Behavior In Adult Offspring Research Articles

Mother's microbes.

Metabolites regulated by the microbiota of pregnant mice modulates the developing embryonic brain and influences thalamocortical axon formation and subsequent sensorimotor behaviour in adult offspring.

Dietary Exposure to Excess Saturated Fat During Early Life Alters Hippocampal Gene Expression and Increases Risk for Behavioral Disorders in Adulthood.

PurposeMaternal and postnatal diets result in long-term changes in offspring brain and behavior; however, the key mediators of these developmental changes are not well-defined. In this study, we investigated the impact of maternal and post-weaning high-fat diets on gene expression of key components mediating hippocampal synaptic efficacy. In addition, we evaluated the risk for impaired stress-coping and anxiety-like behaviors in adult offspring exposed to obesogenic diets during early life.MethodsDams were fed a control (C) or high-fat (HF) diet prior to mating, pregnancy, and lactation. Male offspring from control chow and high-fat fed dams were weaned to control chow or HF diets. The forced swim test (FST) and the elevated-plus maze (EPM) were used to detect stress-coping and anxiety-like behavior, respectively. Real-time RT-PCR and ELISA were used to analyze hippocampal expression of genes mediating synaptic function.ResultsAnimals fed a HF diet post-weaning spent more time immobile in the FST. Swimming time was reduced in response to both maternal and post-weaning HF diets. Both maternal and post-weaning HF diets contributed to anxiety-like behavior in animals exposed to the EPM. Maternal and post-weaning HF diets were associated with a significant decrease in mRNA and protein expression for hippocampal GDNF, MAP2, SNAP25, and synaptophysin. Hippocampal mRNA expression of key serotonergic and glutamatergic receptors also exhibited differential responses to maternal and post-weaning HF diets. Hippocampal serotonergic receptor 5HT1A mRNA was reduced in response to both the maternal and post-weaning diet, whereas, 5HT2A receptor mRNA expression was increased in response to the maternal HF diet. The glutamate AMPA receptor subunit, GluA1, mRNA expression was significantly reduced in response to both diets, whereas no change was detected in GluA2 subunit mRNA expression.ConclusionThese data demonstrate that the expression of genes mediating synaptic function are differentially affected by maternal and post-weaning high-fat diets. The post-weaning high-fat diet clearly disturbs both behavior and gene expression. In addition, although the transition to control diet at weaning partially compensates for the adverse effects of the maternal HF diet, the negative consequence of the maternal HF diet is exacerbated by continuing the high-fat diet post-weaning. We present evidence to support the claim that these dietary influences increase the risk for anxiety and impaired stress-coping abilities in adulthood.

Behavioral impairments in infant and adult mouse offspring exposed to 2,3,7,8-tetrabromodibenzofuran in utero and via lactation

Polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/DFs) have been unintentionally produced and emitted from the lifecycle of products containing brominated flame retardants, such as polybrominated diphenyl ether, which is suspected to cause developmental neurotoxicity (DNT). Although it is plausible that PBDD/DFs can also induce DNT, information regarding their neurotoxic potential is currently limited. Hence, in the present study, we examined the effects of in utero and lactational exposure to brominated dibenzofurans on infant and adult offspring behavior to understand the mechanism of PBDD/DFs toxicity and detect effective behavioral endpoints in DNT assessment. We analyzed the behavior of mouse offspring born to dams administered 2,3,7,8-tetrabromodibenzofuran (2,3,7,8-TeBDF; dose of 0, 9, or 45 μg/kg) or 2,3,8-tribromodibenzofuran (2,3,8-TrBDF; dose of 0, 75.6, or 378 μg/kg) on gestational day 12.5. In mouse offspring born to dams exposed to 2,3,7,8-TeBDF, the exploratory behavior in a novel environment in adulthood and ultrasonic vocalization (USV) during infancy were significantly reduced. Additionally, AhR-target genes, such as Cyp1a1, were induced in the liver of 2,3,7,8-TeBDF-exposed offspring in a dose-dependent manner. Conversely, no significant changes in the infant and adult behaviors and expression level of AhR-target genes were observed in the 2,3,8-TrBDF-exposed offspring. These results suggest that 2,3,7,8-TeBDF can induce DNT and that the analysis of exploratory behavior in a novel environment and USV may be useful endpoints to assess DNT of dioxin-related substances.

