced with prenatal stress. Administration of antioxidants in the pregnant dams may allow its delivery to the fetus through the placenta and remain in the fetal tissues. These antioxidants improve oxidative stress in the fetus and prevent neuronal damage, thus conferring protection from altered pain responses in the offspring exposed to prenatal stress.
Nitric oxide (NO) is an important signaling molecule with many functions in the nervous system. Derived from the enzymatic conversion of arginine by several nitric oxide synthases (NOS), NO plays significant roles in neuronal developmental events such as the establishment of dendritic branching or arbors. A brief summary of the discovery, molecular biology, and chemistry of NO, and a description of important NO-mediated signal transduction pathways with emphasis on the role for NO in the development of dendritic branching during neurodevelopment are presented. Important sex differences in neuronal nitric oxide synthase expression during neuronal development are considered. Finally, a survey of endogenous and exogenous substances that disrupt dendritic patterning is presented with particular emphasis on how these molecules may drive NO-mediated sex differences in dendritic branching.
Over several decades, there is a growing evidence, which has shown that prenatal stress (PS) contributes to depression in offspring. Grape seed proanthocyanidins (GSPs), which contain dimers, trimers, oligomers of catechin and epicatechin, are known to possess antidepressant effects. The present study aimed to investigate the mechanism of antidepressant effects of GSPs on female juvenile prenatally stressed offspring rats. The results showed that the female juvenile offspring rats exposed to PS exhibited depression-like behavior manifested as longer immobility time and lesser consumption of sucrose solution. Prenatal stress reduced the number of hippocampal neurons and increased the level of the reactive oxygen species (ROS) in the hippocampus of the female juvenile offspring rats. Furthermore, the expression of PYD domains-containing protein 3 (NLRP3) and its downstream cytokines, Caspase-1, and interleukin-1β (IL-1β), were increased in the hippocampus of the female juvenile offspring rats exposed to PS. Administration of GSPs not only improved depression-like behavior and enhanced the number of hippocampal neurons, but also abated excessive ROS generation and inhibited the activation of the NLRP3-Caspase-1 signaling pathway. Taken together, GSPs counteract PS-induced hippocampal neuron loss and depression-like behavior by alleviating oxidative stress and NLRP3 activation. The present study provides a new insight for GSPs as an effective therapeutic agent for adolescent depression.
A large body of literature has demonstrated that prenatal stress (PS) can induce depression-like behavior in the offspring. However, the underlying mechanism remains largely unknown. CREB-regulated transcriptional coactivator 1(CRTC1) has recently been shown to involve in mood regulation. This research aims to investigate whether CRTC1 signaling was involved in the depression-like behavior of prenatally stressed offspring rats. Sucrose preference test (SPT), forced swimming test (FST) and open field test (OFT) were adopted to test the depression-like behavior in the male offspring rats, and CRTC1 signaling was measured. The results showed that there were significantly reduced sucrose intake in SPT and prolonged immobility time in FST in PS-exposure offspring rats. It was also found decreased levels of total CRTC1, nuclear CRTC1, calcineurin, brain-derived neurotrophic factor (BDNF) and c-fos, but increased cytoplasmic p-CRTC1 in the hippocampus (HIP) and prefrontal cortex (PFC) of the offspring rats. Furthermore, the mRNA level of CRTC1, calcineurin, BDNF, c-fos were down-regulated. Abnormal expression of CRTC1 signaling could be alleviated by fluoxetine treatment. In conclusion, our research indicated that the aberration of CRTC1 expression and/or phosphorylation activity might play a vital role in PS-induced depression-like behavior of offspring rats.
While neurotransmitter dysfunction represents a key component in mental illnesses, there is now a wide agreement for a central pathophysiological hub that includes hormones, neuroinflammation, redox mechanisms as well as oxidative stress. With respect to oxidation-reduction (redox) mechanisms, preclinical and clinical evidence suggests that an imbalance in the pro/anti-oxidative homeostasis toward the increased production of substances with oxidizing potential may contribute to the etiology and manifestation of different psychiatric disorders. The substantial and continous demand for energy renders the brain highly susceptible to disturbances in its energy supply, especially following exposure to stressful events, which may lead to overproduction of reactive oxygen and nitrogen species under conditions of perturbed antioxidant defenses. This will eventually induce different molecular alterations, including extensive protein and lipid peroxidation, increased blood-brain barrier permeability and neuroinflammation, which may contribute to the changes in brain function and morphology observed in mental illnesses. This view may also reconcile different key concepts for psychiatric disorders, such as the neurodevelopmental origin of these diseases, as well as the vulnerability of selective cellular populations that are critical for specific functional abnormalities. The possibility to pharmacologically modulate the redox system is receiving increasing interest as a novel therapeutic strategy to counteract the detrimental effects of the unbalance in brain oxidative mechanisms. This review will describe the main mechanisms and mediators of the redox system and will examine the alterations of oxidative stress found in animal models of psychiatric disorders as well as in patients suffering from mental illnesses, such as schizophrenia and major depressive disorder. In addition, it will discuss studies that examined the effects of psychotropic drugs, including antipsychotics and antidepressants, on the oxidative balance as well as studies that investigated the effectiveness of a direct modulation of oxidative mechanisms in counteracting the behavioral and functional alterations associated with psychiatric disorders, which supports the promising role of the redox system as a novel therapeutic target for the improved treatment of brain disorders.
The old classification of depression as reactive and endogenous, which are still observed in clinical practice, both cannot be accommodated under the current rubric of major depression. This is because psychiatric nosology under the Diagnostic and Statistical Manual of Mental Disorders (DSM) and its latest fifth edition (DSM-V) is still descriptive and not etiologic. The aim of this review was to revisit reactive and endogenous categories of depression from the perspective of today's understanding of etiological pathways. From an epigenetic perspective, the old dichotomy of reactive versus endogenous is interrelated through the impact of the environment (e.g., stress). This includes familial or prenatal depression, where the environmental impact is before birth, or childhood depression, where the early life stress is the precipitating factor to genetic susceptibility. In conclusion, searching for both environmental impact (e.g., stressors) and genetic predispositions in depression, even at a clinical level, could help clinicians with better therapeutic decisions.
Substantial evidence has demonstrated that prenatal stress (PS) impairs spatial learning and memory in offspring. The neuron-specific protein kinase C gamma (PKCγ) has been proposed to be unique in spatial learning and memory. The present study proposes to determine whether hippocampal PKCγ is involved in the detrimental effects of PS on spatial learning and memory in offspring, and to further explore the effects of PS-induced PKCγ-dependent growth-associated protein 43 (GAP-43) and neurogranin (Ng) phosphorylation alteration on calcium/calmodulin-dependent protein kinase II (CaMKII) activation. Prenatal restraint stress models were established, and lentivirus-mediated overexpression of PKCγ in the hippocampal CA1 area was applied. The results demonstrated that PS impaired spatial learning acquisition and memory retrieval on the Morris Water Maze test, especially in juvenile female rats. Hippocampal PKCγ membrane translocation and cytosolic PKCγ levels were decreased in PS females. The expression of phosphorylated GAP-43 (p-GAP-43) and phosphorylated Ng (p-Ng), as well as phosphorylated CaMKII (p-CaMKII), was significantly reduced in the hippocampus of PS females. Overexpression of PKCγ in the hippocampal CA1 area recovered the ability of spatial learning and memory in PS female offspring. Furthermore, enhancing PKCγ reversed PS-induced membrane and cytosolic PKCγ reduction, and restored levels of GAP-43 and Ng phosphorylation, and CaMKII activation in the hippocampus. In conclusion, PS possibly decreases hippocampal PKCγ activity, resulting in a reduction of p-GAP-43 and p-Ng, which underlies insufficient CaMKII activation, thereby impairing spatial learning and memory.
