Period Of Brain Development Research Articles

Tales from Two Cohots

Background/Aim: Developmental neurotoxicity is a global health concern. Neurotoxicants easily cross the placenta and fetal blood brain barrier, and their constant presence in maternal blood ensures that the fetus is exposed during critical periods of brain development. Exposure to neurotoxicants has been shown to be associated with children's neurobehavioural outcomes, which in turn has economic, social and health consequences. The aim of this presentation is to describe two large longitudinal pregnancy cohorts investigating associations between prenatal and childhood exposures to neurotoxicants and children's neurodeveloopmental outcomes in a high (Canada) and a low income country (Tanzania).Method and Results: The Alberta Pregnancy Outcomes and Nutrition (APrON) cohort (2189 mothers) was recruited in Alberta, Canada. Data on prenatal exposure to endocrine disruptors (i.e., BPA, BPS, phthalates), heavy metals (i.e., methyl mercury, lead, arsenic, manganese) and perfluorooctane sulfonate (PFOS) during the second trimester of pregnancy has been collected for 563 children. In addition, we have collected biosamples at 3-4 years of age to assess childhood exposure levels. Children’s neurodevelopment and behaviour at 2, 3-4 and 5-6 years is being assessed across multiple domains using standardized measures. The Mining and Health cohort (N = 1056) was recruited in Geita and Magu Districts, Tanzania where artisanal and small scale gold mining is a significant industry. In this cohort, data is being collected on prenatal exposure to mercury, arsenic and other heavy metals, pregnancy and birth outcomes, and early childhood health and development.Conclusions: These two pregnancy cohorts, one from a high income country and the other from a low income country, are providing much needed data on known and emerging neurotoxicants and their long term effects on children’s health, neurodevelopment and behaviour.

Maternal immune activation alters brain microRNA expression in mouse offspring.

ObjectiveMaternal immune activation (MIA) is associated with an increased risk of autism spectrum disorder (ASD) in offspring. Herein, we investigate the altered expression of microRNAs (miRNA), and that of their target genes, in the brains of MIA mouse offspring.MethodsTo generate MIA model mice, pregnant mice were injected with polyriboinosinic:polyribocytidylic acid on embryonic day 12.5. We performed miRNA microarray and mRNA sequencing in order to determine the differential expression of miRNA and mRNA between MIA mice and controls, at 3 weeks of age. We further identified predicted target genes of dysregulated miRNAs, and miRNA‐target interactions, based on the inverse correlation of their expression levels.ResultsMice prenatally subjected to MIA exhibited behavioral abnormalities typical of ASD, such as a lack of preference for social novelty and reduced prepulse inhibition. We found 29 differentially expressed miRNAs (8 upregulated and 21 downregulated) and 758 differentially expressed mRNAs (542 upregulated and 216 downregulated) in MIA offspring compared to controls. Based on expression levels of the predicted target genes, 18 downregulated miRNAs (340 target genes) and three upregulated miRNAs (60 target genes) were found to be significantly enriched among the differentially expressed genes. miRNA and target gene interactions were most significant between mmu‐miR‐466i‐3p and Hfm1 (ATP‐dependent DNA helicase homolog), and between mmu‐miR‐877‐3p and Aqp6 (aquaporin 6).InterpretationOur results provide novel information regarding miRNA expression changes and their putative targets in the early postnatal period of brain development. Further studies will be needed to evaluate potential pathogenic roles of the dysregulated miRNAs.

Arsenic induces autophagy in developmental mouse cerebral cortex and hippocampus by inhibiting PI3K/Akt/mTOR signaling pathway: involvement of blood-brain barrier's tight junction proteins.