Prenatal ethanol exposure increases susceptibility to depression- and anxiety-like behavior in adult female offspring and its underlying mechanism

Epidemiological investigations have found that maternal alcohol intake increases the risk of mental illness in offspring. Our study investigated changes of depression- and anxiety-like behaviors in adult offspring caused by prenatal ethanol exposure (PEE) and explored the potential mechanism. After Wistar rats were intragastrically administered ethanol at a dose of 4 g/kg·d on the 9–20 t h days of pregnancy, the offspring were given 21 days of chronic unpredictable mild stress (CUMS) starting from the 9th week after birth. Before CUMS, the behavioral results showed that the PEE offspring appeared excited and anxious. After CUMS, the PEE offspring rats were more sensitive to the same intensity of stimulation, and then the behavioral disorders aggravated. In adult offspring from the PEE group, the intercellular space was enlarged in the hippocampus, and there was a loss of pyramidal cells. The expression of brain-derived neurotrophic factor (BDNF) decreased; the mRNA expression of the glucocorticoid receptor and synaptic plasticity-related genes decreased; the apoptosis-related genes expressed disrupted. In order to determine whether hippocampal injury and dysfunction resulted from ethanol directly or indirectly, we performed in vitro study. The outcome was accompanied by disrupted gene expression related to neurogenesis and synaptic plasticity. PEE increases the susceptibility of adult female offspring to depression- and anxiety-like behaviors, and its mechanism may be related to the toxic effects of ethanol, both directly and indirectly. The latter inhibits the hippocampal BDNF pathway, leading to the disruption of hippocampal neurogenesis, apoptosis and decreased synaptic plasticity.

VEGF Treatment Ameliorates Depression-Like Behavior in Adult Offspring After Maternal Immune Activation.

Maternal immune activation (MIA) during pregnancy impacts offspring neurodevelopmental trajectories and induces lifelong consequences, including emotional and cognitive alterations. Using the polyinosinic:polycytidilic acid (PIC) MIA model we have previously demonstrated enhanced depression-like behavior in adult MIA offspring, which was associated with reduced expression of the vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) in the hippocampus. Since VEGF mediates the effects of various antidepressant agents, we here set out to explore whether VEGF administration could rescue the depression-like behavioral deficits in MIA offspring. To test our hypothesis, control and MIA offspring were intracerebroventricularly (i.c.v.) infused with either VEGF or vehicle solution and depression-related behavior was assessed in the sucrose preference test (SPT) and the tail suspension test (TST). As a surrogate of VEGF activity, the phosphorylation of the extracellular signal-regulated kinase (ERK) in hippocampus was quantified. We found that VEGF treatment reduced depression-related behavioral despair in the TST in MIA offspring but had no effect on anhedonia-like behavior in the SPT. While VEGF administration induced the phosphorylation of ERK in the hippocampus of control offspring, this effect was blunted in the MIA offspring. We conclude that VEGF administration, at the dosage tested, beneficially affects some aspects of the depression-like phenotype in the adult MIA offspring, inviting further studies using different dosage regimes to further explore the therapeutic potential of VEGF treatment in MIA-related changes in brain function and behavior.

Interleukin-18 levels in the hippocampus and behavior of adult rat offspring exposed to prenatal restraint stress during early and late pregnancy.

