Prenatal maternal stress and offspring aggressive behavior: Intergenerational and transgenerational inheritance.

Even though studies have shown that prenatal maternal stress is associated with increased reactivity of the HPA axis, the association between prenatal maternal stress and fetal glucocorticoid exposure is complex and most likely dependent on unidentified and poorly understood variables including nature and timing of prenatal insults. The precise mechanisms in which prenatal maternal stress influence neuroendocrine signaling between the maternal-placental-fetal interface are still unclear. The aim of this review article is to bring comprehensive basic concepts about prenatal maternal stress and mechanisms of transmission of maternal stress to the fetus. This review covers recent studies showing associations between maternal stress and alterations in offspring aggressive behavior, as well as the possible pathways for the "transmission" of maternal stress to the fetus: (1) maternal-fetal HPA axis dysregulation; (2) intrauterine environment disruption due to variations in uterine artery flow; (3) epigenetic modifications of genes implicated in aggressive behavior. Here, we present evidence for the phenomenon of intergenerational and transgenerational transmission, to better understands the mechanism(s) of transmission from parent to offspring. We discuss studies showing associations between maternal stress and alterations in offspring taking note of neuroendocrine, brain architecture and epigenetic changes that may suggest risk for aggressive behavior. We highlight animal and human studies that focus on intergenerational transmission following exposure to stress from a biological mechanistic point of view, and maternal stress-induced epigenetic modifications that have potential to impact on aggressive behavior in later generations.

Why Men Rape: Perspectives From Incarcerated Rapists in a KwaZulu-Natal Prison, South Africa.

Sexual offending is a global problem but is particularly prevalent on the African continent and in South Africa. Childhood experiences related to abuse, alcohol use, and criminal activities in the household and community has been associated with an increased risk for violence perpetration in adulthood. Less is known about sexual violence perpetration, especially in the South African context. In this study, the experiences of incarcerated male perpetrators of rape in South Africa are investigated along with the collective social context and individual childhood experiences that potentially contribute to rape perpetration. Eighteen male perpetrators of rape who were inmates at Westville Correctional Services in KwaZulu Natal, South Africa, were interviewed. The semi-structured in-depth qualitative interviews were transcribed, coded and annotated using an interpretive paradigm and thematic analysis approach. Five main themes emerged from the research and included (1) childhood trauma and adverse events, e.g., an absent father, being raised without parents, exposure to criminal or violent behavior, physical abuse, sexual abuse and poverty, (2) understanding rape, e.g., rape as sex by force and without consent, rape as a violent act, rape as sex with a minor, myths about rape (3) substance abuse, e.g., history of alcohol and drug use, and intoxication during rape perpetration, (4) gender roles and avoiding responsibility, e.g., victim blaming, rape as male prerogative, transactional sex, being framed or set-up, ignoring an ancestral call and (5) recidivism. The findings revealed that all rape perpetrators were exposed to at least one childhood trauma type. Family and community violence and criminality was common. Most participants avoided taking responsibility for their actions and blamed the victim and recidivism/prior convictions were often reported. The findings demonstrate the complex personality dynamic involved in the cycle of abuse and the evolution of criminal behavior, starting as a victim and ending as a perpetrator. The findings also highlight the need for interventions aimed at reducing childhood trauma exposure and improving the social and relational context of those at risk for childhood neglect and abuse.

The effect of oxytocin and an enriched environment on anxiety-like behaviour and corticosterone levels in a prenatally stressed febrile seizure rat model.

Background: Febrile seizures (FS) are a neurological abnormality which occur following a fever that has resulted from a systemic infection and are characterised by convulsions. These convulsions occur due to abnormally increased signalling of interleukin-1 beta, resulting in increased neuronal hyper-excitability. Furthermore, exposure to prenatal stress has been shown to exacerbate seizure duration, elicit anxiety-like behaviour and corticosterone levels. Oxytocin is a neuropeptide with anxiolytic, social bonding, and stress regulation effects. Therefore, the aim of the study was to assess whether oxytocin can attenuate the anxiety-like behaviour and increased corticosterone in rat offspring exposed to prenatal stress and FS. Method: Sprague Dawley rats were mated. On GND14, prenatal stress was induced on pregnant dams for 1 hr/7 days. On PND 14, rat pups were injected with lipopolysaccharide (LPS, 200 µg/kg, i.p.) followed 2.5 h later by an i.p. injection of kainic acid (KA, 1.75 mg/kg). Oxytocin (1 mg/kg) was induced via different routes (intraperitoneal or intranasal) as well an enriched environment between PND 22-26. The enriched environment included larger cages (1560 cm2) with only 4 pups per cage, compared to those groups not receiving enrichment (646 cm2), as well as cardboard rolls and plastic toys. On PND 27-33 the light/dark box and elevated plus maze were used to assess anxiety-like behaviour. On PND 34 all rats were euthanized using a sharp guillotine, trunk blood and hypothalamic tissue were collected for neurochemical analysis (ELISA kit). Results: Our findings confirmed that exposure to both prenatal stress and febrile seizures resulted anxiety-like behaviour and significantly higher plasma corticosterone concentrations compared to their counterparts. Environmental enrichment was significantly effective in attenuating the increased basal corticosterone levels and anxiety-like behaviour seen in the prenatally stressed FS rat. Although direct administration of oxytocin showed higher significance in reducing corticosterone plasma levels when compared to the enriched environment. Furthermore, hypothalamic oxytocin levels were not significant in rat exposed to environmental enrichment while oxytocin treatment showed a significant effect when compared to their counterparts. Conclusion: Therefore, oxytocin administration during early postnatal development shows great potential in reversing the effects of prenatal stress and its subsequent exacerbation of FS.