Increasing evidence has shown that prenatal stress (PS) could cause depression-like behavior in the offspring, which is sex-specific. However, the underlying mechanisms remain to be elucidated. This study is to investigate the involvement of tryptophan hydroxylase 2 (Tph2) H3K9 acetylation (H3K9ac) modification on PS-induced depression-like behavior in juvenile offspring rats (JOR). PS models were established, with or without trichostatin A (TSA) treatment. Animal behavior was assessed by the sucrose preference test (SPT) and forced swimming test (FST). The mRNA and protein expression levels of TPH2 in the dorsal raphenucleus (DRN), hippocampus, and prefrontal cortex were detected with quantitative real-time PCR and Western blot analysis, respectively. The Tph2 H3K9ac levels in the hippocampus were also analyzed. SPT and FST showed significantly reduced sucrose preference and significantly prolonged immobility in PS-induced male juvenile offspring rats (MJOR). Moreover, the mRNA and protein expression levels of TPH2 in the DRN and hippocampus were significantly declined, while the hippocampal Tph2 H3K9ac levels were significantly declined in the PS-induced MJOR. Furthermore, the PS-induced effects in MJOR could be reversed by the microinjection of TSA. However, no significant effects were observed for the female juvenile offspring rats (FJOR). In conclusion, our results showed that the Tph2 H3K9ac modification is only involved in PS-induced depression-like behavior in MJOR, in a sex specific manner. These findings might contrite to the understanding of the disease pathogenesis and clinical treatment in future.
The hippocampus of the rat loses neurons with age, a loss which may eventuate in some of the functional impairments typical of senescence. Cumulative exposure to corticosterone (CORT) over the lifespan may be a cause of this neuronal loss, as it is prevented by adrenalectomy at mid- age. In this study, we demonstrate that prolonged exposure to CORT accelerates the process of cell loss. Rats were injected daily with sufficient CORT to produce prolonged elevations of circulating titers within the high physiological range. Animals treated for 3 months (chronic subjects) resembled aged rats in a number of ways. First, both groups had extensive and persistent depletions of CORT receptors in the hippocampus; in the case of chronic rats, no recovery of receptor concentrations occurred 4 months after the end of steroid treatment. Second, autoradiographic analysis revealed that the receptor depletion was due, in part, to a loss of CORT-concentrating cells, especially in the CA3 cell field. Remaining cells bound significantly less [3H]corticosterone than did those of control rats. Finally, analysis of size distributions of hippocampal cell bodies indicated that chronic subjects lost neurons of the same size as those lost in the aged hippocampus. Furthermore, chronic subjects also had increased numbers of small, darkly staining cells of CA3; these corresponded in size to the dark glia whose numbers increase in the aged hippocampus, and which are thought to infiltrate in response to neuronal damage or destruction. Thus, this study supports the hypothesis that cumulative exposure to CORT over the lifespan may contribute to age-related loss of neurons in the hippocampus, and that prolonged stress or exposure to CORT accelerates this process.
The hippocampus of the rat loses neurons with age, a loss which may eventuate in some of the functional impairments typical of senescence. Cumulative exposure to corticosterone (CORT) over the lifespan may be a cause of this neuronal loss, as it is prevented by adrenalectomy at mid-age. In this study, we demonstrate that prolonged exposure to CORT accelerates the process of cell loss. Rats were injected daily with sufficient CORT to produce prolonged elevations of circulating titers within the high physiological range. Animals treated for 3 months (chronic subjects) resembled aged rats in a number of ways. First, both groups had extensive and persistent depletions of CORT receptors in the hippocampus; in the case of chronic rats, no recovery of receptor concentrations occurred 4 months after the end of steroid treatment. Second, autoradiographic analysis revealed that the receptor depletion was due, in part, to a loss of CORT-concentrating cells, especially in the CA3 cell field. Remaining cells bound significantly less [3H]corticosterone than did those of control rats. Finally, analysis of size distributions of hippocampal cell bodies indicated that chronic subjects lost neurons of the same size as those lost in the aged hippocampus. Furthermore, chronic subjects also had increased numbers of small, darkly staining cells of CA3; these corresponded in size to the dark glia whose numbers increase in the aged hippocampus, and which are thought to infiltrate in response to neuronal damage or destruction. Thus, this study supports the hypothesis that cumulative exposure to CORT over the lifespan may contribute to age-related loss of neurons in the hippocampus, and that prolonged stress or exposure to CORT accelerates this process.
Sharp wave bursts, induced by a cooperative discharge of CA3 pyramidal cells, are the most synchronous physiological pattern in the hippocampus. In conjunction with sharp wave bursts, CA1 pyramidal cells display a high-frequency (200 Hz) network oscillation (ripple). In the present study extracellular field and unit activity was recorded simultaneously from 16 closely spaces sites in the awake rat and the intracellular activity of CA1 pyramidal cells during the network oscillation was studied under anesthesia. Current source density analysis of the high-frequency oscillation revealed circumscribed sinks and sources in the vicinity of the pyramidal layer. Single pyramidal cells discharged at a low frequency but were phase locked to the negative peak of the locally derived field oscillation. Approximately 10% of the simultaneously recorded pyramidal cells fired during a given oscillatory event. Putative interneurons increased their discharge rates during the field ripples severalfold and often maintained a 200 Hz frequency during the oscillatory event. Under urethane and ketamine anesthesia the frequency of ripples was slower (100-120 Hz) than in the awake rat (180-200 Hz). Halothane anesthesia prevented the occurrence of high-frequency field oscillations in the CA1 region. Both the amplitude (1-4 mV) and phase of the intracellular ripple, but not its frequency, were voltage dependent. The amplitude of intracellular ripple was smallest between -70 and -80 mV. The phase of intracellular oscillation relative to the extracellular ripple reversed when the membrane was hyperpolarized more than -80 mV. A histologically verified CA1 basket cell increased its firing rate during the network oscillation and discharged at the frequency of the extracellular ripple. These findings indicate that the intracellularly recorded fast oscillatory rhythm is not solely dependent on membrane currents intrinsic to the CA1 pyramidal cells but it is a network driven phenomenon dependent upon the participation of inhibitory interneurons. We hypothesize that fast field oscillation (200 Hz) in the CA1 region reflects summed IPSPs in pyramidal cells as a result of high-frequency barrage of interneurons. The sharp wave associated synchronous discharge of pyramidal cells in the millisecond range can exert a powerful influence on retrohippocampal targets and may facilitate the transfer of transiently stored memory traces from the hippocampus to the entorhinal cortex.
We argue for the critical role of oxidative damage in causing the mitochondrial dysfunction of aging. Oxidants generated by mitochondria appear to be the major source of the oxidative lesions that accumulate with age. Several mitochondrial functions decline with age. The contributing factors include the intrinsic rate of proton leakage across the inner mitochondrial membrane (a correlate of oxidant formation), decreased membrane fluidity, and decreased levels and function of cardiolipin, which supports the function of many of the proteins of the inner mitochondrial membrane. Acetyl-L-carnitine, a high-energy mitochondrial substrate, appears to reverse many age-associated deficits in cellular function, in part by increasing cellular ATP production. Such evidence supports the suggestion that age-associated accumulation of mitochondrial deficits due to oxidative damage is likely to be a major contributor to cellular, tissue, and organismal aging.