For the past decade, there has been an increased concern about the health risks from arsenic (As) exposure, because of its neurotoxic effects on the developing brain. The exact mechanism underlying As-induced neurotoxicity during sensitive periods of brain development remains unclear, especially the role of blood-brain barrier's (BBB) tight junction (TJ) proteins during As-induced neurotoxicity. Here, we highlight the involvement of TJ proteins in As-induced autophagy in cerebral cortex and hippocampus during developmental periods [postnatal day (PND) 21, 28, 35 and 42]. Here, the administration of arsenic trioxide (As2O3) at doses of 0.15mg or 1.5mg or 15mg As2O3/L in drinking water from gestational to lactational and continued to the pups till PND42 resulted in a significant decrease in the mRNA expression levels of TJ proteins (Occludin, Claudin, ZO-1 and ZO-2) and Occludin protein expression level. In addition, As exposure significantly decreased PI3K, Akt, mTOR, and p62 with a concomitant increase in Beclin1, LC3I, LC3II, Atg5 and Atg12. Moreover, As exposure also significantly downregulated the protein expression levels of mTOR with a concomitant upregulation of Beclin 1, LC3 and Atg12 in all the developmental age points. However, no significant alterations were observed in low and medium dose-exposed groups of PND42. Histopathological analysis in As-exposed mice revealed decreased number of pyramidal neurons in hippocampus; and neurons with degenerating axons, shrinkage of cells, remarkable vacuolar degeneration in cytoplasm, karyolysis and pyknosis in cerebral cortex. Ultrastructural analysis by transmission electron microscopy revealed the occurrence of autophagosomes and vacuolated axons in the cerebral cortex and hippocampus of the mice exposed to high dose As at PND21 and 42. The severities of changes were found to more persist in the cerebral cortex than in the hippocampus of As-exposed mice. Finally, we conclude that the leaky BBB in cerebral cortex and hippocampus may facilitate the transfer of As and induces autophagy by inhibiting PI3K/Akt/mTOR signaling pathway in an age-dependent manner, i.e., among the four different developmental age points, PND21 animals were found to be more vulnerable to the As-induced neurotoxicity than the other three age points.

CNS Persistence of HIV-1 in Children: the Untapped Reservoir.

The central nervous system (CNS) represents a potential HIV-1 reservoir that may need to be specifically targeted by remission strategies. Perinatally HIV-1-infected children and youth are exposed to HIV-1 at a critical period of brain development. This review summarizes the current literature regarding HIV-1 and the CNS in perinatal infection. HIV-1-associated encephalopathy is prevalent with perinatal infection and neurocognitive impairment persists even following antiretroviral treatment (ART)-mediated suppression of viremia. Compartmentalization of HIV-1 between plasma and CSF of ART-naïve, perinatally infected children suggests the presence of a CNS reservoir; however, similar studies have not yet been conducted with ART suppression. CSF viral escape where CSF and plasma virus concentrations are discordant has been reported in this population, but larger studies with well-defined virologic and immunologic parameters are needed. A better understanding of HIV-1 persistence in the CNS with perinatal infection is essential for improving long-term neurocognitive outcomes and for designing strategies to induce HIV-1 remission in this population.

The combined impacts of docosahexaenoic acid, endurance physical exercise, and prolonged fasting on brain function.

Docosahexaenoic acid (DHA), a long chain polyunsaturated fatty acid (PUFA) is highly enriched in the membrane phospholipids of the brain, neuronal tissue and retina. Accumulating evidence suggests that brain DHA is necessary for maintaining for optimal function of the cognition and the visual system, particularly the photoreceptor, the retina. Loss of brain DHA, especially during crucial brain development period, was highly associated with visual and cognitive defects. Here it would be addressed the effect of DHA on brain functions as assessed by spatial task performance using a first generation model which is similar to human nutrition case. And also, it was well known that prolonged fasting and energy restriction with endurance physical exercise stimulate cognitive function and brain function, which is caused by upregulated ketone body and upregulated brain-derived neurotropic factor (BDNF) responses. In the DHA intake or prolonged physical exercise, upregulated BDNF can activate mitochondrial biogenesis to elevate neuronal bioenergetics and enable synaptic formation. And it also can activate DNA repair in neurons. Further study on the mechanisms about the combine effects of supplementation of DHA and energy restriction on brain function is urgently needed in this area.

