Executive functions (EFs) are a set of skills responsible for the cognitive control of emotional states and behavior as well as for information processing required for learning and memory. ...Impairments in these abilities, such as focused attention, working memory, cognitive flexibility, and self-regulation, are implicated in a variety of psychopathologies across the lifespan. EF development shows a protracted course that begins in early childhood and continues throughout adolescence and into early adulthood. Maturation of EFs is subject to environmental influences such that adversity during development can affect multiple EF-mediated processes and outcomes. In this review, we describe sensitive periods for the development of EFs and the effects of adverse environmental exposures, with consideration of the underlying neurobiological mechanisms. However, there is considerable interindividual variation in the impact of adversity, with some individuals more vulnerable and some more resilient to its effects. We explore the evidence for the genetic contribution to interindividual variation in EFs, providing an overview of classic studies, followed by the results of recent genome-wide association studies and innovative genomic methods. Finally, we review studies investigating the interdependence between early-life adversities and genetic factors on EFs. We discuss the importance of novel functional genomics approaches, multilevel analyses, and big data to elucidate the complexity of the relationships between genes, environment, and the development of EFs.
Background:
Methylphenidate (MPH) is a stimulant drug mainly prescribed to treat cognitive impairments in attention-deficit/hyperactivity disorder (ADHD). We demonstrated that neonatal ...hypoxia-ischemia (HI) induced attentional deficits in rats and MPH administration reversed these deficits. However, MPH effects on memory deficits after the HI procedure have not been evaluated yet.
Aims:
We aimed to analyze learning and memory performance of young hypoxic-ischemic rats after MPH administration and associate their performance with brain-derived neurotrophic factor (BDNF) levels in the prefrontal cortex and hippocampus.
Methods:
Male Wistar rats were divided into four groups (n=11–13/group): control saline (CTS), control MPH (CTMPH), HI saline (HIS) and HIMPH. The HI procedure was conducted at post-natal day (PND) 7 and memory tasks between PND 30 and 45. MPH administration (2.5 mg/kg, i.p.) occurred 30 min prior to each behavioral session and daily, for 15 days, for the BDNF assay (n=5–7/group).
Results:
As expected, hypoxic-ischemic animals demonstrated learning and memory deficits in the novel-object recognition (NOR) and Morris water maze (MWM) tasks. However, MPH treatment did not improve learning and memory deficits of these animals in the MWM—and even disrupted the animals’ performance in the NOR task. Increased BDNF levels were found in the hippocampus of HIMPH animals, which seem to have been insufficient to improve memory deficits observed in this group.
Conclusions:
The MPH treatment was not able to improve memory deficits resulting from the HI procedure considering a dose of 2.5 mg/kg. Further studies investigating different MPH doses would be necessary to determine a dose–response relationship in this model.
Impulsivity, as observed in patients diagnosed with Attention-deficit/hyperactivity disorder (ADHD), can induce dysregulated behaviors such as binge eating and drug addiction. We previously ...demonstrated that neonatal hypoxia-ischemia (HI) resulted in ADHD-like behaviors in rats and that methylphenidate (MPH) administration (the first therapeutic option for ADHD) reversed these deficits. Here, we aimed at investigating addictive-like behaviors, such as the reward-based feeding behavior (using the BioDAQ monitor) and ethanol consumption (using the IA2BC procedure) in adult animals subjected to neonatal HI and treated with or without MPH. Male Wistar rats were divided into four groups (n = 10–12/group): control saline (CTS), CTMPH, HI saline (HIS) and HIMPH. The HI procedure was conducted at postnatal day (PND) 7 and behavioral analyses between PND 60–90, in which MPH (2.5 mg/kg, i.p.) was administered 30 min prior to each behavioral evaluation (6 sessions in BioDAQ and 12 sessions in the IA2BC protocol). HI animals had a dysregulated feeding intake shortly after eating a small piece of the palatable diet, and MPH reversed this dysregulated pattern. However, when the palatable diet was freely available, MPH stimulated a higher intake of this diet in the first exposure day, and this effect was potentialized in HIMPH rats. Increased ethanol intake was observed in HI rats, and MPH administration alleviated this behavior; contrarily, MPH treatment in control rats induced an increase in ethanol consumption. The present findings give additional support to the relationship between neonatal HI and ADHD but the differential response to MPH in control or HI animals highlights the importance of avoiding indiscriminate use of MPH by healthy individuals.
•Neonatal hypoxia-ischemia (HI) induced ADHD-related outcomes in rats.•Methylphenidate (MPH) reversed or reduced addictive-like behaviors in HI rats.•MPH altered the sensitivity to reward in both HI and control (CT) groups.•MPH showed differential effects concerning ethanol consumption in CT or HI rats.