Exposure to maternal stress during prenatal life is associated with an increased risk of neuropsychiatric disorders, such as depression and anxiety, in offspring. It has also been increasingly observed that prenatal stress alters the phenotype of offspring via immunological mechanisms and that immunological dysfunction, such as elevated interleukin-18 levels, has been reported in cultures of microglia. Prenatal restraint stress (PRS) in rats permits direct experimental investigation of the link between prenatal stress and adverse outcomes. However, the majority of studies have focused on the consequences of PRS delivered in the second half of pregnancy, while the effects of early prenatal stress have rarely been examined. Therefore, pregnant rats were subjected to PRS during early/middle and late gestation (days 8-14 and 15-21, respectively). PRS comprised restraint in a round plastic transparent cylinder under bright light (6500 lx) three times per day for 45 minutes. Differences in interleukin-18 expression in the hippocampus and in behavior were compared between offspring rats and control rats on postnatal day 75. We found that adult male offspring exposed to PRS during their late prenatal periods had higher levels of anxiety-related behavior and depression than control rats, and both male and female offspring exhibited higher levels of depression-related behavior, impaired recognition memory and diminished exploration of novel objects. Moreover, an elevated level of interleukin-18 was observed in the dorsal and ventral hippocampus of male and female early- and late-PRS offspring rats. The results indicate that PRS can cause anxiety and depression-related behaviors in adult offspring and affect the expression of interleukin-18 in the hippocampus. Thus, behavior and the molecular biology of the brain are affected by the timing of PRS exposure and the sex of the offspring. All experiments were approved by the Animal Experimentation Ethics Committee at Kunming Medical University, China (approval No. KMMU2019074) in January 2019.

Lard-rich and canola oil-rich high-fat diets during pregnancy promote rats’ offspring neurodevelopmental delay and behavioral disorders

High-fat diets (HFDs) during pregnancy may damage the neural development and emotional behavior of rat offspring. Therefore, we investigated the neurobehavioral development of rat offspring who were fed a control diet (CD) or an HFD with lard (HFD-lard) or canola oil (HFD-canola oil), during pregnancy. Offspring's neurodevelopment (somatic growth, physical maturation, and ontogenesis reflex) was assessed while they were suckling. The rat's levels of depression, anxiety, and aggression were assessed through forced swimming, elevation plus a maze or open field test, and a foot-shock test on postnatal days 60, 80, and 110, respectively. Maternal HFDs with lard or canola oil promoted rats’ offspring during suckling. They had reduced body weight and growth, physical maturation delay (auditory conduit and eyes opening to both groups HFDs-lard and canola oil; ear unfolding and incisor eruption only HFD-lard) and an ontogenesis reflex (palm grasp/vibrissa placing to both groups HFDs-lard and canola oil, and free-fall righting only in HFD-lard). Negative geotaxis resulted in the faster development of the HFD-lard offspring. Furthermore, in adulthood, the HDFs-offspring were more likely to be overweight, have shorter swimming times in the swim test, greater susceptibility to anxiety with an increased time spent in the closed arm in the elevated plus-maze while spending less time in the open arm, and having a decreased number of crossings and rearing in the open field. On the other hand, aggressive-like behavior was not affected. Therefore, these findings indicate that maternal HFDs enriched with lard or canola oil during pregnancy can impair the neurodevelopment of rat offspring and can perhaps be associated with possible changes to the emotional behavior of adult offspring.

Exposure to valproic acid during middle to late-stage corticogenesis induces learning and social behavioral abnormalities with attention deficit/hyperactivity in adult mice.

Single prenatal exposure to valproic acid (VPA) in rodents is a widely used preclinical model of autism spectrum disorder (ASD). Continuous prenatal VPA exposure has been recently proposed as a new ASD model that closely captures the neuropathological features of ASD, including increases in cerebral cortex volume and the number of cortical upper layer neurons. We investigated the influence of prenatal VPA exposure on the behavior of adult offspring of pregnant dams that received intraperitoneal injections of VPA twice on one day during the genesis of cortical upper layer neurons. Mice exposed to VPA at E14 (E14-VPA) showed typical behavior abnormalities including reduced social interaction, hyperactivity, and poor maze learning due to attention deficit/impulsivity relative to healthy controls. Histological analysis revealed that E14-VPA mice had significantly increased neuronal density and impaired neural activity in the prefrontal cortex, but not the somatosensory area, which is likely linked to the observed abnormalities in social behavior. These results suggest that this VPA exposure method is a good model for gaining new insights into the underlying neuropathology of ASD.

