Prefrontal cortex VAMP1 gene network moderates the effect of the early environment on cognitive flexibility in children.

During development, genetic and environmental factors interact to modify specific phenotypes. Both in humans and in animal models, early adversities influence cognitive flexibility, an important brain function related to behavioral adaptation to variations in the environment. Abnormalities in cognitive functions are related to changes in synaptic connectivity in the prefrontal cortex (PFC), and altered levels of synaptic proteins. We investigated if individual variations in the expression of a network of genes co-expressed with the synaptic protein VAMP1 in the prefrontal cortex moderate the effect of early environmental quality on the performance of children in cognitive flexibility tasks. Genes overexpressed in early childhood and co-expressed with the VAMP1 gene in the PFC were selected for study. SNPs from these genes (post-clumping) were compiled in an expression-based polygenic score (PFC-ePRS-VAMP1). We evaluated cognitive performance of the 4 years-old children in two cohorts using similar cognitive flexibility tasks. In the first cohort (MAVAN) we utilized two CANTAB tasks: (a) the Intra-/Extra-dimensional Set Shift (IED) task, and (b) the Spatial Working Memory (SWM) task. In the second cohort, GUSTO, we used the Dimensional Change Card Sort (DCCS) task. The results show that in 4 years-old children, the PFC-ePRS-VAMP1 network moderates responsiveness to the effects of early adversities on the performance in attentional flexibility tests. The same result was observed for a spatial working memory task. Compared to attentional flexibility, reversal learning showed opposite effects of the environment, as moderated by the ePRS. A parallel ICA analysis was performed to identify relationships between whole-brain voxel based gray matter density and SNPs that comprise the PFC-ePRS-VAMP1. The early environment predicts differences in gray matter content in regions such as prefrontal and temporal cortices, significantly associated with a genetic component related to Wnt signaling pathways. Our data suggest that a network of genes co-expressed with VAMP1 in the PFC moderates the influence of early environment on cognitive function in children.

Sex-specific effects of isolation stress and consumption of palatable diet during the prepubertal period on metabolic parameters.

OBJECTIVES: Social isolation during the prepubertal period may have long-term effects on metabolism. The exposure to stressful events is associated with increased palatable food intake, constituting reward-based eating. However, palatable food consumption in early life may lead to metabolic alterations later in life. We investigated whether isolation stress during early life can lead to metabolic alterations in male and female rats with or without exposure to a palatable diet. METHODS: Animals were stressed by isolation during one week after weaning, with or without exposure to a palatable diet. RESULTS: Stress and palatable diet induced increased caloric consumption. In females, there was a potentiation of consumption in animals exposed to stress and palatable diet, reflected by increased weight gain and triacylglycerol levels in juveniles, as well as increased adiponectin levels. Most of the effects had disappeared in the adults. Different effects were observed in males: in juveniles, stress increased unacylated ghrelin levels, and hypothalamic neuropeptide Y (NPY). Subsequently, adult males that were exposed to a palatable diet during prepuberty showed increased body weight and retroperitoneal fat deposition, increased glycemia, and decreased plasma adiponectin and hypothalamic NPY. Exposure to stress during prepuberty led to increased adrenals during adulthood, decreased LDL-cholesterol and increased triacylglycerol levels. CONCLUSION: Isolation stress and consumption of palatable diet changes metabolism in a sex-specific manner. Prepuberty female rats were more prone to stress effects on food consumption, while males showed more long-lasting effects, being more susceptible to a metabolic programming after the consumption of a palatable diet.

The influence of early life interventions on olfactory memory related to palatable food, and on oxidative stress parameters and Na+/K+-ATPase activity in the hippocampus and olfactory bulb of female adult rats.

The effects of neonatal handling and the absence of ovarian hormones on the olfactory memory related to a palatable food in adulthood were investigated. Oxidative stress parameters and Na+/K+-ATPase activity in the hippocampus and olfactory bulb of adult pre-puberty ovariectomized female rats handled or not in the neonatal period were also evaluated. Litters were non-handled or handled (10 min/day, days 1-10 after birth). Females from each litter were divided into: OVX (subjected to ovariectomy), sham, and intact. When adults, olfactory memory related to a palatable food (chocolate) was evaluate using the hole-board olfactory task. Additionally, oxidative stress parameters and Na+/K+-ATPase activity were measured in the hippocampus and olfactory bulb. No difference between groups was observed considering olfactory memory evaluation. Neonatal handled rats presented an increase in Na+/K+-ATPase activity in the hippocampus and in the olfactory bulb, compared to non-handled ones. Considering the surgical procedure, there was a decrease in Na+/K+-ATPase and catalase activities in sham and OVX groups, compared to intact animals in the olfactory bulb. We concluded that olfactory memory related to a palatable food in adulthood was not affected by neonatal handling or by pre-puberty surgery, with or without removal of ovaries. The difference observed between groups in catalase and Na+/K+-ATPase activity does not seem to be related to the olfactory memory. Additionally, the increase in Na+/K+-ATPase activity (an enzyme that maintains the neurochemical gradient necessary for neuronal excitability) induced by neonatal handling may be related to neuroplastic changes in the hippocampus and olfactory bulb.

Neonatal handling impairs spatial memory and leads to altered nitric oxide production and DNA breaks in a sex specific manner.

Early life events lead to behavioral and neurochemical changes in adulthood. The aim of this study is to verify the effects of neonatal handling on spatial memory, nitric oxide (NO) production, antioxidant enzymatic activities and DNA breaks in the hippocampus of male and female adult rats. Litters of rats were non-handled or handled (10 min/day, days 1-10 after birth). In adulthood they were subjected to a Morris water maze or used for biochemical evaluations. Female handled rats showed impairment in spatial learning. They also showed decreased NO production, while no effects were observed in these parameters in male rats. No effects were observed on the number of hippocampal NADPH diaphorase positive cells. In the Comet Assay, male handled rats showed increased DNA breaks index when compared to non-handled ones. We conclude that neonatal handling impairs learning performance in a sex-specific manner, what may be related to NO decreased levels.