Cafeteria-diet effects on cognitive functions, anxiety, fear response and neurogenesis in the juvenile rat.

Early life, covering childhood and adolescence in humans, is an important period of brain development and maturation. Experimental works in rodents have shown that high-caloric diets are particularly detrimental to young rats, affecting cognition. We studied the effects of two different high-caloric diets, prevalent in human adolescents, on male Wistar rats aged 4 weeks at the beginning of the experiment. Rats were randomly allocated to control (C, n = 10), high-sugar diet (HS, n = 10) and cafeteria diet (CAF, n = 10) groups and fed accordingly for 8 weeks. At the end of this period, behavioral tests were performed to analyze (1) anxiety behavior in the elevated plus-maze and open field tests, (2) learning and memory processes in the Morris water maze and novel object recognition test, (3) fear response in the fear conditioning test, and (4) depression state in the forced swim test. We also examined neurogenesis in the dentate gyrus using the marker of neuroproliferation doublecortin (DCX). Our results show that CAF rats have impaired spatial learning and memory and increased anxiety, without changes in the remaining aspects of behavior, associated with a reduction of the total number of DCX-immunoreactive cells in the subgranular layer of the dentate gyrus. Conversely, HS rats displayed no changes in behavior and neurogenesis. These data demonstrate that diets rich in saturated fats and sugar are more detrimental for juvenile rats than diets with high sugar content in what concerns their effects in anxiety-related behaviors, spatial learning and memory, and neurogenesis. These findings may help explain the cognitive disturbances observed in obese human adolescents, who consume high-caloric diets.

Epigenetic Alterations in Anesthesia-Induced Neurotoxicity in the Developing Brain.

Before birth and early in life, the developing brain is particularly sensitive to environmental and pharmacological influences. Increasing experimental evidence suggests that an association exists between exposure to anesthesia during a vulnerable period of brain development and subsequent poor neurodevelopmental outcomes. However, the mechanisms underlying this association are not fully understood. Epigenetics, broadly defined as the regulation of gene expression without alterations of DNA sequence, has become a field of tremendous interest in neuroscience. In recent years, a growing body of literature suggests that anesthesia-induced long-term changes in gene transcription and functional deficits in learning and behavior later in life are mediated via epigenetic modifications. This brief review provides an overview of epigenetic mechanisms and highlights the emerging roles played by epigenetic dysfunctions in the processes of anesthesia-induced neurotoxicity in the developing brain. Epigenetic targeting of DNA methyltransferases and/or histone deacetylases may have some therapeutic value. Epigenetics may lead to the identification of novel markers that contribute toward considerable translational significance in the field of neuroprotection.

Reduced structural complexity of the right cerebellar cortex in male children with autism spectrum disorder.

The cerebellum contains 80% of all neurons in the human brain and contributes prominently to implicit learning and predictive processing across motor, sensory, and cognitive domains. As morphological features of the cerebellum in atypically developing individuals remain unexplored in-vivo, this is the first study to use high-resolution 3D fractal analysis to estimate fractal dimension (FD), a measure of structural complexity of an object, of the left and right cerebellar cortex (automatically segmented from Magnetic Resonance Images using FreeSurfer), in male children with Autism Spectrum Disorders (ASD) (N = 20; mean age: 8.8 years old, range: 7.13–10.27) and sex, age, verbal-IQ, and cerebellar volume-matched typically developing (TD) boys (N = 18; mean age: 8.9 years old, range: 6.47–10.52). We focus on an age range within the ‘middle and late childhood’ period of brain development, between 6 and 12 years. A Mann-Whitney U test revealed a significant reduction in the FD of the right cerebellar cortex in ASD relative to TD boys (P = 0.0063, Bonferroni-corrected), indicating flatter and less regular surface protrusions in ASD relative to TD males. Consistent with the prediction that the cerebellum participates in implicit learning, those ASD boys with a higher (vs. lower) PIQ>VIQ difference showed higher, more normative complexity values, closer to TD children, providing new insight on our understanding of the neurological basis of differences in verbal and performance cognitive abilities that often characterize individuals with ASD.