The effect of changes in maternal corticosterone concentrations, induced by maternal stress, maternal adrenalectomy or both, on concentration of corticosterone in serum and in adrenals of mouse (Mus domesticus) fetuses was examined. Higher baseline serum corticosterone concentrations were found in female fetuses than in male fetuses; however, there was no sex difference in the content of corticosterone in adrenals collected from these fetuses. Sex differences were observed in the fetal response to changes in maternal concentrations of serum corticosterone resulting from stress (bright light and heat) or adrenalectomy, and both factors eliminated the sex difference in corticosterone in fetal serum. When females were injected i.v. with [3H]corticosterone on day 17 of pregnancy, significantly more 3H was recovered from the serum of female than of male fetuses 15 min after the injection, while more 3H was recovered from placentae of male fetuses. This finding suggests that the difference in serum corticosterone in male and female mouse fetuses is due to greater transport of corticosterone from maternal blood across the placenta of female than of male fetuses.
Metabolism, like other aspects of life, involves tradeoffs. Oxidant by-products of normal metabolism cause extensive damage to DNA, protein, and lipid. We argue that this damage (the same as that produced by radiation) is a major contributor to aging and to degenerative diseases of aging such as cancer, cardiovascular disease, immune-system decline, brain dysfunction, and cataracts. Antioxidant defenses against this damage include ascorbate, tocopherol, and carotenoids. Dietary fruits and vegetables are the principal source of ascorbate and carotenoids and are one source of tocopherol. Low dietary intake of fruits and vegetables doubles the risk of most types of cancer as compared to high intake and also markedly increases the risk of heart disease and cataracts. Since only 9% of Americans eat the recommended five servings of fruits and vegetables per day, the opportunity for improving health by improving diet is great.
Corticotropin-releasing hormone (CRH) plays major roles in coordination of the stress response and regulation of the immune/inflammatory reaction, two important functions associated with sexual dimorphism. Two overlapping segments of the 5' flanking region of the human (h) CRH gene, the proximal 0.9 kb (containing two perfect half-palindromic estrogen-responsive elements [EREs]) and the 2.4 kb (including the former and containing two additional perfect half-palindromic EREs), were examined for their ability to confer estrogen-mediated transcriptional enhancement to a homologous or heterologous promoter. The level of estrogen-induced transactivation by the 0.9- and 2.4-kb segments was determined by chloramphenicol acetyltransferase analysis in CV-1 cells cotransfected with estrogen receptor (ER) cDNA expression plasmids, and found to be respectively approximately 10% and 20% of that of the strongly estrogen-responsive Xenopus vitellogenin A2 enhancer. Gel retardation and immunoprecipitation demonstrated specific association between the perfect half-palindromic EREs of hCRH gene and the DNA binding domain of hER in vitro. These findings may constitute the basis of sexual dimorphism in the expression of the CRH gene in the central nervous system and periphery, and might shed light in existing gender differences in stress response and immune regulation.
Early experiences such as prenatal stress significantly influence the development of the brain and the organization of behavior. In particular, prenatal stress impairs memory processes but the mechanism for this effect is not known. Hippocampal granule neurons are generated throughout life and are involved in hippocampal-dependent learning. Here, we report that prenatal stress in rats induced lifespan reduction of neurogenesis in the dentate gyrus and produced impairment in hippocampal-related spatial tasks. Prenatal stress blocked the increase of learning-induced neurogenesis. These data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for psychopathological vulnerabilities in aging.
The present experiments were designed to investigate the effects of maternal stress on cognitive and endocrine parameters in the adult offspring. Pregnant rats were stressed daily during the last week of pregnancy (days 15-19) by restraint, and the performance of their offspring in the Morris water maze was recorded. Plasma corticosterone levels after swimming and the status of hippocampal glucocorticoid receptors (GRs) were determined. During acquisition of the task, prenatally stressed (PS) males - but not females - showed longer escape latencies than non-stressed controls when swimming in cold (10 degrees C) but not in warm (20 degrees C) water. This sex- and prenatal stress-specific difference was even more pronounced during reversal learning of the task. In contrast, PS females - but not males - had higher basal corticosterone levels and a lower density of hippocampal corticosteroid receptors than non-stressed controls. In all animals irrespective of treatment, swimming in the water maze causes an increase of corticosterone that was smaller on day 8 of swimming than on day 1. After swimming in cold water, the rise in corticosterone levels in females was steeper and returned faster to baseline values than after swimming in warm water. A similar pattern could be seen in PS females when compared to their non-stressed controls. The data suggest that prenatal stress impairs spatial learning in males but not in females. Basal and stress-induced increases in corticosterone levels, however, were altered in PS females and not in PS males; i.e., prenatal stress-induced changes in corticosterone secretion were not paralleled by prenatal stress-induced deficits in spatial learning.
Prenatal stress impairs activity of the hypothalamo–pituitary–adrenal (HPA) axis in response to stress in adult offspring. So far, very few data are available on the effects of prenatal stress on circadian functioning of the HPA axis. Here, we studied the effects of prenatal stress on the circadian rhythm of corticosterone secretion in male and female adult rats. To evaluate the effects of prenatal stress on various regulatory components of corticosterone secretion, we also assessed the diurnal fluctuation of adrenocorticotropin, total and free corticosterone levels, and hippocampal corticosteroid receptors. Finally, in the search of possible maternal factors, we studied the effects of repeated restraint stress on the pattern of corticosterone secretion in pregnant female rats. Results demonstrate that prenatal stress induced higher levels of total and free corticosterone secretion at the end of the light period in both males and females, and hypercorticism over the entire diurnal cycle in females. No diurnal fluctuation of adrenocorticotropin was observed in any group studied. The effects of prenatal stress on corticosterone secretion could be mediated, at least in part, by a reduction in corticosteroid receptors at specific times of day. Results also show that prepartal stress alters the pattern of corticosterone secretion in pregnant females. Those data indicate that prenatally stressed rats exhibit an altered temporal functioning of the HPA axis, which, taken together with their abnormal response to stress, reinforces the idea of a general homeostatic dysfunction in those animals. © 1999 John Wiley & Sons, Inc. J Neurobiol 40: 302–315, 1999
Two neuronal calcium-binding proteins, calbindin-D28k (CaBP) and parvalbumin (PV), were localized in the normal rat hippocampus by using immunocytochemical methods to determine (1) their location and (2) whether a correlation exists between the presence of these two calcium-binding proteins and the selective vulnerability of different hippocampal neuronal populations to experimental seizure activity.
CaBP-like immunoreactivity (CaBP-LI) is present in all dentate granule cells and some, but not all, CA1 and CA2 pyramidal cells. Some CA1 pyramidal cells lack CaBP-LI, and those that do are lightly stained compared to the dentate granule cells. CA3 pyramidal cells appear to contain neither CaBP- nor PV-LI, and no granule or pyramidal cells exhibit PV-LI. CaBP-LI is present in distinct populations of dentate and hippocampal interneurons but absent from others. In area dentata, CaBP-LI is present in a small number of interneurons of the molecular and granule cell layers and in a small population of presumed basket cells in or below the granule cell layer. Conversely, more presumed dentate basket cells exhibit PV-LI than CaBP-LI. In the hilus of area dentata, few cells are CaBP- or PV-immunoreactive. The hilar somatostatin/neuropeptide Y (NPY)-immunoreactive cells and hilar mossy cells, two distinct and large populations, lack CaBP- and PV-LI. In the CA3 region, CaBP-LI is present in a relatively small number of interneurons in each stratum. PV-immunoreactive interneurons in area CA3 are more numerous. In area CA1, CaBP-LI is present in many interneurons in strata radiatum and lacunosum-moleculare. Some, but relatively fewer, CaBP-positive interneurons are present in strata pyramidale and oriens. Conversely, PV-immunoreactive interneurons are numerous in strata pyramidale and oriens but rare in strata radiatum and lacunosummoleculare.