Folic acid (FA) supplementation (400 μg/day) has been recommended during pregnancy to prevent neural tube defects. However, in some countries, flours are required to be fortified with FA, possibly ...increasing the levels of this vitamin in pregnant women. Our previous studies have evidenced a dual effect of the FA treatment in a rat model of neonatal hypoxia-ischemia (HI). Aiming to better correlate with humans, this paper evaluated the effects of two different levels of FA supplementation during pregnancy on memory parameters and neuronal survival and plasticity in the hippocampus of rats submitted to the neonatal HI. During pregnancy, female Wistar rats received one of these diets: standard (SD), supplemented with 2 mg/kg of FA or with 20 mg/kg of FA. At the 7th PND, rats suffered the HI procedure. At the 60th PND rats were evaluated in the open field, Morris water maze, novel-object recognition and inhibitory avoidance tasks. Furthermore, neuronal density, synaptophysin densitometry and BDNF concentration were assessed in the hippocampus. Both doses of FA prevented the HI-induced memory impairments. The supplementation reversed the BDNF late increase in the hippocampus of the HI rats, but did not inhibit the neuronal death. In conclusion, FA supplementation during pregnancy prevented memory deficits and BDNF imbalance after neonatal HI. These findings are particularly relevant because neuroprotection was achieved even in the high level of FA supplementation during pregnancy, indicating that this intervention would be considered secure for the offspring development.
Genetic polymorphisms of the dopamine transporter gene (DAT1) and perinatal complications associated with poor oxygenation are risk factors for attentional problems in childhood and may show ...interactive effects.
We created a novel expression-based polygenic risk score (ePRS) reflecting variations in the function of the DAT1 gene network (ePRS-DAT1) in the prefrontal cortex and explored the effects of its interaction with perinatal hypoxic-ischemic–associated conditions on cognitive flexibility and brain gray matter density in healthy children from two birth cohorts—MAVAN from Canada (n = 139 boys and girls) and GUSTO from Singapore (n = 312 boys and girls).
A history of exposure to several perinatal hypoxic-ischemic–associated conditions was associated with impaired cognitive flexibility only in the high-ePRS group, suggesting that variation in the prefrontal cortex expression of genes involved in dopamine reuptake is associated with differences in this behavior. Interestingly, this result was observed in both ethnically distinct birth cohorts. Additionally, parallel independent component analysis (MAVAN cohort, n = 40 children) demonstrated relationships between single nucleotide polymorphism–based ePRS and gray matter density in areas involved in executive (cortical regions) and integrative (bilateral thalamus and putamen) functions, and these relationships differ in children from high and low exposure to hypoxic-ischemic–associated conditions.
These findings reveal that the impact of conditions associated with hypoxia-ischemia on brain development and executive functions is moderated by genotypes associated with dopamine signaling in the prefrontal cortex. We discuss the potential impact of innovative genomic and environmental measures for the identification of children at high risk for impaired executive functions.
Attention-deficit hyperactivity disorder (ADHD) may be caused by genetic or environmental factors. Among environmental factors, perinatal complications are related, such as neonatal hypoxia-ischemia ...(HI). Thus, the aim of this study was to investigate whether HI contributes to the development of characteristics related to ADHD in adult rats, and to correlate the behavioral results with brain damage volume. Male Wistar rats were divided into 2 groups: HI and control. The HI procedure consisted of a permanent occlusion of the right common carotid artery followed by a period of hypoxia (90 min; 8% O2 and 92% N2) on the 7th postnatal day. Two months later, animals were evaluated in the open field test during a single 5-min session, and in the 5-choice serial reaction time task (5-CSRTT), over 25 weeks. Our results demonstrated that animals submitted to HI manifest cognitive impairments in task acquisition, deficits in sustained attention, and increases in impulsivity and compulsivity in response to task manipulation in the 5-CSRTT. Locomotor activity observed in open field did not differ between groups. Moreover, brain volume loss in the total hemisphere, cerebral cortex, white matter, hippocampus, and striatum were observed in HI animals, especially on the side ipsilateral to the lesion. From these results, we can infer that neonatal HI is an environmental factor that could contribute to the development of behavioral characteristics observed in ADHD that are associated with general brain atrophy.
•Exercise was able to reverse the hyperactivity after the neonatal hypoxia-ischemia.•The acrobatic training decreased brain atrophy caused by neonatal hypoxia-ischemia.•The acrobatic exercise caused ...locomotion improvement after the hypoxia-ischemia.•Neonatal hypoxia-ischemia did not impact on morphology in motor control structures.
