•Maternal separation increased sensitivity to frustration in adult males but not females.•Maternal separation did not affect frustration during adolescence.•Dorsal hippocampus NMDA receptor ...composition was altered in the susceptible animals.•This molecular shift possibly signals a stronger memory of the devaluation experience.•Strong emotional memories might hinder the ability to cope with frustration.
Early life stress may lead to lifelong impairments in psychophysiological functions, including emotional and reward systems. Unpredicted decrease in reward magnitude generates a negative emotional state (frustration) that may be involved with susceptibility to psychiatric disorders. We evaluated, in adolescents and adult rats of both sexes, whether maternal separation (MS) alters the ability to cope with an unexpected reduction of reward later in life. Litters of Wistar rats were divided into controls (non handled − NH) or subjected to MS. Animals were trained to find sugary cereal pellets; later the amount was reduced. Increased latency to reach the reward-associated area indicates higher inability to regulate frustration. The dorsal hippocampus (dHC) and basolateral amygdala (BLA) were evaluated for protein levels of NMDA receptor subunits (GluN2A/GluN2B), synaptophysin, PSD95, SNAP-25 and CRF1. We found that adult MS males had greater vulnerability to reward reduction, together with decreased GluN2A and increased GluN2B immunocontent in the dHC. MS females and adolescents did not differ from controls. We concluded that MS enhances the response to frustration in adult males. The change in the ratio of GluN2A and GluN2B subunits in dHC could be related to a stronger, more difficult to update memory of the aversive experience.
Variations in serotoninergic signaling have been related to behavioral outcomes. Alterations in the genome, such as DNA methylation and histone modifications, are affected by serotonin ...neurotransmission. The amygdala is an important brain region involved in emotional responses and impulsivity, which receives serotoninergic input. In addition, studies suggest that the serotonin transporter gene network may interact with the environment and influence the risk for psychiatric disorders. We propose to investigate whether/how interactions between the exposure to early life adversity and serotonin transporter gene network in the amygdala associate with behavioral disorders. We constructed a co-expression-based polygenic risk score (ePRS) reflecting variations in the function of the serotonin transporter gene network in the amygdala and investigated its interaction with postnatal adversity on attention problems in two independent cohorts from Canada and Singapore. We also described how interactions between ePRS-5-HTT and postnatal adversity exposure predict brain gray matter density and variation in DNA methylation across the genome. We observed that the expression-based polygenic risk score, reflecting the function of the amygdala 5-HTT gene network, interacts with postnatal adversity, to predict attention and hyperactivity problems across both cohorts. Also, both postnatal adversity score and amygdala ePRS-5-HTT score, as well as their interaction, were observed to be associated with variation in DNA methylation across the genome. Variations in gray matter density in brain regions linked to attentional processes were also correlated to our ePRS score. These results confirm that the amygdala 5-HTT gene network is strongly associated with ADHD-related behaviors, brain cortical density, and epigenetic changes in the context of adversity in young children.
•Early-life stress (ELS) frequently modifiesmemory processes in adulthood.•The intensity of stress is particularly important in determining ELS effects.•Animal age when memory is evaluated influences ...the outcome observed.•ELS effects on adult memory involve neuroendocrine, neurochemical and cellular changes.•ELS effects on adult memory might be sex-specific.
Exposure to stressors in early postnatal life induces long-lasting modifications in brain function. This plasticity, an essential characteristic of the brain that enables adaptation to the environment, may also induce impairments in some psychophysiological functions, including learning and memory. Early life stress (ELS) has long-term effects on the hypothalamic–pituitary–adrenal axis response to stressors, and has been reported to lead to neuroinflammation, altered levels of neurotrophic factors, modifications in neurogenesis and synaptic plasticity, with changes in neurotransmitter systems and network functioning. In this review, we focus on early postnatal stress in animal models and their effects on learning and memory. Many studies have reported ELS-induced impairments in different types of memories, including spatial memory, fear memory, recognition (both for objects and social) memory, working memory and reversal learning. Studies are not always in agreement, however, no effects, or sometimes facilitation, being reported, depending on the nature and intensity of the early intervention, as well as the age when the outcome was evaluated and the sex of the animals. When considering processes occurring after consolidation, related with memory maintenance/persistence or transformation, there are a very reduced number of reports. Future studies addressing the mechanisms underlying memory changes for ELS should shed some light on the understanding of the different effects induced by stressors of different types and intensities on cognitive functions.