Staining with the particulate chromagen benzidine hydrochloride revealed a previously undescribed dense band of CaBP-LI in the inner dentate molecular layer, a lamina enriched with kainate-displaceable glutamate-binding sites and innervated by the apparently excitatory ipsilateral associational/commissural (IAC) pathway that originates in the CaBP-negative hilar mossy cells. Bilateral electrical stimulation of the perforant path was performed in order to destroy the hilar mossy cells and to determine if this band of CaBP-LI is normally present within the mossy cell terminals. Perforant path stimulation that destroyed hilar mossy cells throughout the dorsal portions of both hippocampi did not abolish the dense CaBP-like immunoreactivity in the inner molecular layer.
In summary, the cell populations visualized by immunocytochemical staining for CaBP- or PV-LI are clearly distinct. All of the relatively seizure-resistant dentate granule cells and many basket cells and hippocampal CA2 pyramidal cells are darkly stained for either CABP- or PV-LI. The seizuresensitive dentate hilar somatostatin/NPY-positive cells, hilar mossy cells, and hippocampal CA3 pyramidal cells appear devoid of both CaBP- and PV-LI. The seizure sensitive CA1 pyramidal cells are devoid of PV-LI and exhibit less CaBP-LI than the seizure-resistant granule cells. Therefore, a positive correlation exists between the presence of at least one of these calcium-binding proteins in hippocampal neurons and their relative resistance to seizure-induced neuronal damage.
These data suggest that the relative vulnerability of different cell populations may be related to differences in the concentration of cytoplasmic proteins capable of sequestering free intracellular calcium.
Stress may contribute to aging acceleration and age-related degenerative diseases. Stress and adaptation to stress require
numerous homeostatic adjustments including hormones, neurotransmitters, oxidants, and other mediators. The stress-induced
hormones, neurotransmitters, and oxidants all have beneficial, but also harmful effects if out of balance. Therefore, the
homeostasis of stress and adaptation should be governed by the hormone balance, neurotransmitter balance, and oxidant balance,
as well as the interactions among these substances. The imbalance and the over-interaction of these balances may ultimately
cause increased oxidant generation and oxidative damage to biomolecules. This increased oxidative damage may add to the oxidant
burden associated with normal aerobic metabolism, which in itself, generates oxidants, causes accumulation of oxidative damage
in mitochondria, and contributes to normal aging. Therefore, the stress-associated increase of oxidative damage may, in part,
contribute to stress-associated aging acceleration and age-related neurodegenerative diseases.
Postnatal environmental manipulations naturally occur on the background of prenatal experiences. In the laboratory rat, both pre- and postnatal environmental manipulations have been shown to alter adult behaviour. Additionally, it has been demonstrated that the consequences of postnatal manipulations can be altered by previous prenatal stress experience (PS). In the present study, we investigated long-term behavioural consequences of combined PS and postnatal experience, namely repeated maternal separation (MS). PS primarily increases emotionality and fear-related behaviour, while postnatal repeated MS has been previously reported to affect primarily attentional processes. Thus, we tested adult male and female Wistar rats on paradigms involving both emotionality and attention, namely open field, prepulse inhibition (PPI), and latent inhibition (LI) in the active avoidance and the conditioned emotional response paradigms. In line with previous reports, PS decreased open-field locomotion and impaired avoidance learning (increased emotionality), while MS enhanced LI (selective attention) and improved avoidance learning. Further, PS also increased PPI. There was little interaction between the two manipulations: The increased PPI seen after PS was normalised by MS, and the MS-induced enhancement of LI (using the active avoidance paradigm) was not evident in subjects previously subjected to PS. Taken together, these results suggest that the effects of PS and repeated MS are not synergistic in any of the investigated paradigms but can antagonise each other. Thus, in assessing the effects of postnatal manipulations, attention should be paid to the inadvertent occurrence of prenatal stress.
The concentration of calcium in the cytosol regulates many vital cellular processes, yet until recently techniques for measuring free calcium have been technically demanding and applicable to few cell types. The recent introduction of a novel fluorescent indicator, quin2, and a simple way of trapping it in the cytosol of intact cells, has provided a widely applicable method for measuring and manipulating intracellular free calcium.
The use of dichlorofluorescin (DCFH) as a measure of reactive oxygen species was studied in aqueous media. Hydrogen peroxide oxidized DCFH to fluorescent dichlorofluorescein (DCF), and the oxidation was amplified by the addition of ferrous iron. Hydrogen peroxide-induced DCF formation in the presence of ferrous iron was completely inhibited by deferoxamine and partially inhibited by ethylenediaminetetraacetic acid, but was augmented by diethylenetriaminepentaacetic acid. Iron-peroxide-induced oxidation of DCFH was partially inhibited by catalase but not by horseradish peroxidase. Nonchelated iron-peroxide oxidation of DCFH was partially inhibited by several hydroxyl radical scavengers, but was independent of the scavenger concentration, and this suggests that free hydroxyl radical is not involved in the oxidation of DCFH in this system. Superoxide anion did not directly oxidize DCFH. Data suggest that H2O2-Fe(2+)-derived oxidant is mainly responsible for the nonenzymatic oxidation of DCFH. In addition, peroxidase alone and oxidants formed during the reduction of H2O2 by peroxidase oxidize DCFH. Since DCFH oxidation may be derived from several reactive intermediates, interpretation of specific reactive oxygen species involved in biological systems should be approached with caution. However, DCFH remains an attractive probe as an overall index of oxidative stress in toxicological phenomena.
Previous experiments revealed that 14-day-old prenatally stressed rats have significantly elevated concentrations of plasma adrenocorticotrophic hormone (ACTH) and corticosterone suggesting these animals have an overactive hypothalamic-pituitary-adrenal (HPA) system. In these studies, however, stress-induced hormone levels were determined only immediately after exposure to an acute stressor. Therefore, in the current study, we examined in postnatal days 7, 14 and 21 prenatally stressed rats the stress-induced time course of this pituitary-adrenal hormone elevation. Plasma ACTH and corticosterone were measured in the basal state and at 0.0, 0.5, 1.0, 2.0 and 4.0 h after a 10-min exposure period to foot shocks administered in the context of social isolation. Results indicated that at all 3 ages, plasma ACTH in prenatally stressed rats was significantly elevated. Corticosterone concentrations were also significantly higher in prenatally stressed than in control rats, especially in day 14 rats. Analysis of stress-induced hormone fluctuations over time indicated that by 14 days of age, both prenatally stressed than in control and control rats had significant increases in plasma ACTH and corticosterone after exposure to stress. Furthermore, although prenatally stressed rats had significantly higher pituitary-adrenal hormone concentrations than control animals, the post-stress temporal patterns of decline in ACTH and corticosterone levels were similar between groups. Results suggest that throughout the preweaning period, prenatal stress produces an HPA system that functions in a manner similar to that of controls but at an increased level.
