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Multidimensional analyses. Multidimensional analysis of the protein data set (markers of the glutamatergic synapse, synaptic vesicles-associated proteins, and stress-/anti-stress-related
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Brain aging may be programmed by early-life stress. Aging affects males and females differently, but how perinatal stress (PRS) affects brain aging between sexes is unknown. We showed behavioral and neurobiological sex differences in non-stressed control rats that were strongly reduced or inverted in PRS rats. In particular, PRS decreased risk-taki...
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... = p < 0.05; ** = p < 0.01; *** = p < 0.001. Males vs females # = p < 0.05; ## = p < 0.01; ### = p < 0.001 13.705, ##p = 0.0014; n = 6 rats/group) and GFAP (sex effect, F (1,19) = 16.466, ###p = 0.00067; n = 6 rats/group) in females of both groups (Fig. 5e). Representative immunoblots of GR and MR are shown in Fig. 5f. All immunoblots are shown in Supplementary Figs. 7, 8, and ...
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... multidimensional analyses revealed a demasculinization profile of the glutamatergic synapse induced by PRS in the ventral hippocampus ( Fig. 7a; demasculinization score, 1.41; Mann-WhitneyWilcoxon test, p = 0.002; n = 5-7 rats/group), in the dorsal hippocampus ( Fig. 7b; demasculinization score, 1.55; Mann-Whitney-Wilcoxon test, p = 0.0006; n = 5-9 rats/group) as well as in the prefrontal cortex ( Fig. 7c; demasculinization score, 1.50; Mann-WhitneyWilcoxon test, p < 0.0001; n ...
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... multidimensional analyses revealed a demasculinization profile of the glutamatergic synapse induced by PRS in the ventral hippocampus ( Fig. 7a; demasculinization score, 1.41; Mann-WhitneyWilcoxon test, p = 0.002; n = 5-7 rats/group), in the dorsal hippocampus ( Fig. 7b; demasculinization score, 1.55; Mann-Whitney-Wilcoxon test, p = 0.0006; n = 5-9 rats/group) as well as in the prefrontal cortex ( Fig. 7c; demasculinization score, 1.50; Mann-WhitneyWilcoxon test, p < 0.0001; n = 6-7 rats/group) but not in the striatum ( Fig. 7d; demasculinization score, 1.26; Mann-Whitney-Wilcoxon test, p = 0.06; n = ...
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... profile of the glutamatergic synapse induced by PRS in the ventral hippocampus ( Fig. 7a; demasculinization score, 1.41; Mann-WhitneyWilcoxon test, p = 0.002; n = 5-7 rats/group), in the dorsal hippocampus ( Fig. 7b; demasculinization score, 1.55; Mann-Whitney-Wilcoxon test, p = 0.0006; n = 5-9 rats/group) as well as in the prefrontal cortex ( Fig. 7c; demasculinization score, 1.50; Mann-WhitneyWilcoxon test, p < 0.0001; n = 6-7 rats/group) but not in the striatum ( Fig. 7d; demasculinization score, 1.26; Mann-Whitney-Wilcoxon test, p = 0.06; n = 6-7 rats/group). PRS did not induce a global defeminization profile of glutamatergic synapses in any of the brain regions studied. Of ...
Citations
... The rat model of perinatal stress (PRS), in which exposure of pregnant dams to restraint stress reduces maternal behavior [12], has face, construct, and pharmacological validity as an epigenetic model of stress-related disorders [8], where the age-dependent threshold for neurochemical and behavioral dysfunction is lowered [13]. The PRS rat model exhibits in the offspring stress-related hallmarks, including a lifelong disruption in the activity and feedback regulation of the hypothalamic-pituitary-adrenal stress axis [8], disrupted circadian rhythms and sleep-wake cycle, and a systemic proinflammatory profile in both adults [8] and aged rats [14]. During aging, PRS rats are also characterized by a display of hyperglycemia both under fasting conditions and in response to a glucose load, whereas insulinemia is not affected in adult and old PRS male rats and middle-aged (10-month-old) PRS females [15]. ...