Neonatal Inhibition of Connexin 36 Ameliorates Fetal Brain Injury Induced by Maternal Noninfectious Fever in Mice

Prenatal fever could result in brain function impairments in the offspring. The present study investigated the effect of interleukin-6 (IL-6)-induced maternal fever on the offspring and the involvement of connexin 36 in this process. Pregnant C57BL/6J mice were injected with IL-6 on gestational day 15. The levels of iNOS and COX-2 were measured as an index of neuroinflammation in the brain of newborn pups. Offspring were treated with the connexin 36 (Cx36) inhibitor mefloquine at postnatal day (P)1–P3 or at P40–P42. Rotarod, grip traction, and foot fault tests were carried out to evaluate the motor behavior of adult offspring. Injection of IL-6 led to an elevation of the core temperature in the pregnant dams. Offspring of these dams showed significantly increased COX-2 and iNOS mRNA expression and protein levels in the whole-brain samples and significantly increased Cx36 in the cerebellum. Moreover, offspring of these dams showed motor deficits at an adult age. Neonatal administration of the Cx36 inhibitor mefloquine could prevent these motor deficits. Maternal fever during pregnancy induced by IL-6 injection could lead to neuroinflammation and motor deficits in the offspring. Neonatal inhibition of Cx36 could ameliorate the motor deficits in the offspring, indicating an involvement of Cx36 in the IL-6-induced maternal fever.

Multiple prenatal stresses increase sexual dimorphism in adult offspring behavior

IntroductionMaternal gestational stress and immune activation have independently been associated with affective and neurodevelopmental disorders across the lifespan. We investigated whether rats exposed to prenatal maternal stressors (PNMS) consisting of psychological stress, interleukin (IL)-1β or both (two-hit stress) during critical developmental windows displayed a behavioral phenotype representative of these conditions. MethodsLong-Evans dams were exposed to psychological stressors consisting of restraint stress and forced swimming from gestational day (GD)12 to 18 or to no stress (controls). From GD17 until day of delivery, these same animals were injected with saline or IL-1β as a second hit and immune stressor (5 μg/day, intraperitoneally). The behavior of F1 offspring adults was tested on the open field test, elevated plus maze and affective exploration task on postnatal days (P)90, 100 and 110 respectively. ResultsThe effects of PNMS differed depending on the specific testing environment and potentially the age at assessment, especially in female offspring. Both locomotion and anxiety-like behavioral measures were susceptible to PNMS effects. In females, psychological stress increased anxiety-like behavior, whereas IL-1β had an opposite effect, inducing exploration and risk-taking behavior on the open field test and the elevated plus maze. When present, interactions between both stressors limited the anxiogenic effect of psychological stress on its own. In contrast, prenatal psychological stress increased anxiety-like behavior in adult males overall. A similar anxiogenic effect of IL-1β was only found on the open field test while the Stress*IL-1β interaction appeared to limit the effect of either alone. Contrarily, the PNMS effects on anxiety-like behavior on the affective exploration task were highly similar between both sexes. Analysis of males and females together revealed an additive effect of Stress and IL-1β on the number of exits from the refuge, a measure of risk assessment and thus correlated with anxiety. ConclusionPNMS affected offspring adult behavior in a sex-dependent manner. Effects on females were more variable, whereas psychological stress mostly induced anxiety-like behavior in males. These data highlight the sexual dimorphism in vulnerability to prenatal stressors. Maternal or stress-induced programming of the stress response and neuroinflammation may play an important role in mediating stress effects on offspring adult behavior.