Neurotoxic effects of prenatal administration of dexamethasone were examined in the fetal rhesus monkey brain at 135 and 162 days of gestation (term is 165 days). In an experimental design mimicking human clinical trials, dexamethasone was given intramuscularly to pregnant monkeys on day 132 (single injection with doses of 0.5, 5, or 10 mg/kg maternal body weight) or on days 132 and 133 (multiple injections at 12-h intervals with 0.125 x 4, 1.25 x 4, or 2.5 mg/kg x 4). The fetuses were delivered by caesarean section on day 135 or day 162 and hippocampal slices were prepared for evaluation. Light and electron microscopic observation revealed decreased numbers of pyramidal neurons in the hippocampal CA regions and of granular neurons in the dentate gyrus associated with degeneration of neuronal perikarya and dendrites. Axodendritic synaptic terminals of the mossy fibers in the CA3 hippocampal region showed pronounced degeneration. Degeneration was dose-dependent and multiple injections induced more severe damage than single injections of the same total dose. Even the lowest dose (0.5 mg/kg, which is similar to the dose used in human clinical trials) produced these changes. Degenerative changes induced by dexamethasone treatment (5 mg/kg) on days 132 and 133 were also clearly evident in fetuses studied at 162 days. Therefore, caution is recommended in the use of prenatal corticosteroids in premature deliveries.
Two receptor systems for corticosterone (CORT) can be distinguished in rat brain: mineralocorticoid-like or CORT receptors (CR) and glucocorticoid receptors (GR). The microdistribution and extent of occupation of each receptor population by CORT were studied. The CR system is restricted predominantly to the lateral septum and hippocampus. Within the hippocampus, the highest density occurs in the subiculum +/- CA1 cell field (144 fmol/mg protein) and the dentate gyrus (104 fmol/mg protein). Affinity of CR for CORT was very high (Kd, approximately 0.5 nM). The GR system has a more widespread distribution in the brain. The highest density for GR is in the lateral septum (195 fmol/mg protein), the dentate gyrus (133 fmol/mg protein), the nucleus tractus solitarii and central amygdala. Substantial amounts of GR are present in the paraventricular nucleus and locus coeruleus and low amounts in the raphe area and the subiculum + CA1 cell field. The affinity of GR for CORT (Kd, approximately 2.5-5 nM) was 6- to 10-fold lower than that of CR. Occupation of CR by endogenous ligand was 89.5% during morning trough levels of pituitary-adrenal activity (plasma CORT, 1.4 micrograms/100 ml). Similar levels of occupation (88.7% and 97.6%) were observed at the diurnal peak (plasma CORT, 27 micrograms/100 ml) and after 1 h of restraint stress (plasma CORT, 25 micrograms/100 ml), respectively. Furthermore, a dose of 1 microgram CORT/100 g BW, sc, resulted in 80% CORT receptor occupation, whereas GR were not occupied. For 50% occupation of GR, doses needed to be increased to 50-100 micrograms/100 g BW, and for 95% occupation, a dose of 1 mg CORT was required. The plasma CORT level at the time of half-maximal GR occupation was about 25 micrograms/100 ml, which is in the range of levels attained after stress or during the diurnal peak of pituitary-adrenal activity. Thus, CR are extensively filled (greater than 90%) with endogenous CORT under most circumstances, while GR become occupied concurrent with increasing plasma CORT concentrations due to stress or diurnal rhythm. We conclude that CORT action via CR may be involved in a tonic (permissive) influence on brain function with the septohippocampal complex as a primary target. In view of the almost complete occupation of CR by endogenous hormones, the regulation of the CORT signal via CR will, most likely, be by alterations in the number of such receptors. In contrast, CORT action via GR is involved in its feedback action on stress-activated brain mechanisms, and GR occur widely in the brain.(ABSTRACT TRUNCATED AT 400 WORDS)
Neuronal injury resulting from acute brain insults and some neurodegenerative diseases implicates N-methyl-D-aspartate (NMDA) glutamate receptors. The fact that antioxidants reduce some types of brain damage suggests that oxygen radicals may have a role. It has been shown that mutations in Cu/Zn-superoxide dismutase (SOD), an enzyme catalysing superoxide (O2.-) detoxification in the cell, are linked to a familial form of amyotrophic lateral sclerosis (ALS). Here we report that O2.- is produced upon NMDA receptor stimulation in cultured cerebellar granule cells. Electron paramagnetic resonance was used to assess O2.- production that was due in part to the release of arachidonic acid. Activation of kainic acid receptors, or voltage-sensitive Ca2+ channels, did not produce detectable O2.-. We also find that the nitrone DMPO (5,5-dimethyl pyrroline 1-oxide), used as a spin trap, is more efficient than the nitric oxide synthase inhibitor, L-NG-nitro-arginine, in reducing NMDA-induced neuronal death in these cultures.
Previous research indicates that the offspring of dams exposed to stress during late gestation show altered hypothalamic-pituitary-adrenal (HPA) responses to stress. However, the results are inconsistent and a review of the literature suggests that the effects may differ depending upon the gender of the offspring. In the present study, we measured plasma adrenocorticotropin (ACTH) and corticosterone (B) levels prior to, and at 0, 20, 40 and 70 min following restraint stress in catheterized adult male and female offspring of dams stressed in the last week of gestation (i.e. days 15-19 of gestation). Prenatal stress significantly increased both plasma ACTH and B levels in response to restraint, but only in females; male offspring were largely unaffected. In addition, plasma corticosteroid-binding globulin (CBG) levels were significantly increased in prenatally-stressed females, but not in males. Despite these differences in plasma CBG, estimated free B levels following restraint were also significantly elevated in prenatally-stressed females. We then examined glucocorticoid receptor binding in a variety of forebrain structures. Prenatal stress had no effect on glucocorticoid receptor density in the hypothalamus or hippocampus in either males or females. Differences in glucocorticoid receptor density across groups were observed in the septum, frontal cortex, and amygdala. However, the pattern of observed differences across the groups was not consistent with the pattern of hormonal differences. In summary, the effect of prenatal stress on HPA function is substantially more marked in females than in males. Interestingly, a similar pattern of effects on HPA activity has been reported for prenatal alcohol exposure.