Associations between 24-Hour Movement Behaviours and Global Cognition in a Cross-Sectional Sample of American Children

Background: Childhood is a critical period for brain development, and the behaviours that comprise a typical 24-hour day contribute to cognitive performance in children. This study investigated the relationship between cognition and meeting the 24-hour movement behaviour guidelines of ≥60 minutes of physical activity, ≤2 hours of recreational screen time, and 9-11 hours of sleep per day in 9-10 year olds. Methods: This study presents cross-sectional data from the first annual curated release of the Adolescent Brain Cognitive Development Study (ABCD) - a 10-year longitudinal, observational study investigating brain development in American children. Data were collected from 21 study sites across the United States between September 2016 and 2017. Participants were 4,524 American children aged 9-10 years. Exposures were physical activity, recreational screen time, and sleep duration. The primary outcome was global cognition and secondary outcomes were crystallized and fluid intelligence. Findings: The mean (SD) number of guideline recommendations met was 1·1 (0·9). Overall, 50·9% of participants met the sleep recommendation, 36·5% met screen time, and 17·5% met the physical activity recommendation. 65·3% of participants met at least 1, whereas 4·7% of participants met all 3 recommendations. Multi-level regression analysis revealed a significant positive gradient between global cognition and each additional recommendation met [β=1·48 (95% CI: 0·86, 2·11), p<0·001]. For combinations of behaviours, there was a significant positive association between global cognition and meeting sleep screen [β=5·26 (95% CI: 3·67, 6·86), p<0·001] or meeting the screen-only [β=4·37 (95% CI: 2·61, 6·13, p<0·001] compared to not meeting any recommendations.

Mouse maternal protein restriction during preimplantation alone permanently alters brain neuron proportion and adult short-term memory

Maternal protein malnutrition throughout pregnancy and lactation compromises brain development in late gestation and after birth, affecting structural, biochemical, and pathway dynamics with lasting consequences for motor and cognitive function. However, the importance of nutrition during the preimplantation period for brain development is unknown. We have previously shown that maternal low-protein diet (LPD) confined to the preimplantation period (Emb-LPD) in mice, with normal nutrition thereafter, is sufficient to induce cardiometabolic and locomotory behavioral abnormalities in adult offspring. Here, using a range of in vivo and in vitro techniques, we report that Emb-LPD and sustained LPD reduce neural stem cell (NSC) and progenitor cell numbers at E12.5, E14.5, and E17.5 through suppressed proliferation rates in both ganglionic eminences and cortex of the fetal brain. Moreover, Emb-LPD causes remaining NSCs to up-regulate the neuronal differentiation rate beyond control levels, whereas in LPD, apoptosis increases to possibly temper neuron formation. Furthermore, Emb-LPD adult offspring maintain the increase in neuron proportion in the cortex, display increased cortex thickness, and exhibit short-term memory deficit analyzed by the novel-object recognition assay. Last, we identify altered expression of fragile X family genes as a potential molecular mechanism for adverse programming of brain development. Collectively, these data demonstrate that poor maternal nutrition from conception is sufficient to cause abnormal brain development and adult memory loss.

Pharmacological Inhibition of ERK Signaling Rescues Pathophysiology and Behavioral Phenotype Associated with 16p11.2 Chromosomal Deletion in Mice.