Leptin influences eating behavior. Exposure to early adversity is associated with eating behaviour disorders and metabolic syndrome, but the role of the leptin receptor on this relationship is poorly ...explored. We investigated whether individual differences in brain region specific leptin receptor (LepR) gene networks could moderate the effects of early adversity on eating behavior and metabolism. We created an expression-based polygenic risk score (ePRS) reflecting variations in the function of LepR gene network in prefrontal cortex and hypothalamus to investigate the interactions between a cumulative index of postnatal adversity on eating behavior in two independent birth cohorts (MAVAN and GUSTO). To explore whether variations in the prefrontal cortex or hypothalamic genetic scores could be associated with metabolic measurements, we also assessed the relationship between LepR-ePRS and fasting blood glucose and leptin levels in a third independent cohort (ALSPAC). We identified significant interaction effects between postnatal adversity and prefrontal-based LepR-ePRS on the Child Eating Behavior Questionnaire scores. In MAVAN, we observed a significant interaction effect on food enjoyment at 48 months (β = 61.58, p = 0.015) and 72 months (β = 97.78, p = 0.001); food responsiveness at 48 months (β = 83.79, p = 0.009) satiety at 48 months (β = -43.63, p = 0.047). Similar results were observed in the GUSTO cohort, with a significant interaction effect on food enjoyment (β = 30.48, p = 0.006) food fussiness score (β = -24.07, p = 0.02) and satiety score at 60 months (β = -17.00, p = 0.037). No effects were found when focusing on the hypothalamus-based LepR-ePRS on eating behavior in MAVAN and GUSTO cohorts, and there was no effect of hypothalamus and prefrontal cortex based ePRSs on metabolic measures in ALSPAC. Our study indicated that exposure to postnatal adversity interacts with prefrontal cortex LepR-ePRS to moderate eating behavior, suggesting a neurobiological mechanism associated with the development of eating behavior problems in response to early adversity. The knowledge of these mechanisms may guide the understanding of eating patterns associated with risk for obesity in response to fluctuations in stress exposure early in life.
Previous studies focused on the relationship between prenatal conditions and neurodevelopmental outcomes later in life, but few have explored the interplay between gene co-expression networks and ...prenatal adversity conditions on cognitive development trajectories and gray matter density.
We analyzed the moderation effects of an expression polygenic score (ePRS) for the Brain-derived Neurotrophic Factor gene network (BDNF ePRS) on the association between prenatal adversity and child cognitive development. A score based on genes co-expressed with the prefrontal cortex (PFC) BDNF was created, using the effect size of the association between the individual single nucleotide polymorphisms (SNP) and the BDNF expression in the PFC. Cognitive development trajectories of 157 young children from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) cohort were assessed longitudinally in 4-time points (6, 12, 18, and 36 months) using the Bayley-II mental scales.
Linear mixed-effects modeling indicated that BDNF ePRS moderates the effects of prenatal adversity on cognitive growth. In children with high BDNF ePRS, higher prenatal adversity was associated with slower cognitive development in comparison with those exposed to lower prenatal adversity. Parallel-Independent Component Analysis (pICA) suggested that associations of expression-based SNPs and gray matter density significantly differed between low and high prenatal adversity groups. The brain IC included areas involved in visual association processes (Brodmann area 19 and 18), reallocation of attention, and integration of information across the supramodal cortex (Brodmann area 10).
Cognitive development trajectories and brain gray matter seem to be influenced by the interplay of prenatal environmental conditions and the expression of an important BDNF gene network that guides the growth and plasticity of neurons and synapses.
•Adversity exposure in early life contributes to the development of eating disorder.•Neonatal stress increases anxiogenic-like behavior, but only in male rats.•Maternal deprivation induces decreased ...hypothalamic POMC levels in adult males.•Early life adversities affect serotonergic activity in the hypothalamus and amygdala.•Effects of neonatal stress are sexually dimorphic.
Early life experiences have strong influences on brain programming and can affect eating behavior control and body weight later in life. However, there is no consensus about the relationship between neonatal stress and feeding behavior. We evaluated whether maternal deprivation (MD) and maternal separation (MS) alter body weight and appetite using standard rat chow consumption and palatable food. Also, we evaluated anxiety and the expression of the leptin receptor, neuropeptides POMC, CART, NPY in the hypothalamus, as well as the serotoninergic system in the amygdala and hypothalamus as possible modulators of these behaviors. We found a decrease in standard rat chow consumption in MD. However, both neonatal stress protocols increased the consumption of palatable food and led to anxiogenic behavior in male animals. MD led to decreased hypothalamic POMC levels in adult males. Serotonin in the hypothalamus was decreased by both stress models in males and females. In the amygdala, MS decreased serotonin levels while MD increased its metabolite levels. We observed that males are more vulnerable and females are more resilient to the effects of neonatal stress on anxiety-like behavior, as well as on food consumption and on the central changes observed. These data together add support to the concept that the early environment contributes to the development of eating disorders later in life.