Severe and prolonged physical and psychological stress is known to cause brain damage; long-term torture victims in prison have later developed psychiatric disorders and cerebral cortical atrophy observed in CT scans (Jensen, Genefke, Hyldebrandt, Pedersen, Petersen, and Weile, 1982). In nonhuman primates, we observed degeneration and depletion of the hippocampal neurons in African green monkeys that had been severely abused by cagemates and died with complications of multiple gastric ulcers and adrenal cortical hyperplasia (Uno, Tarara, Else, Suleman and Sapolsky, 1989). In our previous studies the administration of dexamethasone (DEX) (5 mg/kg) to pregnant rhesus monkeys at 132 to 133 days of gestation induced degeneration and depletion of the hippocampal pyramidal and dentate granular neurons in the brains of 135-gestation-day fetuses, and these changes were retained in the brains of fetuses at near term, 165 days of gestation (Uno, Lohmiller, Thieme, Kemnitz, Engle, Roecker, and Farrell, 1990). We also found that implantation of a cortisol pellet in the vicinity of the hippocampus in adult vervet monkeys induced degeneration of the CA3 pyramidal neurons and their dendritic branches (Sapolsky, Uno, Rebert, and Finch, 1990). Thus, hippocampal pyramidal neurons containing a high concentration of glucocorticoid receptors appear to be highly vulnerable to either hypercortisolemia caused by severe stress or to exposure to exogenous glucocorticoids. To study the long-term postnatal sequelae of prenatal brain damage, eight rhesus monkeys were treated with either DEX (5 mg/kg), 5 animals, or vehicle, 3 animals, at 132 to 133 days of gestation. After natural birth, all animals lived with their mothers for 1 year. At 9 months of age, we found that DEX-treated animals had significantly high plasma cortisol at both base and post-stress (isolation) levels compared to age-matched vehicle-treated animals. Magnetic resonance images (MRI) of the brain at 20 months of age showed an approximately 30% reduction in size and segmental volumes of the hippocampus in DEX-treated compared to vehicle-treated animals. Measurements of whole brain volume by MRI showed no significant differences between DEX and vehicle groups. Prenatal administration of a potent glucocorticoid (DEX) induced an irreversible deficiency of the hippocampal neurons and high plasma cortisol at the circadian baseline and post-stress levels in juvenile rhesus monkeys. These results suggest that the hippocampus mediates negative feedback of cortisol release; a lack or deficiency of the hippocampal neurons attenuates this feedback resulting in hypercortisolemia.(ABSTRACT TRUNCATED AT 400 WORDS)
The hippocampal damage caused by stress has been attributed to an increased glutamatergic tone brought about by secretion of glucocorticoids. Although exposure to stress has been shown to increase the outflow of glutamate, direct involvement of glucocorticoid in this phenomenon has not been examined. The present study demonstrates that adrenalectomy attenuates the stress-induced outflow of glutamate in the hippocampus and prefrontal cortex and that glucocorticoid replacement abolishes this attenuation.
The effect of stress to the pregnant mother on hormonal responses of the offspring to stressful events was investigated in juvenile rhesus monkeys. Six pregnant monkeys were repeatedly removed from their home cages and exposed to unpredictable noise during mid- to late gestation (Days 90-145 postconception), while six undisturbed pregnant mothers served as controls. Blood samples were collected from the juvenile offspring under anesthesia on four occasions and assayed for ACTH and cortisol. In a second experiment, blood samples were collected from the awake offspring under a baseline and four progressively stressful conditions. Offspring of stressed mothers showed higher ACTH and cortisol levels than control offspring at all four anesthesia samples and at a nonanesthesized home cage baseline. Prenatally stressed offspring also showed higher ACTH values in all four stress conditions. Cortisol values were similar for the two groups under the stress conditions. The disparity between the two groups in the relationship between ACTH and cortisol was greatest in the most stressful condition, suggesting regulatory differences between the two groups. These results indicate that offspring of primate mothers stressed during pregnancy show enhanced HPA axis responsivity to stressors later in life, and concur with rodent findings indicating that prenatal stress may have long-term effects on HPA axis regulation.
The immature human brain undergoes remarkable organizational changes during intrauterine and postnatal life. These changes create potential temporal 'windows' of selective vulnerability to damage. For example, the temporary germinal matrix is vulnerable to hemorrhage in the third trimester fetus and premature infant. The immature oligodendroglia present in developing white matter of the fetus are also vulnerable to injury producing periventricular leukomalacia. Similar changes take place in the synapses that make up the infant's neuronal circuitry. In human cerebral cortex, synapses are produced in greater than adult numbers by postnatal age 2 years and then reduced over the next decade. Over the same period receptors for glutamate, the most important excitatory neurotransmitter, change their characteristics to allow them to participate in activity dependent synaptic plasticity. For example, the immature N-methyl-D-aspartate (NMDA) type glutamate receptor/channel complex, which plays important roles in long term potentiation (LTP), neuronal migration and synaptic pruning, contains subunits that allow the channel to be opened more easily for a longer period than adult channels. These developmental changes make the immature brain selectively vulnerable to NMDA receptor overstimulation that can occur during hypoxia-ischemia and other insults. Several types of neuropathology in the developing brain can be understood on the basis of these organizational principles.
Modern populations are constantly exposed to a variety of compounds in the workplace and the environment that promote formation of reactive oxygen species (ROS) within susceptible tissues. Due to its high oxygen consumption, the brain may be particularly vulnerable to oxidative damage and degeneration. Agents that impact cellular oxidative homeostasis would therefore be expected to alter the toxicity of ROS generating compounds. We are testing this hypothesis using endogenous stress hormones, glucocorticoids, to perturb neuronal homeostasis, and adriamycin to generate ROS. Glucocorticoids (GCs) are hormones secreted by the adrenals in response to stress, and are also prescribed clinically to control inflammatory and autoimmune disorders in millions of people annually. Therefore, high GC levels may not be uncommon in individuals exposed to low levels of toxic compounds. Also, GCs appear to act on cellular pathways relevant to ROS as seen by their potentiation of neurodegeneration following insults such as stroke, hypoglycemia and seizure. Using rat primary neuronal culture, we determined neuronal susceptibility to adriamycin toxicity by cell counting (using MAP-2 staining). Dichlorofluorescein fluorescence confirmed ROS generation after adriamycin administration. Physiological levels of GCS (up to mM concentrations) in the culture media exacerbated both adriamycin toxicity and ROS generation. We hypothesize that GCs may exacerbate the toxicity of three neurotoxins whose mechanisms of action overlap GC pathways.
Mild prenatal stress affects the serotonergic system in the hippocampus of rat offspring. Pregnant rats were daily exposed to mild stress treatments (consisting of crowding and saline injection) during days 15 to 21 of pregnancy. Their offspring were assessed by a series of biochemical, histological and behavioral tests. On 35 days after birth, 5-hydroxytryptamine (5-HT) level was decreased by 17% (P < 0.05), whereas 5-hydroxyindolacetic acid (5-HIAA) level was increased by 18% (P < 0.05) in the offspring of prenatally stressed rats. The metabolic rate (5-HIAA/5-HT) was increased by 49% (P < 0.01). Synaptic density in the hippocampus of prenatally stressed offspring was also decreased by 32% (P < 0.0001) on postnatal day 35. There was no significant group difference in the spatial learning acquisition test of the Morris water maze; however, in the reversal task, prenatally stressed 5-week old rats spent more time than control animals searching for the platform of the pool. Escape latency in the cued test showed no significant difference. Together with data in our previous studies, that have shown 5-HT to facilitate synapse formation and maintenance in the central nervous system, synaptic loss is suggested to occur in relation to changes of 5-HT system in the hippocampus of prenatally stressed offspring. This may be associated with reported changes in behavior and learning ability in prenatally stressed offspring.
Experiments were conducted to test the hypothesis that exposure to uncontrollable stress during pregnancy results in a heightened elevation of plasma glucocorticoids. Rats were exposed to uncontrollable electric tail shocks every other day during the 3 weeks of pregnancy. Plasma corticosterone concentrations in stressed dams increased significantly from gestation days 4 to 20. Importantly, this increase in plasma corticosterone occurred 24- and 48-h after exposure to stress suggesting a prolonged elevation in stress-induced glucocorticoid secretion. In addition, the stress-induced rise in plasma corticosterone was accompanied by a significant decrease in maternal levels of corticosteroid binding globulin which suggests increased circulating levels of free corticosterone. Significant stress-induced elevations in plasma corticosterone also occurred in fetuses that were examined on gestation day 20. Furthermore, a significant positive correlation was found between maternal and fetal plasma corticosterone. Results demonstrate that repeated exposure to uncontrollable stress increases plasma concentrations of glucocorticoids throughout pregnancy. In the unbound state, corticosterone may be highly effective in producing alterations in brain development of offspring. These data have important implications for understanding the process underlying the effects of prenatal stress.