The aim of this study was to evaluated motor function and morphological aspects of the components involved in motor control (sensorimotor cortex, spinal cord, sciatic nerve, neuromuscular junctions and skeletal muscle) in male Wistar rats exposed to a model of neonatal hypoxic-ischemic encephalopathy (HIE) and the possible influence of different physical exercise protocols – treadmill and acrobatic. Male Wistar rats at the 7th post-natal day (PND) were submitted to the HIE model and from the 22nd until 60th PND the exercise protocols (treadmill or acrobatic training) were running. After the training, the animals were evaluated in Open Field, Ladder Rung Walking and Rotarod tasks and after samples of the motor control components were collected. Our results evidenced that the acrobatic training reversed the hyperactivity and anxiety, caused locomotion improvement and decreased brain atrophy in HIE animals. We did not find morphological differences on sensorimotor cortex, spinal cord, sciatic nerve, neuromuscular junctions and skeletal muscle in the animals submitted to HIE model. These intriguing data support the statement of the Rice-Vannucci model does not seem to reproduce, in structures involved in control function, the damage found in humans that suffer HIE. Regarding the protocols of exercise, we proposed that the acrobatic exercise could be a good therapeutic option especially in children affected by neonatal HIE and can be responsible for good results in cognitive and motor aspects.
Fetal restriction (FR) alters insulin sensitivity, but it is unknown how the metabolic profile associated with restriction affects development of the dopamine (DA) system and DA-related behaviors. ...The Netrin-1/DCC guidance cue system participates in maturation of the mesocorticolimbic DA circuitry. Therefore, our objective was to identify if FR modifies Netrin-1/DCC receptor protein expression in the prefrontal cortex (PFC) at birth and mRNA in adulthood in rodent males. We used cultured HEK293 cells to assess if levels of miR-218, microRNA regulator of DCC, are sensitive to insulin. To assess this, pregnant dams were subjected to a 50% FR diet from gestational day 10 until birth. Medial PFC (mPFC) DCC/Netrin-1 protein expression was measured at P0 at baseline and Dcc/Netrin-1 mRNA levels were quantified in adults 15 min after a saline/insulin injection. miR-218 levels in HEK-293 cells were measured in response to insulin exposure. At P0, Netrin-1 levels are downregulated in FR animals in comparison to controls. In adult rodents, insulin administration results in an increase in Dcc mRNA levels in control but not FR rats. In HEK293 cells, there is a positive correlation between insulin concentration and miR-218 levels. Since miR-218 is a Dcc gene expression regulator and our in vitro results show that insulin regulates miR-218 levels, we suggest that FR-induced changes in insulin sensitivity could be affecting Dcc expression via miR-218, impacting DA system maturation and organization. As fetal adversity is linked to nonadaptive behaviors later in life, this may contribute to early identification of vulnerability to chronic diseases associated with fetal adversity.
Perinatal complications such as birth asphyxia were associated with a higher risk for Attention-Deficit/Hyperactivity Disorder (ADHD) in humans. Data from a rat model of neonatal hypoxia-ischemia ...(HI) have revealed inattention, impulsive behavior and dopamine (DA) disturbances in the prefrontal cortex (PFC), confirming the face validity and construct validity for ADHD study. However, the predictive validity (similar therapeutic efficacy of the pharmacological treatment available in the clinic) should be considered. Therefore, we aimed to investigate the effects of methylphenidate (MPH) - the treatment of choice for ADHD - on exploratory and attentional flexibility behaviors and DA-related proteins in the PFC of animals submitted to neonatal HI. Male Wistar rats were divided into four groups: control saline (CTS, n = 12), control MPH (CTMPH, n = 12), HI saline (HIS, n = 13) and HIMPH (n = 12). The HI procedure was conducted at postnatal day (PND) 7 and behavioral measures between PND 30–40, followed by protein analysis in the PFC. The MPH administration (2.5 mg/kg, i.p.) occurred 30 min prior each behavioral session and euthanasia for western blot analysis. We observed that the MPH increased the locomotor activity in the open field especially in HI rats. In the attentional-set shifting task, the MPH reversed the HI- induced attentional inflexibility, but impaired the task acquisition in control rats. Neonatal HI resulted in lower DA D2 receptors expression but also decreased DA transporter (responsible for DA reuptake) and increased pTH (phosphorylated-tyrosine hydroxylase) levels in the PFC, probably to compensate the dysfunctional DA transmission. This compensation was higher in the HIMPH group and it could explain the improvement in the attentional flexibility as well as the increased locomotor activity in this group. Taken this data together, we can assume the predictive validity of the HI model for the ADHD study concerning the impact of MPH treatment on attentional parameters.
•Methylphenidate increased locomotor activity especially in hypoxic-ischemic rats.•Neonatal hypoxia-ischemia impaired attentional flexibility in adolescent rats.•Methylphenidate reversed attentional inflexibility resulting from hypoxia-ischemia.•Task acquisition learning was impaired by the methylphenidate in control rats.•Hypoxia-ischemia disrupted the dopaminergic system in the prefrontal cortex.