... Spatial recognition: 17-month-old control and PRS rats whose mothers were treated with vehicle or carbetocin were tested using a 2-trial memory task in a Y-maze as previously described [14,49]. The Y-maze (Imetronic, Pessac, France) consisted of 3 identical arms illuminated by a dim light (35 lux) and enclosed by 36 cm high side walls. ...
The rat model of perinatal stress (PRS), in which exposure of pregnant dams to restraint stress reduces maternal behavior, is characterized by a metabolic profile that is reminiscent of the “metabolic syndrome”. We aimed to identify plasma metabolomic signatures linked to long-term programming induced by PRS in aged male rats. This study was conducted in the plasma and frontal cortex. We also investigated the reversal effect of postpartum carbetocin (Cbt) on these signatures, along with its impact on deficits in cognitive, social, and exploratory behavior. We found that PRS induced long-lasting changes in biomarkers of secondary bile acid metabolism in the plasma and glutathione metabolism in the frontal cortex. Cbt treatment demonstrated disease-dependent effects by reversing the metabolite alterations. The metabolomic signatures of PRS were associated with long-term cognitive and emotional alterations alongside endocrinological disturbances. Our findings represent the first evidence of how early life stress may alter the metabolomic profile in aged individuals, thereby increasing vulnerability to CNS disorders. This raises the intriguing prospect that the pharmacological activation of oxytocin receptors soon after delivery through the mother may rectify these alterations.
... We speculate that high maternal ACEs may have dysmasculinized fetal adrenal development in males. This is in line with preclinical studies in mice and rats showing that prenatal stress or gestational exposure to corticosteroids produce male offspring dysmasculinized across a range of outcomes, such as stress responsivity [58,59], gene expression in the brain [60], anogenital distance [20], sexual motivation and behavior [61][62][63][64], spatial memory [65], as well as play, exploratory, and risk-taking behaviors [65,66]. The underlying mechanism for these effects may be stress hormone disruption of testosterone production during important early developmental stages of sex differentiation [67]. ...
... We speculate that high maternal ACEs may have dysmasculinized fetal adrenal development in males. This is in line with preclinical studies in mice and rats showing that prenatal stress or gestational exposure to corticosteroids produce male offspring dysmasculinized across a range of outcomes, such as stress responsivity [58,59], gene expression in the brain [60], anogenital distance [20], sexual motivation and behavior [61][62][63][64], spatial memory [65], as well as play, exploratory, and risk-taking behaviors [65,66]. The underlying mechanism for these effects may be stress hormone disruption of testosterone production during important early developmental stages of sex differentiation [67]. ...
Background:
The mechanisms by which parental early life stress can be transmitted to the next generation, in some cases in a sex-specific manner, are unclear. Maternal preconception stress may increase susceptibility to suboptimal health outcomes via in utero programming of the fetal hypothalamic-pituitary-adrenal (HPA) axis.
Methods:
We recruited healthy pregnant women (N = 147), dichotomized into low (0 or 1) and high (2+) adverse childhood experience (ACE) groups based on the ACE Questionnaire, to test the hypothesis that maternal ACE history influences fetal adrenal development in a sex-specific manner. At a mean (standard deviation) of 21.5 (1.4) and 29.5 (1.4) weeks gestation, participants underwent three-dimensional ultrasounds to measure fetal adrenal volume, adjusting for fetal body weight (waFAV).