Early stress increases the risk for psychiatric disorders. Glucocorticoids are stress mediators that regulate transcriptional activity and morphology in the hippocampus, which is implicated in the ...pathophysiology of multiple psychiatric conditions. We aimed to establish the relevance of hippocampal, glucocorticoid-induced transcriptional as a mediator of the effects of early life on later psychopathology in humans.
RNA-sequencing was performed with anterior (aDG) and posterior hippocampal dentate gyrus (pDG) from adult female macaques (N= 12/group) chronically treated with betamethasone (glucocorticoid receptor agonist) or vehicle. Co-Expression Network Analysis identified a preserved gene network in the pDG that was strongly associated with glucocorticoid exposure. The SNPs in the genes in this network were used to create an expression-based polygenic score (ePGS) in humans.
The ePGS significantly moderated the association between early adversity and psychotic disorders in adulthood (UK Biobank, women, N=44519) and on child peer relations (ALSPAC, girls, N=1666 for 9 years old and N=1594 for 11 years old), an endophenotype for later psychosis. Analyses revealed that this network was enriched for glucocorticoid-induced epigenetic remodeling in human hippocampal cells. We also found a significant association between SNPs from the ePGS and adult brain gray matter density.
We provide an approach for the use of transcriptomic data from animal models together with human data to study the impact of environmental influences on mental health. The results are consistent with the hypothesis that hippocampal glucocorticoid-related transcriptional activity mediates the effects of early adversity on neural mechanisms implicated in psychiatric disorders.
•Oxandrolone promotes anxiety-like behaviors at both doses (therapeutic and excessive).•An increase in catalase expression was observed in the hippocampus of TD animals.•No changes in TNF-α and ...dopamine receptor 2 (DrD2) were observed in any evaluated areas.
Oxandrolone (OXA) is a synthetic steroid used for the treatment of clinical conditions associated with catabolic states in humans, including children. However, its behavioral effects are not well known. Our goal was to evaluate the anxiety-like behavior induced in young adult rats after the treatment of juvenile animals with OXA.
Four-week-old male rats were separated into three groups: Control (CON), therapeutic-like OXA dose (TD), and excessive OXA dose (ED), in which 2.5 and 37.5 mg/kg/day of OXA were administered via gavage for four weeks for TD and ED, respectively. Behavior was evaluated through the elevated plus maze (EPM) and open field (OF) tests. Protein expression of catalase (CAT), superoxide dismutase (SOD), Tumor necrosis factor-α (TNF-α), and dopamine receptor 2 (DrD2) were analyzed in tissue samples of the hippocampus, amygdala, and prefrontal cortex by Western Blot.
OXA induced anxiety-like behaviors in both TD and ED animals; it decreased the time spent in the open arms of the EPM in both groups and reduced the time spent in the central zone of the OF in the TD group. In the hippocampus, CAT expression was higher in TD compared with both control and ED animals. No differences were found in the amygdala and prefrontal cortex. TNF-α, SOD, and DrD2 levels were not altered in any of the assessed areas.
Treatment of juvenile rats with OXA led to anxiety-like behavior in young adult animals regardless of the dose used, with minor changes in the antioxidant machinery located in the hippocampus.
Acute organophosphate (OP) poisoning, particularly by suicide attempts, generates high mortality and morbidity. Few studies have systematically addressed the consequences of acute OP intoxication on ...cognition and memory of survivors. Preclinical evidence suggests that acute OP-induced effects are associated with inhibiting the brain acetylcholinesterase (AChE) enzyme. The OP triazophos has been used worldwide, although its effects on mnemonic processing are yet to be investigated. Based on the above, the present study investigated whether acute triazophos intoxication interferes with the expression and extinction of contextual fear memory in rats. Hippocampal and amygdalar AChE activity and plasma butyrylcholinesterase (BChE) were measured at the end of the experiment to confirm the cholinergic overstimulation. Independent cohorts of animals intoxicated with triazophos were evaluated in the novel object recognition (NOR) test, a less aversive associative memory task. At the dose of 15 mg/kg, triazophos administered immediately after contextual fear conditioning impaired the extinction but not the expression of freezing behavior. Triazophos poisoning induced no changes in the discrimination index in the NOR test. Triazophos inhibited the AChE activity in a time- and brain region-dependent manner. Our findings suggest that fear memory extinction deficits induced by acute triazophos intoxication are accompanied by hippocampal AChE inhibition. The deficient fear extinction associated with acute OP poisoning may represent a behavioral and biochemical phenotype helpful to study mechanisms of neurotoxicity and treatment approach of OP suicide survivors.
•A single dose of triazophos induces fear extinction deficit in rats.•Acute triazophos exposure does not affect the contextual fear expression.•Triazophos poisoning induces no changes in the novel object recognition.•Acute triazophos exposure inhibits hippocampal and amygdalar acetylcholinesterase.
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