Interest in the role of mitochondria in aging has intensified in recent years. This focus on mitochondria originated in part from the free radical theory of aging, which argues that oxidative damage plays a key role in degenerative senescence. Among the numerous mechanisms known to generate oxidants, leakage of the superoxide anion and hydrogen peroxide from the mitochondrial electron transport chain are of particular interest, due to the correlation between species-specific metabolic rate ("rate of living") and life span. Phenomenological studies of mitochondrial function long ago noted a decline in mitochondrial function with age, and on-going research continues to add to this body of knowledge. The extranuclear somatic mutation theory of aging proposes that the accumulation of mutations in the mitochondrial genome may be responsible in part for the mitochondrial phenomenology of aging. Recent studies of mitochondrial DNA (mtDNA) deletions have shown that they increase with age in humans and other mammals. Currently, there exist numerous important and fundamental questions surrounding mitochondria and aging. Among these are (1) How important are mitochondrial oxidants in determining overall cellular oxidative stress? (2) What are the mechanisms of mitochondrial oxidant generation? (3) How are lesions and mutations in mtDNA formed? (4) How important are mtDNA lesions and mutations in causing mitochondrial dysfunction? (5) How are mitochondria regulated, and how does this regulation change during aging? (6) What are the dynamics of mitochondrial turnover? (7) What is the relationship between mitochondrial damage and lipofuscinogenesis? (8) What are the relationships among mitochondria, apopotosis, and aging? and (9) How can mitochondrial function (ATP generation and the establishment of a membrane potential) and dysfunction (oxidant generation) be modulated and degenerative senescence thereby treated?
The present study was undertaken to determine if the concentration of brain N-acetyl-aspartate (NAA), a putative neuronal marker, is reduced in adult rats subjected to stress during the perinatal period. As the prenatal stressor, pregnant rats were subjected to restraint stress for one hour twice daily from days 14-21 of gestation; stressed offspring were reared by normal dams and studied as adults. As the postnatal stressor, normal pups were reared by prenatally 'stressed' dams and studied as adults. As compared to non-stressed controls (n=6), NAA concentrations were significantly reduced 21 and 25% in left frontal cortex from the prenatal (n=4) and postnatal (n=6) stress groups. respectively. The data suggest that in perinatally stressed adult offspring permanent neuronal damage or loss has occurred. While no direct causal associations between perinatal stress and the developmental of particular disorders can be inferred from these limited data, the effects of perinatal stress on subsequent brain neuropathology are reviewed. particularly in relation to NAA. For hypothesis-generating purposes, the possible relevance of stress and NAA to the neurodevelopmental hypothesis of schizophrenia is discussed in greater detail.
Prenatal stress impairs activity of the hypothalamo-pituitary-adrenal (HPA) axis in response to stress in adult offspring. So far, very few data are available on the effects of prenatal stress on circadian functioning of the HPA axis. Here, we studied the effects of prenatal stress on the circadian rhythm of corticosterone secretion in male and female adult rats. To evaluate the effects of prenatal stress on various regulatory components of corticosterone secretion, we also assessed the diurnal fluctuation of adrenocorticotropin, total and free corticosterone levels, and hippocampal corticosteroid receptors. Finally, in the search of possible maternal factors, we studied the effects of repeated restraint stress on the pattern of corticosterone secretion in pregnant female rats. Results demonstrate that prenatal stress induced higher levels of total and free corticosterone secretion at the end of the light period in both males and females, and hypercorticism over the entire diurnal cycle in females. No diurnal fluctuation of adrenocorticotropin was observed in any group studied. The effects of prenatal stress on corticosterone secretion could be mediated, at least in part, by a reduction in corticosteroid receptors at specific times of day. Results also show that prepartal stress alters the pattern of corticosterone secretion in pregnant females. Those data indicate that prenatally stressed rats exhibit an altered temporal functioning of the HPA axis, which, taken together with their abnormal response to stress, reinforces the idea of a general homeostatic dysfunction in those animals.
During the development of the nervous system, a large number of neurons are eliminated through naturally occurring neuronal death. Many morphological and biochemical properties of such dying neurons are reminiscent of apoptosis, a type of death involving the action of genetically-programmed events but also epigenetic phenomena including oxidative stress. The following review contains three parts focusing respectively on basic knowledge of neuronal death and redox regulation, the mechanisms involved in neuronal death which are ordered in three sequential phases, and on the complex relations between neuronal fate and the redox status. Finally, we point out that oxidants are not always detrimental for neuronal survival. On the one hand, dying neurons often display signs of oxidative stress, including an elevation of their intracellular concentration of free radicals. Antioxidants may reduce the extent of neuronal death, suggesting a causal implication of free radicals in the death-process. On the other hand, at high concentrations antioxidants may lose their protective effects on developing neurons, and a non-lethal oxidative stress may potentiate the protective effects of other agents. These data suggest that free radicals, perhaps through their effects on cellular signalling pathways, may have positive effects on neuronal survival, provided that their intraneuronal concentrations are maintained at low levels. Much evidence suggests that the neuronal redox status must be maintained within a narrow range of values compatible with survival. Antioxidants may protect neurons subjected to an oxidative stress following axotomy or trophic factor-deprivation; but excessive reduction may become equally detrimental for neurons.
The generation of reactive oxygen species (ROS) and resultant oxidative stress have been implicated in the mechanism of brain dysfunction due to age-related neurodegenerative diseases or exposure to environmental chemicals. We have investigated intrinsic age-related differences in the ability of the various brain regions to generate ROS in the absence and presence of Fe(2)+. ROS production in crude brain homogenates from adult rats was linear with respect to time and tissue concentration, and was stimulated to a greater extent by Fe(2)+ than was TBARS production. ROS production was then determined in homogenates from cerebral cortex, striatum, hippocampus, and cerebellum of 7-day-old, 14-day-old, 21-day-old, adult (3-6-month old), and aged (24-month-old) rats using the fluorescent probe 2',7'-dichlorodihydrofluorescin (DCFH). Basal levels of ROS production were similar in 7-, 14-, and 21-day olds, increased in adults, and highest in aged rats, and did not differ between brain regions. ROS production was stimulated by Fe(2)+ (0. 3-30 microM) in a concentration-dependent manner in all brain regions. However, the stimulation of ROS production by Fe(2)+ varied with age. ROS production was greater in 14- and 21-day-old rats compared with adult and aged animals. ROS production in 7-day-old rats was decreased at low Fe(2)+ concentrations and increased at high Fe(2)+ concentrations compared to adult and aged rats. These data show that brain homogenates from neonatal rats respond differently to Fe(2)+, and suggest that developing animals may be more sensitive to oxidative stress in the brain after exposure to toxicants. Published by Elsevier Science Inc.