The human 16p11.2 microdeletion is one of the most common gene copy number variations linked to autism, but the pathophysiology associated with this chromosomal abnormality is largely unknown. The 593 kb deletion contains the ERK1 gene and other genes that converge onto the ERK/MAP kinase pathway. Perturbations in ERK signaling are linked to a group of related neurodevelopmental disorders hallmarked by intellectual disability, including autism. We report that mice harboring the 16p11.2 deletion exhibit a paradoxical elevation of ERK activity, cortical cytoarchitecture abnormalities and behavioral deficits. Importantly, we show that treatment with a novel ERK pathway inhibitor during a critical period of brain development rescues the molecular, anatomical and behavioral deficits in the 16p11.2 deletion mice. The ERK inhibitor treatment administered to adult mice ameliorates a subset of these behavioral deficits. Our findings provide evidence for potential targeted therapeutic intervention in 16p11.2 deletion carriers.SIGNIFICANCE STATEMENT The ERK/MAPK pathway is genetically linked to autism spectrum disorders and other syndromes typified by intellectual disability. We provide direct evidence connecting the ERK/MAP kinases to the developmental abnormalities in neurogenesis and cortical cytoarchitecture associated with the 16p11.2 chromosomal deletion. Most importantly, we demonstrate that treatment with a novel ERK-specific inhibitor during development rescues aberrant cortical cytoarchitecture and restores normal levels of cell-cycle regulators during cortical neurogenesis. These treatments partially reverse the behavioral deficits observed in the 16p11.2del mouse model, including hyperactivity, memory as well as olfaction, and maternal behavior. We also report a rescue of a subset of these deficits upon treatment of adult 16p11.2del mice. These data provide a strong rationale for therapeutic approaches to this disorder.

NR3C1 hypermethylation in depressed and bullied adolescents

The disruption of key epigenetic processes during critical periods of brain development can increase an individual’s vulnerability to psychopathology later in life. For instance, DNA methylation in the glucocorticoid receptor gene (NR3C1) in adulthood is known to be associated with early-life adversities and has been suggested to mediate the development of stress-related disorders. However, the association between NR3C1 methylation and the emergence of internalizing symptoms in childhood and adolescence has not been studied extensively. In the present report, we used saliva DNA from a cohort of Swedish adolescents (13–14 years old; N = 1149) to measure NR3C1 methylation in the exon 1F region. Internalizing psychopathological symptoms were assessed using the Center for Epidemiologic Studies Depression Scale for Children (CES-DC). We found that NR3C1 hypermethylation was cross-sectionally associated with high score for internalizing symptoms in the whole group as well as among the female participants. In addition, an analysis of social environmental stressors revealed that reports of bullied or lacking friends were significantly associated with NR3C1 hypermethylation. This cross-sectional association of NR3C1 exon 1F hypermethylation with internalizing psychopathology in adolescents, as well as with bullying and lack of friends are novel results in this field. Longitudinal studies are needed to address whether NR3C1 methylation mediates the link between social stressors and psychopathology in adolescence.

The Brain/MINDS project aimed at establishing the marmoset as a model organism for neurobiology and establishing the genetic and biochemical elements of their neural development

The brain is the most sophisticated and intricate organ in the body. Billions of neurons interconnect and form distinct regions which process different neural activities. The development of the brain during pregnancy and early post-natal life is extremely sensitive, complex and crucial to proper function over the life of a person. This is the most plastic time of the brain. It is changing constantly and reacting to the different stimuli encountered by the individual. The lack of a particular stimulus can have a profound effect on the later structure and function of the brain. For example, if a newborn mouse has an eye covered so it receives no light, visual cortex, where normally processes binocular visual stimuli, develops to process visual stimuli only from the open eye. This cannot be altered later on even when both eyes are opened; the mouse remains weak in one eye despite there being nothing wrong with the eye itself. Studying this early time period of brain development presents many problems. Investigation is hampered by the difficulty in accessing and manipulating the brain as well as the huge variety of factors that contribute to brain development. Currently, most work is conducted in rodents, primarily because there are a large range of genetic tools available. This is useful to an extent and has demonstrated key findings that appear to be relevant to most mammalian species. However, the human brain is quite different to the mouse brain. It has adapted to very different tasks required of mice compared to humans and therefore there is a knowledge gap to bridge in this area. In addition to this, examination of global gene expression in the brain has only truly become viable in the last 10 years. The same can also be said of the ability to analyse the development process at a biochemical level. Dr Tomomi Shimogori of the RIKEN Center for Brain Science, Japan, has been tackling these difficulties through her work on the molecular mechanisms of brain development. She has worked on rodents, but is now developing a model in the common marmoset based around the creation of a gene atlas. Working on the primate should help fill in the gap between rodent and human. Shimogori explains why the marmoset was chosen: 'One of the biggest advantages of using marmosets as a model animal is that many of its behaviours share similarities with human behaviours, and thus has potential for use in understanding the underlying mechanisms of human brain function and mental disease