Results:
At ultrasound 1, waFAV was smaller in high versus low ACE males (b = - 0.17; z = - 3.75; p < .001), but females did not differ significantly by maternal ACE group (b = 0.09; z = 1.72; p = .086). Compared to low ACE males, waFAV was smaller for low (b = - 0.20; z = - 4.10; p < .001) and high ACE females (b = - 0.11; z = 2.16; p = .031); however, high ACE males did not differ from low (b = 0.03; z = .57; p = .570) or high ACE females (b = - 0.06; z = - 1.29; p = .196). At ultrasound 2, waFAV did not differ significantly between any maternal ACE/offspring sex subgroups (ps ≥ .055). Perceived stress did not differ between maternal ACE groups at baseline, ultrasound 1, or ultrasound 2 (ps ≥ .148).
Conclusions:
We observed a significant impact of high maternal ACE history on waFAV, a proxy for fetal adrenal development, but only in males. Our observation that the waFAV in males of mothers with a high ACE history did not differ from the waFAV of females extends preclinical research demonstrating a dysmasculinizing effect of gestational stress on a range of offspring outcomes. Future studies investigating intergenerational transmission of stress should consider the influence of maternal preconception stress on offspring outcomes.
... This finding needs further investigation because previous studies found that men had higher SARS-CoV-2 infectivity rates compared to women [39][40][41][42], and male participants with underlying conditions, including diabetes, hypertension, and cardiovascular diseases developed a severe form of the infection, with increased mortality rate [43,44]. Many factors such as hormone-specific reaction and activity of X-linked genes, which modulate the innate and adaptive immune response to virus infection were suggested [41,42,[45][46][47][48]. As possible reasons for these observations. ...
... All the changes were reversed by treatment of finasteride and E2, respectively (Reynaert et al., 2016). In female elderly rats, PRS could enhance the expression of MRs and brain-derived neurotrophic factor (BDNF) in the ventral hippocampus, besides enhancing the expression of glial fibrillary acidic protein (GFAP) and BDNF in the PFC (Verhaeghe et al., 2021). It was reported that there was still no significant difference in plasma sex hormone content between the MS group (the MS group: 14-16 days after birth, 6 h a day) and the control group, but ERβ played a key role through a DNA methylation mechanism in early stress-mediated emotion and emotion-induced late LTP in adult male rats hippocampus (Wang et al., 2013). ...
Depression is a common psychiatric disease caused by various factors, manifesting with continuous low spirits, with its precise mechanism being unclear. Early life stress (ELS) is receiving more attention as a possible cause of depression. Many studies focused on the mechanisms underlying how ELS leads to changes in sex hormones, neurotransmitters, hypothalamic pituitary adrenocortical (HPA) axis function, and epigenetics. The adverse effects of ELS on adulthood are mainly dependent on the time window when stress occurs, sex and the developmental stage when evaluating the impacts. Therefore, with regard to the exact sex differences of adult depression, we found that ELS could lead to sex-differentiated depression through multiple mechanisms, including 5-HT, sex hormone, HPA axis, and epigenetics.
... В ходе постнатального развития происходит смена НР2Б-рецепторной субъединицы на НР2A-рецепторную. Чрезмерные уровни глюкокортикоидов стимулируют высвобождение глутамата (Verhaeghe et al. 2021), вызывая нейротоксичность, усиливающую апоптоз, что показано в гиппокампе и других областях мозга в течение первой послеродовой недели у крысы (Dührsen et al. 2013;Lu et al. 2003). Показано, что избирательная потеря белка НР2Б и последующая синаптическая дисфункция ослабляют активность префронтальной коры во время развития и провоцируют возникновение ранних когнитивных нарушений (Gulchina et al. 2017). ...