Developmental outcomes after gestational antidepressant treatment with sertraline and its discontinuation in an animal model of maternal depression

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to women before or during pregnancy to manage their depressive symptoms. However, there is still little knowledge regarding the long-term development effects of SSRI exposure for the fetus or the effects of discontinuing SSRI treatment during pregnancy. This study utilized a translational animal model of maternal depression (based on giving high levels of corticosterone (CORT, 40 mg/kg, s.c.) or vehicle (Oil) for 21 days prior to conception) to investigate the effects of sertraline (a frequently prescribed SSRI; 20 mg/kg p.o., treatment started ∼7 days prior to conception) and its discontinuation during pregnancy (on gestational day 16) compared to vehicle (water) treatment on the development of the offspring. Our results revealed that both corticosterone exposure prior to pregnancy and sertraline administration and its discontinuation during gestation had sex-specific effects on behavior in the adult offspring. In particular, pre-conceptional maternal corticosterone treatment impacted the stress response, anxiety-like behavior and cognitive performance in adult female offspring, while gestational SSRI exposure and its discontinuation compared to full-term exposure affected impulsivity in females, and exploratory behavior in males. More research is needed on the effects of exposure to antidepressant medication and its discontinuation compared to depression during pregnancy and how each impacts development to better help women make informed decisions about their medication use during pregnancy.

Prenatal Inflammation Dampens Neurogenesis and Enhances Serotonin Transporter Expression in the Hippocampus of Adult Female Rats

Background/Aims: Prenatal exposure to lipopolysaccharide (LPS) dampens hippocampal neurogenesis. This effect is associated with increased anxiety-like behavior in adult offspring. Furthermore, blocking serotonin transporters (SERT) promotes adult neurogenesis. Previous studies were performed largely in males. Therefore, we explored the impact of prenatal LPS on neurogenesis, SERT expression in the hippocampus, and anxiety-like behavior in female rats during prepubertal and adulthood stages. Materials and Methods: Timed pregnant rats were injected with either saline or LPS (100 µg/kg, i.p.) on gestational days 15, 17, and 19. Newly born neurons were monitored by immunohistochemistry, and anxiety-like behavior was monitored using the elevated plus maze and open-field test. SERT expression in the hippocampus was assessed by Western blot and immunofluorescence. Results: Prenatal LPS led to reduced hippocampal neurogenesis in adult but not in prepubertal female offspring. This reduced neurogenesis was associated with enhanced hippocampal expression of SERT protein. However, there was no significant impact of prenatal LPS on anxiety-like behavior. Conclusions: Prenatal LPS-induced reduction in neurogenesis was dissociated from anxiety-like behavior in adult female rats. Furthermore, the long-lasting impact of prenatal LPS on neurogenesis in female offspring was age-dependent.

Stress early in life leads to cognitive impairments, reduced numbers of CA3 neurons and altered maternal behavior in adult female mice.

The hippocampus is a crucial part of the limbic system involved both in cognitive processing and in the regulation of responses to stress. Adverse experiences early in life can disrupt hippocampal development and lead to impairment of the hypothalamic-pituitary-adrenal axis response to subsequent stressors. In our study, two types of early-life stress were used: prolonged separation of pups from their mothers (for 3 hours/day, maternal separation, MS) and brief separation (for 15 minutes/day, handling, HD). In the first part of our study, we found that adult female mice (F0) who had experienced MS showed reduced locomotor activity and impairment of long-term spatial and recognition memory. Analysis of various hippocampal regions showed that MS reduced the number of mature neurons in CA3 of females, which is perhaps a crucial hippocampal region for learning and memory; however, neurogenesis remained unchanged. In the second part, we measured maternal care in female mice with a history of early-life stress (F0) as well as the behavior of their adult offspring (F1). Our results indicated that MS reduced the level of maternal care in adult females (F0) toward their own progeny and caused sex-specific changes in the social behavior of adult offspring (F1). In contrast to MS, HD had no influence on female behavior or hippocampal plasticity. Overall, our results suggest that prolonged MS early in life affects the adult behavior of F0 female mice and hippocampal neuronal plasticity, whereas the mothers' previous experience has effects on the behavior of their F1 offspring through disturbances of mother-infant interactions.