The Pathogenesis of Fever-Induced Febrile Seizures and Its Current State.

Febrile seizures, commonly in children between the ages of 3 months to 5 years, are a neurological abnormality characterized by neuronal hyper-excitability, that occur as a result of an increased core body temperature during a fever, which was caused by an underlying systemic infection. Such infections cause the immune system to elicit an inflammatory response resulting in the release of cytokines from macrophages. The cytokines such as interleukin (IL)- 1ß, IL-6, and tumour necrosis factor-α (TNF-α) combat the infection in the localized area ultimately spilling over into circulation resulting in elevated cytokine levels. The cytokines, along with pathogen-associated molecular patterns (PAMPs) expressed on pathogens for example, lipopolysaccharide (LPS), interact with the blood brain barrier (BBB) causing a 'leaky' BBB which facilitates cytokines and LPS entry into the central nervous system. The cytokines activate the microglia which release their own cytokines, specifically IL1ß. IL-ß interacts with the brain endothelium resulting in the activation of cyclooxygenase 2 which catalyzes the production of prostaglandin 2 (PGE2). PGE2 enters the hypothalamic region and induces a fever. Abnormally increased IL-1ß levels also progressively increases excitatory (glutamatergic) neurotransmission, and decreases inhibitory (GABAergic) neurotransmission, thus mediating the pathogenesis of convulsions. Current treatments for febrile seizures present with side effects that are detrimental to health, which fosters the need for an alternative, more affordable treatment with fewer adverse side effects, and 1 that is easily accessible, especially in low income areas that are also affected by other underlying socio-economic factors, in which febrile seizures are of growing concern.

The Effect of Quercetin on Pro- and Anti-Inflammatory Cytokines in a Prenatally Stressed Rat Model of Febrile Seizures.

Febrile seizures are childhood convulsions resulting from an infection that leads to an inflammatory response and subsequent convulsions. Prenatal stress has been shown to heighten the progression and intensity of febrile seizures. Current medications are costly and have adverse effects associated with prolonged use. Quercetin flavonoid exhibits anti-inflammatory, anti-convulsant, and anti-stress effects. This study was aimed to investigate the therapeutic effect of quercetin in a prenatally stressed rat model of febrile seizures. We hypothesized that quercetin will alleviate the effects of prenatal stress in a febrile seizure rat model. On gestational day 13, Sprague-Dawley rat dams were subjected to restraint stress for 1 hour/d for 7 days. Febrile seizures were induced on postnatal day 14 on rat pups by intraperitoneally injecting lipopolysaccharide followed by kainic acid and quercetin on seizure onset. Hippocampal tissue was harvested to profile cytokine concentrations. Our results show that quercetin suppresses prenatal stress-induced pro-inflammatory marker (interleukin 1 beta) levels, subsequently attenuating febrile seizures. This shows that quercetin can be therapeutic for febrile seizures in prenatally stressed individuals.

Searsia chirindensis reverses the potentiating effect of prenatal stress on the development of febrile seizures and decreased plasma interleukin-1ß levels.

It is estimated that more than 80% of patients with epilepsy live in developing countries with 50-60% of them being children. This high prevalence is perpetuated by low socio-economic challenges, poor health care facilities and lack of drug affordability. Searsia chirindensis formerly known as rhus chirindensis and commonly known as 'Red Current' is a popular traditional medicinal plant, which has been used to treat a number of illnesses such as heart complaints and neurological disorders. The aim of this study is to investigate the effects of S. chirindensis on the development of febrile seizure in a prenatally stressed rat. Febrile seizures were induced by administering lipopolysaccharide to 14-day-old rat pups followed by kainic acid. A subset of the rats was treated with Searsia after induction of febrile seizures. Interleukin-1ß (IL-1ß) levels were measured in plasma. Lipid peroxidation was determined in liver tissue. Our data shows that treatment with Searsia reduced interleukin-1ß levels in plasma of the febrile seizure rats and prevented lipid oxidation in the liver. Prenatal stress is dampened by the beneficial effects of Searsia on seizure development in rat pups. These results highlight the potentiating effects of Searsia in the reversal of febrile seizures and prenatal stress effects.