Kangaroo mother care and infant biopsychosocial outcomes in the first year: A meta-analysis

AimA systematic review and meta-analysis was conducted to examine the relationship between KMC and infant/toddler biopsychosocial outcomes. MethodPubMed, MEDLINE (OvidSP), MEDLINE in Process (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), and AMED (OvidSP) were searched. Observational studies and randomized control trials through October 2015 that investigated the association between KMC intervention and infant/toddler biopsychosocial outcomes were included. Studies with <10 participants, those using skin-to-skin only during painful procedures or only on the day of birth, and those that did not report quantitative outcomes were excluded. Data were extracted by two coders and estimates were examined using random-effects. Results3177 studies were screened with 13 meeting inclusion criteria and representing 5 child outcomes (cognitive, motor, self-regulation, socio-emotional and temperament). Among LBW/premature neonates, KMC compared to conventional care was associated with improved infant self-regulation. Moderated effects were identified for cognitive (duration of KMC) and motor development (duration of KMC, country-level mortality ratio, and infant gender). InterpretationsKMC administered to vulnerable neonates during a sensitive period of brain development has a lasting impact on self-regulation skills later in infancy. Further research examining the longer-term effect of KMC on cognitive and motor development, socioemotional skills, and temperament is needed.

Sex- and Age-dependent Effects of Orexin 1 Receptor Blockade on Open-Field Behavior and Neuronal Activity

Adolescence is a sensitive and critical period in brain development where psychiatric disorders such as anxiety, depression and post-traumatic stress disorder are more likely to emerge following a stressful life event. Females are two times more likely to suffer from psychiatric disorders than males. Patients with these disorders show alterations in orexins (also called hypocretins), important neuropeptides that regulate arousal, wakefulness and the hypothalamic–pituitary–adrenal axis activity. Little is known on the role of orexins in mediating arousal behaviors in male and female rats during adolescence or adulthood. Here, we examine the influence of orexin 1 receptor blockade by SB334867 in open-field behavior in male and female rats during early adolescence (PND 31–33) or adulthood (PND 75–77). Animals were injected with 0 (vehicle), 1, 10, or 30 mg/kg SB334867 (i.p.). Thirty minutes later, they were placed in an open field, and behavior and neuronal activity (c-Fos) were assessed. In adolescent males, SB334867 significantly increased immobility in the 10 mg/kg group compared to vehicle. However, this increase in immobility in adolescent males was not observed in adolescent females. In contrast to adolescent males, adult males in the 10 mg/kg dose group showed the opposite effect on immobility compared to vehicle. These results indicate that 10 mg/kg dose of SB334867 has opposing effects in adolescent and adult males, but few effects in adolescent and adult females. Differences in functional networks between limbic regions may underlie these effects of orexin receptor blockade that are sex- and age-dependent in rats.