High-Salt Exposure During Perinatal Development Enhances Stress Sensitivity.

Excess consumption of dietary sodium during pregnancy has been shown to impair offspring cardiovascular function and enhance salt preference in adulthood, but little is known regarding the long-term impact of this nutritional surplus on offspring brain morphology and behavior. Using a combination of cellular and behavioral approaches, we examined the impact of maternal salt intake during the perinatal period on structural plasticity in the prefrontal cortex (PFC) and nucleus accumbens (NAc) in weanling and adult offspring as well as reward- and stress-driven behaviors in adult offspring. We found that weanling rats born to 4% NaCl-fed dams exhibited an increase and decrease in thin spine density in the infralimbic PFC (IL-PFC) and prelimbic PFC (PL-PFC), respectively, as well as an increase in mushroom spine density in the NAc shell, compared to 1% NaCl-fed controls. Structural changes in the IL-PFC and NAc shell persisted into adulthood, the latter of which is a phenotype that has been observed in rats exposed to early life stress. There was no effect of maternal salt intake on reward-driven behaviors, including sucrose preference, conditioned place preference (CPP) for cocaine, and forced swim stress (FSS)-induced reinstatement of cocaine-induced CPP. However, rats born to high-salt fed dams spent less time swimming in the FSS and displayed heightened plasma CORT levels in response to the FSS compared to controls, suggesting that early salt exposure increases stress sensitivity. Overall, our results suggest that perinatal salt exposure evokes lasting impacts on offspring physiology and behavior.

Prenatal stress leads to chromatin and synaptic remodeling and excessive alcohol intake comorbid with anxiety-like behaviors in adult offspring

Epidemiologic evidence suggests that individuals during their prenatal development may be especially vulnerable to the effects of environmental factors such as stress that predisposes them to psychiatric disorders including alcohol use disorder (AUD) later in life. Currently, the epigenetic mechanisms of anxiety comorbid with AUD induced by prenatal stress (PRS) remain to be elucidated. Here, we examined anxiety-like and alcohol drinking behaviors in adult offspring of prenatally stressed dam (PRS-mice) using elevated plus maze, light/dark box and two-bottle free-choice paradigm. It was found that PRS-mice exhibit heightened anxiety-like behaviors and increased alcohol intake in adulthood and these behavioral deficits were associated with a significant decrease in dendritic spine density (DSD) in medial prefrontal cortex (mPFC) relative to non-stressed mice (NS mice). To determine the mechanisms by which PRS reduces DSD, we examined the expressions of key genes associated with synaptic plasticity, including activity regulated cytoskeleton associated protein (Arc), spinophilin (Spn), postsynaptic density 95 (Psd95), tropomyosin receptor kinase B (TrkB), protein kinase B (Akt), mammalian target of rapamycin (mTOR) and period 2 (Per2) in mPFC of PRS and NS mice. The mRNA levels of these genes were significantly decreased in PRS mice. Methylated DNA and chromatin immunoprecipitation studies revealed hyper DNA methylation or reduced histone H3K14 acetylation on promoters of above genes suggesting that epigenetic dysregulation may be responsible for the deficits in their expression. Findings from this study suggest that prenatal stress induced abnormal epigenetic mechanisms and synaptic plasticity-related events may be associated with anxiety-like and alcohol drinking behaviors in adulthood.