Exposure of pregnant rats to stress results in offspring that exhibit abnormally fearful behavior and have elevated neuroendocrine responses to novelty and aversive stimuli. This study examined the effects of prenatal stress on plasma corticosterone, adrenal weight, defensive withdrawal behavior, and the density of receptors for corticotropin releasing factor (CRF) in the amygdala. Pregnant Sprague-Dawley rats were stressed by daily handling and saline injection (s.c., 0.9%, 0.1 mL) during the last week of gestation. Male offspring were studied at adulthood (60-120 days of age). Adrenal hypertrophy and increased plasma corticosterone were observed in the prenatally stressed offspring. Defensive withdrawal, an ethological measure of the conflict between exploratory behavior and retreat, was quantified in naive offspring, and in offspring exposed to restraint stress (2 h). Restraint stress increased defensive withdrawal in both control and prenatally stressed offspring. Both naive and restraint-stressed prenatally stressed offspring exhibited increased defensive withdrawal compared to control offspring. There was a significant interaction between prenatal stress and restraint stress, suggesting increased vulnerability of prenatally stressed offspring. The effects of restraint in the defensive withdrawal test were reduced by intracerebroventricular administration of the CRF antagonists, alpha-helical CRF9-41 (20 microg every hour) or D-phe(12), Nle(21, 38), C(alpha)-MeLeu(37)]-CRF((12-41)) (5 microg every hour) during the restraint period. The difference between control and prenatally stressed offspring was abolished by the CRF antagonists, suggesting that increased activation of CRF receptors may be a factor in the behavioral abnormalities of prenatally stressed rats. Measurement of CRF receptors in amygdala revealed a 2.5-fold increase in binding in prenatally stressed offspring. In light of previous work from this laboratory demonstrating increased content and release of CRF in amygdala from prenatally stressed offspring, the present study suggests that the increased fearfulness of prenatally stressed rats may be a consequence of increased activity of CRFergic systems in the amygdala.
The hormones and other physiological agents that mediate the effects of stress on the body have protective and adaptive effects in the short run and yet can accelerate pathophysiology when they are over-produced or mismanaged. Here we consider the protective and damaging effects of these mediators as they relate to the immune system and brain. 'Stress' is a principle focus, but this term is rather imprecise. Therefore, the article begins by noting two new terms, allostasis and allostatic load that are intended to supplement and clarify the meanings of 'stress' and 'homeostasis'. For the immune system, acute stress enhances immune function whereas chronic stress suppresses it. These effects can be beneficial for some types of immune responses and deleterious for others. A key mechanism involves the stress-hormone dependent translocation of immune cells in the blood to tissues and organs where an immune defense is needed. For the brain, acute stress enhances the memory of events that are potentially threatening to the organism. Chronic stress, on the other hand, causes adaptive plasticity in the brain, in which local neurotransmitters as well as systemic hormones interact to produce structural as well as functional changes, involving the suppression of ongoing neurogenesis in the dentate gyrus and remodelling of dendrites in the Ammon's horn. Under extreme conditions only does permanent damage ensue. Adrenal steroids tell only part of the story as far as how the brain adapts, or shows damage, and local tissue modulators - cytokines for the immune response and excitatory amino acid neurotransmitters for the hippocampus. Moreover, comparison of the effects of experimenter-applied stressors and psychosocial stressors show that what animals do to each other is often more potent than what experimenters do to them. And yet, even then, the brain is resilient and capable of adaptive plasticity. Stress-induced structural changes in brain regions such as the hippocampus have clinical ramifications for disorders such as depression, post-traumatic stress disorder and individual differences in the aging process.
The effects of maternal stress, termed prenatal stress (PNS) on the neuroendocrine regulation of reproduction and the stress reactivity of offspring were studied in rats. PNS prevented the formation of sexual dimorphism in catecholamine levels, aromatase activity, and androgen 5alpha-reductase activity in the preoptic area of the brain and the mediobasal hypothalamus in 10-day-old rats. The morphological correlate of the functional lesions induced by PNS consisted of the elimination of gender-related differences in the volumes of neuron nuclei in the suprachiasmatic nucleus. Prenatal stress altered the stress and adrenergic reactivities of the hypothalamo-hypophyseal-adrenal system in mature males and females. The long-term effects of PNS were regarded as a consequence of the disruption of the hormone-neurotransmitter imprinting of the neuroendocrine system.
Retrospective studies in humans suggest that chronic maternal stress during pregnancy, associated with raised plasma levels of CRH, ACTH and cortisol may increase the likelihood of preterm birth, developmental delays and behavioural abnormalities in the children. In adulthood, it may contribute to the significant association between the incidence of schizophrenia, increased left or mixed handedness, reduction in cerebral asymmetry and anomalies in brain morphology. Our studies and others have shown that prenatal stress in rats can mimic these developmental and behavioural alterations. These rats show a reduced propensity for social interaction, increased anxiety in intimidating or novel situations and a reduction in cerebral asymmetry and dopamine turnover, consistent with those in schizophrenic humans. Prenatally-stressed (PS) rats also show behaviour consistent with depression, including a phase-shift in their circadian rhythm for corticosterone, sleep abnormalities, a hedonic deficit and greater acquisition of learned helplessness under appropriate conditions. These behavioural abnormalities are associated with impaired regulation of the hypothalamic-pituitary-adrenal axis response to stress and increased CRH activity. PS males may show demasculinisation and feminisation of their sexual behaviour. The developmental and behavioural abnormalities in PS offspring could occur through sensitisation of the foetal brain by maternal stress hormones to the action of glucocorticoid and CRH and to neurotransmitters affected by them. This may have long-lasting consequences and could explain the precipitation of depressive symptoms or schizophrenia by psychosocial stress in later life. The character of the behavioural abnormalities probably depends on the timing of the maternal stress in relation to development of the particular neuronal systems.
It has been recognized for some years that a prolonged Ca(2+) elevation that is predictive of impending cell death develops in cultured neurons following excitotoxic insult. In addition, neurons exhibit enhanced sensitivity to excitotoxic insult with increasing age in culture. However, little is known about the processes that selectively regulate the post-insult Ca(2+) elevation and therefore, it remains unclear whether it is associated specifically with age-dependent toxicity.Here, we tested the hypothesis that a group I metabotropic glutamate receptor antagonist selectively modulates the prolonged Ca(2+) elevation in direct association with its protective effects against excitotoxicity. Rat hippocampal cultures of two ages (8-9 and 21-28 days in vitro) were exposed to a 5-min glutamate insult (400 microM in younger and 10 microM in older cultures) sufficient to kill >50% of the neurons, and were treated with vehicle or the specific group I metabotropic glutamate receptor antagonist 1-aminoindan-1,5-dicarboxylic acid (AIDA; 1 mM), throughout and following the insult. Neuronal survival was quantified 24 h after insult. In parallel studies, neurons of similar age in culture were imaged ratiometrically with a confocal microscope during and for 60 min after the glutamate insult. A large post-insult Ca(2+) elevation was present in older but not most younger neurons. The N-methyl-D-aspartate receptor antagonist, MK-801, blocked the Ca(2+) elevation both during and following the insult. In contrast, AIDA blocked only the post-insult prolonged Ca(2+) elevation in older neurons. Moreover, AIDA was neuroprotective in older but not younger cultures. From these results we suggest that the post-insult Ca(2+) elevation is regulated differently from the Ca(2+) elevation during glutamate insult and is modulated by group I metabotropic glutamate receptors. Further, the prolonged Ca(2+) elevation appears to be directly linked to an age-dependent component of vulnerability.
The effect of different stage of prenatal stress on the spatial learning and memory of offspring rats
- Li X
Glucocorticoids may enhance oxygen radical‐mediated neurotoxicity
- McIntosh LJ