F58. Low-Dose Penicillin Exposure in Adolescent Mice Leads to Long-Term Deficits in Social Odour Recognition: Implications for Microbiota & Olfaction in Disorders Involving Social Communication

Recent work has demonstrated that low-dose penicillin treatment of mice during pre- and early post-natal periods has long-term effects on offspring behavior, brain neurochemistry and microbiome (Leclercq et al 2017), many of which are prevented by concurrent treatment with a probiotic. We have now observed that low-dose penicillin during adolescence results in long-term behavioural change. Adolescence is a vulnerable period in brain development, and a time in humans when psychiatric illness often first manifests. While processing of olfactory cues is recognized as integral to rodent behavior, this is often neglected in such studies. We therefore examined the impact of low-dose penicillin treatment during adolescence on social odour discrimination.

Age‐Dependent Anti‐seizure and Neuroprotective Effect of Cannabidivarin in Neonatal Rats

Neonatal seizures and seizures of infancy represent a significant cause of morbidity. 30–40% of infants and children with seizures will fail to achieve seizure remission with current anti‐epileptic drug (AED) treatment. Moreover, pharmacotherapy during critical periods of brain development can adversely affect nervous system function. We, and others, have shown that early life exposure to AEDs including phenobarbital, phenytoin, and valproate are associated with induction of enhanced neuronal apoptosis during a confined period of postnatal development in rats. Thus, identification of new therapies for neonatal/infantile epilepsy syndromes that provide seizure control without neuronal toxicity is a high priority.Current clinical trials report that modulation of the cannabinoid system with the phytocannabinoid cannabidiol exerts anti‐seizure effects in children with epilepsy. While cannabidiol and the propyl analog cannabidivarin (CBDV) display anti‐seizure efficacy in adult animal models of seizures/epilepsy, they remained unexplored in neonatal models. Therefore, we investigated the therapeutic potential of CBDV in multiple neonatal rodent seizure models. To evaluate the therapeutic potential of CBDV, we tested its anti‐seizure efficacy in five models of neonatal seizures: pentylenetetrazole (PTZ), DMCM, hypoxia, kainate and NMDA‐evoked spasms, each representing a different clinical seizure phenotype. We also evaluated the preclinical safety profile in the developing brain.Postnatal day (P) 10 or P20 male, Sprague‐Dawley rat pups were pretreated with CBDV or vehicle prior to chemically or hypoxia induced seizures. CBDV only displayed anticonvulsant effects in the P20 rat pups in the PTZ and DMCM models, with no effect on seizure severity or latency in the P10 animals. Therefore, we next measured the relative expression of known targets for CBDV (TRPV1, TRPA1) to determine a mechanism for which CBDV is anticonvulsant in P20, but not P10 animals. The P20 animals show increased expression of TRPV1 in key brain regions implicated in epileptogenic activity.Finally, CBDV was administered to the developmentally sensitive P7 rat pups and neuronal cell death was examined 24 hours post‐treatment. Fluoro‐Jade B staining was used to label apoptosis in several brain regions including: cingulate cortex, striatum, lateral septum. CBDV did not enhance developmental apoptosis above vehicle control levels.Together, these results indicate that modulation of the cannabinoid system in a receptor independent manner can provide seizure control in developing animals, but in an age specific manner. Further, during a developmentally sensitive neonatal period, drugs targeting the cannabinoid system do not induce neuronal apoptosis characteristic of many other AEDs. These results provide some of the first systemic, preclinical data evaluating CBDV in pediatric models of epilepsy.Support or Funding InformationCenter for Excellence in Regulatory Science and Innovation (CERSI)NIH TL1‐TR001431 Translational Biomedical Science ProgramThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

From Adolescent Neurogenesis to Schizophrenia: Opportunities, Challenges and Promising Interventions