Maternal High-fat Diet Programs Offspring Emotional Behavior in Adulthood

Prenatal exposure to high-fat diet (HFD) might predispose offspring to develop metabolic and mental disorders later in life. Insight into the molecular and behavioral consequences of maternal HFD on offspring is sparse but may involve both neuroinflammation and a dysregulated neuroendocrine stress axis. Thus, the aim of this work was to: (i) investigate the influence of maternal HFD on memory, anxiety and depression-like behavior in adult offspring and (ii) identify possible biological biomarkers related to neuroinflammation and stress responses.Seven-week-old, female Sprague–Dawley rats received a control diet or a HFD eight weeks prior to conception and during gestation and lactation. We investigated the phenotype of the offspring in the in elevated plus maze, forced swim test, novel object recognition and open field test. Furthermore, hippocampal gene expression related to neuroinflammation and the stress axis was quantitated by real-time qPCR.We found that maternal HFD led to an anxiogenic offspring phenotype in the elevated plus maze, independent of sex. This behavioral alteration was accompanied by significantly higher mRNA levels of the hippocampal pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) mRNA and monocyte-chemoattractant protein-1 (MCP-1), both of which correlated with degree of behavioral change. Maternal exposure to HFD increased the offspring’s levels of hippocampal, corticosteroid releasing hormone receptor 2 (CRHR2) and kynurenine mono oxygenase (KMO) mRNA, whereas kynurenine aminotransferase I (KAT1) mRNA levels were decreased.The present results suggest that neuroinflammatory and stress axis pathways in the hippocampus may contribute to anxiogenic effects of maternal HFD in offspring.

Effects of postnatal handling on adult behavior and brain mRNA expression of serotonin receptor, brain-derived neurotrophic factor and GABA-A receptor subunit

Development of brain and behavior is influenced by the interaction of genetic and environmental factors. Postnatal handling, a manipulation that briefly separates mouse offspring from their mother during the postnatal period, has been reported to yield beneficial effects on the behavior of adult offspring. However, brain mechanisms underlying the effects on the behavior have not been well understood. Here we first examined effects of postnatal handling on the behavior of adult male BALB/c mice. Offspring were separated for 15 min every day between postnatal day 1 (P1) and P14 and then various behaviors were tested in the adulthood. Postnatal handling reduced anxiety-like behavior in elevated plus maze and improved spatial learning and memory in Morris water maze without effects on depression-like behavior in forced swim test. Next, to elucidate mechanisms underlying the behavioral effects, we evaluated mRNA expression of the serotonin 1A (5-HT1A) receptor, brain-derived neurotrophic factor (BDNF), and GABA-A receptor subunits in the medial prefrontal cortex, amygdala, dorsal and ventral hippocampi, and dorsal raphe nucleus by quantitative RT-PCR, since these genes and brain regions have been shown to be involved in cognition and emotion. Postnatal handling up-regulated mRNA expression of the 5-HT1A receptor in the dorsal raphe nucleus and down-regulated 5-HT1A receptor mRNA expression in the amygdala on P15 and P71. In adulthood, mRNA expression of BDNF was up-regulated in the amygdala and dorsal hippocampus and down-regulated in the dorsal raphe nucleus, whereas that of GABA-A receptor α2 subunit was down-regulated in the amygdala. Taken together, the present study suggests that postnatal handling reduced anxiety-like behavior and improved learning and memory, which were accompanied by changes in mRNA expression of 5-HT1A receptor, BDNF and GABA-A receptor α2 subunit in the amygdala, 5-HT1A receptor in the dorsal raphe nucleus and BDNF in the dorsal hippocampus.

Pre-reproductive stress and fluoxetine treatment in rats affect offspring A-to-I RNA editing, gene expression and social behavior.

Adenosine to inosine RNA editing is an epigenetic process that entails site-specific modifications in double-stranded RNA molecules, catalyzed by adenosine deaminases acting on RNA (ADARs). Using the multiplex microfluidic PCR and deep sequencing technique, we recently showed that exposing adolescent female rats to chronic unpredictable stress before reproduction affects editing in the prefrontal cortex and amygdala of their newborn offspring, particularly at the serotonin receptor 5-HT2c (encoded by Htr2c). Here, we used the same technique to determine whether post-stress, pre-reproductive maternal treatment with fluoxetine (5 mg/kg, 7 days) reverses the effects of stress on editing. We also examined the mRNA expression of ADAR enzymes in these regions, and asked whether social behavior in adult offspring would be altered by maternal exposure to stress and/or fluoxetine. Maternal treatment with fluoxetine altered Htr2c editing in offspring amygdala at birth, enhanced the expression of Htr2c mRNA and RNA editing enzymes in the prefrontal cortex, and reversed the effects of pre-reproductive stress on Htr2c editing in this region. Furthermore, maternal fluoxetine treatment enhanced differences in editing of glutamate receptors between offspring of control and stress-exposed rats, and led to enhanced social preference in adult offspring. Our findings indicate that pre-gestational fluoxetine treatment affects patterns of RNA editing and editing enzyme expression in neonatal offspring brain in a region-specific manner, in interaction with pre-reproductive stress. Overall, these findings imply that fluoxetine treatment affects serotonergic signaling in offspring brain even when treatment is discontinued before gestation, and its effects may depend upon prior exposure to stress.