The deleterious effects of adversity are likely intergenerational, such that one generation’s adverse experiences can affect the next. Epidemiological studies link maternal adversity to offspring depression and anxiety, possibly via transmission mechanisms that influence offspring fronto-limbic connectivity. However, studies have not thoroughly disassociated postnatal exposure effects nor considered the role of offspring sex. We utilized infant neuroimaging to test the hypothesis that maternal childhood maltreatment (CM) would be associated with increased fronto-limbic connectivity in infancy and tested brain-behavior associations in childhood. Ninety-two dyads participated (32 mothers with CM, 60 without; 52 infant females, 40 infant males). Women reported on their experiences of CM and non-sedated sleeping infants underwent MRIs at 2.44 ± 2.74 weeks. Brain volumes were estimated via structural MRI and white matter structural connectivity (fiber counts) via diffusion MRI with probabilistic tractography. A subset of parents ( n = 36) reported on children’s behaviors at age 5.17 ± 1.73 years. Males in the maltreatment group demonstrated greater intra-hemispheric fronto-limbic connectivity ( b = 0.96, p= 0.008, [95%CI 0.25, 1.66]), no differences emerged for females. Fronto-limbic connectivity was related to somatic complaints in childhood only for males ( r = 0.673, p = 0.006). Our findings suggest that CM could have intergenerational associations to offspring brain development, yet mechanistic studies are needed.
Background
The mechanisms by which parental early life stress can be transmitted to the next generation, in some cases in a sex-specific manner, are unclear. Maternal preconception stress may increase susceptibility to suboptimal health outcomes via in utero programming of the fetal hypothalamic-pituitary-adrenal (HPA) axis.
Methods
We recruited healthy pregnant women (N = 147), dichotomized into low (0 or 1) and high (2+) adverse childhood experience (ACE) groups based on the ACE Questionnaire, to test the hypothesis that maternal ACE history influences fetal adrenal development in a sex-specific manner. At a mean (standard deviation) of 21.5 (1.4) and 29.5 (1.4) weeks gestation, participants underwent three-dimensional ultrasounds to measure fetal adrenal volume, adjusting for body weight (waFAV).
Results
At ultrasound 1, waFAV was smaller in high versus low ACE males (b= -0.17; z=-3.75; p < .001), but females did not differ by maternal ACE group (b = 0.09; z = 1.72; p = .086). Compared to low ACE males, waFAV was smaller for low (b=-0.20; z=-4.10; p < .001) and high ACE females (b=-0.11; z = 2.16; p = .031); however, high ACE males did not differ from low (b = 0.03; z = .57; p = .570) or high ACE females (b=-0.06; z=-1.29; p = .196). At ultrasound 2, compared to low ACE males, high ACE males (b=-0.08; z=-1.58; p = .114) and low ACE females (b=-0.09; z=-1.92; p = .055) had marginally smaller waFAV. Perceived stress did not differ between maternal ACE groups at baseline (t=-0.58; df = 142.18; p = .562), ultrasound 1 (t =-1.46; df = 141.05; p = .148), or ultrasound 2 (t=-0.67; df = 140.55; p = .504).
Conclusions
We observed a significant impact of high maternal ACE history on waFAV, a proxy for fetal adrenal development, but only in males. Our observation that the waFAV in males of mothers with a high ACE history did not differ from the waFAV of females extends preclinical research demonstrating a dysmasculinizing effect of gestational stress on a range of offspring outcomes. Future studies investigating intergenerational transmission of stress should consider the influence of maternal preconception stress on offspring outcomes.
The effect of moderate neonatal stress induced by inflammatory pain in rat pups of both sexes on the hormonal response and cognitive processes in adult animals was studied in the Morris water maze. No significant differences in spatial learning and memory were found in experimental rats exposed to neonatal inflammatory pain vs. control animals. However, experimental rats exhibited sex differences in long-term spatial memory whose efficiency was higher in males vs. females. After long-term memory testing, stress responsiveness of the hypothalamic-pituitary-adrenocortical axis, as assessed by the plasma corticosterone level in the formalin test, was higher in experimental males vs. females. Only experimental females exhibited differences between short-term and long-term memory, with the efficiency being higher in the former. Thus, sexual dimorphism was found in the effect of neonatal nociceptive stress on long-term spatial memory in adult rats: experimental males vs. females demonstrated more effective long-term memory combined with a higher stress reactivity of the hormonal response.