Schizophrenia is a maldevelopmental disease with multifactorial etiopathogenesis linked to disturbances in the prenatal/ perinatal environment and to social factors and/or addictive drugs consumption during adolescence/young adulthood. Adolescence has been demonstrated to represent a very sensitive period for brain development. Exposure to adverse life events (chronic social isolation and/or instability) and/or addictive drugs (opioids, cocaine, cannabinoids, alcohol, nicotine) during adolescence has been linked to deviations in the normal neurodevelopment, producing a brain particularly at risk of mental diseases. Several psychopharmacological drugs and environmental factors have been reported to protect against the detrimental effect on neurogenesis caused by the aforementioned genetic and/or epigenetic vulnerabilities. Nerve growth factor (NGF) is one of the strongest stimuli of adult/adolescent neurogenesis and a promising neuromodulator to prevent and/or ameliorate the various behavioral and cognitive schizophrenic symptoms. Biomed Rev 2017; 28: 62-69. Key words: schizophrenia, neurodevelopment, adolescence, stem cells, adult neurogenesis, addictive drugs, life events, NGF

Developmental Neurotoxicity of Arsenic: Involvement of Oxidative Stress and Mitochondrial Functions

Over the last decade, there has been an increased concern about the health risks from exposure to arsenic at low doses, because of their neurotoxic effects on the developing brain. The exact mechanism underlying arsenic-induced neurotoxicity during sensitive periods of brain development remains unclear, although enhanced oxidative stresses, leading to mitochondrial dysfunctions might be involved. Here, we highlight the generation of reactive oxygen species (ROS) and oxidative stress which leads to mitochondrial dysfunctions and apoptosis in arsenic-induced developmental neurotoxicity. Here, the administration of sodium arsenite at doses of 2 or 4mg/kg body weight in female rats from gestational to lactational (GD6-PD21) resulted to increased ROS, led to oxidative stress, and increased the apoptosis in the frontal cortex, hippocampus, and corpus striatum of developing rats on PD22, compared to controls. Enhanced levels of ROS were associated with decreased mitochondrial membrane potential and the activity of mitochondrial complexes, and hampered antioxidant levels. Further, neuronal apoptosis, as measured by changes in the expression of pro-apoptotic (Bax, Caspase-3), anti-apoptotic (Bcl2), and stress marker proteins (p-p38, pJNK) in arsenic-exposed rats, was discussed. The severities of changes were found to more persist in the corpus striatum than in other brain regions of arsenic-exposed rats even after the withdrawal of exposure on PD45 as compared to controls. Therefore, our results indicate that perinatal arsenic exposure leads to abrupt changes in ROS, oxidative stress, and mitochondrial functions and that apoptotic factor in different brain regions of rats might contribute to this arsenic-induced developmental neurotoxicity.

Unlimited sucrose consumption during adolescence generates a depressive-like phenotype in adulthood.

Depression is highly prevalent worldwide, but its etiology is not fully understood. An overlooked possible contributor to the epidemic of depression is feeding styles, particularly at early age when the brain is intensely changing. We have previously reported that unlimited sucrose consumption during adolescence leads to enduring changes in brain reward function. Here, we tested the hypothesis that sucrose consumption during adolescence would lead to a 'depressive-like' phenotype. Adolescent male rats were given unlimited access to 5% sucrose in their home cages from postnatal day 30 to postnatal day 46 and their emotional behavior was subsequently examined at adulthood. Sucrose consumption during adolescence caused anhedonia, decreased motivation for saccharin, increased immobility in the forced swim test and exacerbated anxiety-like behavior. Additionally, sucrose consumption during adolescence decreased cell proliferation in the hippocampus in adulthood. Chronic treatment with imipramine (10 mg/kg) normalized behavior and restored cell proliferation in the hippocampus of adult rats with a history of sucrose consumption during adolescence. A similar sucrose consumption starting at adulthood only increases immobility in the forced swim test, suggesting that sucrose intake affects also adults' behavior but to a lesser degree. Overall, our findings reveal an unsuspected protracted effect of sucrose consumption on behavior and suggest that unlimited sucrose consumption during critical periods of brain development may play an important role in the etiology of reward-related disorders such as depression.