Maternal protein-free diet during lactation programs male Wistar rat offspring for increased novelty-seeking, locomotor activity, and visuospatial performance.

It is well established that chronic undernutrition has detrimental impacts on brain development and maturation. However, protein malnutrition during the period specifically encompassing the brain growth spurt has not been widely studied, particularly regarding its effects on adolescent and adult offspring behavior. Here, we assessed the effects of a protein-free diet during the 1st 10 postnatal days on the macronutrient content of the milk produced by lactating Wistar rats, on their maternal behavior, and on the offspring's behavior. Lactating dams were fed either a protein-free or a normoprotein diet from litter parturition to Postnatal Day 10 (P10). All dams received the normoprotein diet after P10. Offspring were tested in the elevated plus-maze (anxiety-like behavior), hole board arena (novelty-seeking and locomotor activity), and radial arm water maze (memory-learning) at either P40 (adolescents) or P90 (adults). The protein-free diet reduced milk protein content at P10 but not at P20. Carbohydrate and lipid contents were unaffected. Serum corticosterone levels in the offspring (at P10, P40, or P90) and dams (at P21) were not affected by the protein-free diet. Maternal behavior was also unchanged. In the offspring, no differences were observed between groups regarding anxiety-like behaviors at both ages. The protein-free diet increased adolescent locomotor activity as well as adult novelty-seeking behavior and memory performance. Our results indicate that the brain growth spurt period is particularly sensitive to protein malnutrition, showing that even a brief nutritional insult during this period can cause specific age-dependent behavioral effects on the offspring. (PsycINFO Database Record

Developmental exposure to glyphosate-based herbicide and depressive-like behavior in adult offspring: Implication of glutamate excitotoxicity and oxidative stress.

We have previously demonstrated that maternal exposure to glyphosate-based herbicide (GBH) leads to glutamate excitotoxicity in 15-day-old rat hippocampus. The present study was conducted in order to investigate the effects of subchronic exposure to GBH on some neurochemical and behavioral parameters in immature and adult offspring. Rats were exposed to 1% GBH in drinking water (corresponding to 0.36% of glyphosate) from gestational day 5 until postnatal day (PND)-15 or PND60. Results showed that GBH exposure during both prenatal and postnatal periods causes oxidative stress, affects cholinergic and glutamatergic neurotransmission in offspring hippocampus from immature and adult rats. The subchronic exposure to the pesticide decreased L-[14C]-glutamate uptake and increased 45Ca2+ influx in 60-day-old rat hippocampus, suggesting a persistent glutamate excitotoxicity from developmental period (PND15) to adulthood (PND60). Moreover, GBH exposure alters the serum levels of the astrocytic protein S100B. The effects of GBH exposure were associated with oxidative stress and depressive-like behavior in offspring on PND60, as demonstrated by the prolonged immobility time and decreased time of climbing observed in forced swimming test. The mechanisms underlying the GBH-induced neurotoxicity involve the NMDA receptor activation, impairment of cholinergic transmission, astrocyte dysfunction, ERK1/2 overactivation, decreased p65 NF-κB phosphorylation, which are associated with oxidative stress and glutamate excitotoxicity. These neurochemical events may contribute, at least in part, to the depressive-like behavior observed in adult offspring.