Prenatal stress and early life febrile convulsions compromise hippocampal genes MeCP2/REST function in mid-adolescent life of Sprague-Dawley rats.

Early life neuronal insults exacerbate the development of febrile seizures and can result in epigenetic changes in the hippocampus. The MeCP2 and REST genes play a pivotal role in cognition as both contribute to neuronal function. In this study, cognitive function and expression of the MeCP2 and REST genes in the hippocampus were investigated in four groups of Sprague Dawley rats offspring viz. (1) Normally reared treated with saline (NSS). (2) Prenatally stressed treated with saline (SS). (3) Normally reared with febrile seizures (NSFS). (4) Prenatally stressed with febrile seizures (SFS). Pregnant dams were subjected to 1h of restraint stress for 7days starting on gestational day 14. Following birth, a once-off exposure to saline injections or febrile seizure induction was conducted on postnatal day (PND) 14. Behavioural tests were conducted using the Morris-Water maze on PND 21 and 30. Our results showed a febrile seizure effect on learning and memory in the non-stressed animals. However, febrile seizures did not exacerbate learning deficits in the prenatally stressed animals. Gene analysis found a down-regulation in MeCP2 gene expression and an up-regulation of the REST gene in prenatally stressed animals. Exposure to febrile seizure resulted in down-regulation of both MeCP2 and REST gene expression in the non-stressed animals, but febrile seizures did not exacerbate the stress effect on gene expression. This suggests that exposure to prenatal stress (SS) and febrile seizures (NSFS) may impair cognitive behavioural function. However, in the NSFS animals, there seems to be an attempt to counteract the effects of febrile seizures with time.

Exposure to prenatal stress has deleterious effects on hippocampal function in a febrile seizure rat model.

Prenatal stress has been shown to result in the development of a number of neurological disorders in the offspring. Most of these disorders are a result of an altered HPA axis resulting in higher than normal glucocorticoid levels in the affected neonate. This leaves the offspring prone to immune challenges. Therefore the aim of the present study was to investigate the effects of prenatal stress and febrile seizures on behavior and hippocampal function. Pregnant dams were exposed to restraint stress during the third trimester. Following birth, febrile seizures were induced in two week old pups using lipopolysaccharide and kainic acid. A week later, anxiety-like behavior and navigational ability was assessed. Trunk blood was used to measure basal corticosterone concentration and hippocampal tissue was collected and analyzed. Our results show that exposure to prenatal stress increased basal corticosterone concentration. Exposure to prenatal stress exacerbated anxiety-like behavior and impaired the rat's navigational ability. Exposure to prenatal stress resulted in reduced hippocampal mass that was exacerbated by febrile seizures. However, exposure to febrile seizures did not affect hippocampal mass in the absence of prenatal stress. This suggests that febrile seizures are exacerbated by exposure to early life stressors and this may lead to the development of neurological symptoms associated with a malfunctioning hippocampus.

Exposure to prenatal stress enhances the development of seizures in young rats.

A febrile seizure is a neurological disorder that occurs following an infection that results in a rapid rise in body temperature. It commonly affects 3-5% of children between the ages of 3 months and 5 years. Interleukin-1 beta IL-1ß a pro-inflammatory cytokine has been suggested to play a role in the manifestation of febrile seizures. There is evidence suggesting that neurological disorders can be exacerbated in an offspring that was exposed to stress prenatally. The aim of our study was therefore to investigate whether febrile seizures are exacerbated in the offspring of rats that were prenatally stressed. The offspring of pregnant Sprague-Dawley dams were used in the study. Prenatal stress consisted of exposing the pregnant dams to 45 min of restraint, 3 times per day with 3 h intervals in-between, for 7 days starting on gestational day 14 (GND14). On postnatal day (PND) 14, the pups were injected with lipopolysaccharide (LPS, 200 µg/kg, i.p.) followed 2.5 h later by an i.p. injection of kainic acid (KA, 1.75 mg/kg). All the animals were decapitated on PND 21. Trunk blood was collected to detect plasma interleukin-1beta (IL-1ß) levels in the various groups. Our data showed that i.p. injections of LPS followed by KA led to the development of seizure activity that was associated with increased plasma IL-1ß levels. Prior exposure to prenatal stress resulted in the development of advanced stages of seizure development, leading to an exaggerated seizure response. Prenatal stress alone also led to elevated plasma IL-1ß levels, while previously stressed animals receiving LPS and KA yielded the highest plasma levels of IL-1ß levels. Our data therefore shows that IL-1ß levels may play an important role in the development of febrile seizures.