Stages Of Brain Development Research Articles

Development and genetics of brain temporal stability related to attention problems in adolescent twins

The brain continuously develops and reorganizes to support an expanding repertoire of behaviors and increasingly complex cognition. These processes may, however, also result in the appearance or disappearance of specific neurodevelopmental disorders such as attention problems. To investigate whether brain activity changed during adolescence, how genetics shape this change, and how these changes were related to attention problems, we measured EEG activity in 759 twins and siblings, assessed longitudinally in four waves (12, 14, 16, and 18years of age). Attention problems were assessed with the SWAN at waves 12, 14, and 16. To characterize functional brain development, we used a measure of temporal stability (TS) of brain oscillations over the recording time of 5min reflecting the tendency of a brain to maintain the same oscillatory state for longer or shorter periods. Increased TS may reflect the brain's tendency to maintain stability, achieve focused attention, and thus reduce “mind wandering” and attention problems. The results indicate that brain TS is increased across the scalp from 12 to 18. TS showed large individual differences that were heritable. Change in TS (alpha oscillations) was heritable between 12 and 14 and between 14 and 16 for the frontal brain areas. Absolute levels of brain TS at each wave were positively correlated with attention problems but not significantly. High and low attention problems subjects showed different developmental trajectories in TS, which was significant in a cluster of frontal leads. These results indicate that trajectories in brain TS development are a biomarker for the developing brain. TS in brain oscillations is highly heritable, and age-related change in TS is also heritable in selected brain areas. These results suggest that high and low attention problems subjects are at different stages of brain development.

Proteomic investigation of the prefrontal cortex in the rat clomipramine model of depression

Neonatal rodents chronically treated with the tricyclic antidepressant clomipramine show depression-like behavior, which persists throughout adulthood. Therefore, this animal model is suitable to investigate the pathomechanism of depression, which is still largely unknown at the molecular level beyond monoaminergic dysfunctions. Here, we describe protein level changes in the prefrontal cortex of neonatally clomipramine-treated adult rats correlating with behavioral abnormalities. Clomipramine was administered to rat pups twice daily between postnatal days 8–21, while controls received saline injections. Behavioral tests were performed on 3months old rats. The proteomic study was conducted using two-dimensional differential gel electrophoresis. We have identified 32 proteins by mass spectrometry analysis of the significantly altered protein spots. The changed proteins are related to several biological functions, such as inflammation, transcription, cell metabolism and cytoskeleton organization. Among the altered proteins, the level of macrophage migration inhibitory factor showed the largest alteration, which was confirmed with Western blot. Macrophage migration inhibitory factor showed widespread distribution and was predominantly expressed in astrocytes in the forebrain of rats which were described using immunohistochemistry. We conclude that neonatal clomipramine exposure induces sustained modification in the proteome, which may form the molecular basis of the observed depression-like behavior in adult rats. Biological significanceIt is known that some of the psychiatric disorders, such as autism, depression or schizophrenia may be at least in part, developmental disorders. We hypothesized that clomipramine treatment in early stage of brain development, which is known to induce depression-like behavior in adult rats, results in pathological distortion in neuronal and glial network development, which can be reflected by the cellular proteome in adulthood. Thus, we performed an unbiased proteomics experiment in adult rats, which were neonatally administered with clomipramine to reveal protein level changes three months after treatment. Many of the identified changed proteins are previously associated with depressive symptoms, e.g., the macrophage migration inhibitory factor (MIF), the level of which showed the largest alteration among the identified proteins. Based on our data, we suggest that neonatal clomipramine treatment is a reliable model to study the developmental effect of psychoactive drugs applied in the sensitive early phase of brain development. Furthermore, our findings support the idea that the alteration of early development of the brain induced by antidepressant treatment could result in sustained pathological changes in the cellular phenotype in the prefrontal cortex leading to depression-like behavioral symptoms.

Electrospray Ionization Ion Mobility Mass Spectrometry of Human Brain Gangliosides.

The progress of ion mobility spectrometry (IMS), together with its association to mass spectrometry (MS), opened new directions for the identification of various metabolites in complex biological matrices. However, glycolipidomics of the human brain by IMS MS represents an area untouched up to now, because of the difficulties encountered in brain sampling, analyte extraction, and IMS MS method optimization. In this study, IMS MS was introduced in human brain ganglioside (GG) research. The efficiency of the method in clinical glycolipidomics was demonstrated on a highly complex mixture extracted from a normal fetal frontal lobe (FL37). Using this approach, a remarkably rich molecular ion pattern was discovered, which proved the presence of a large number of glycoforms and an unpredicted diversity of the ceramide chains. Moreover, the results showed for the first time the occurrence of GGs in the human brain with a much higher degree of sialylation than previously reported. Using IMS MS, the entire series starting from mono- up to octasialylated GGs was detected in FL37. These findings substantiate early clinical reports on the direct correlation between GG sialylation degree and brain developmental stage. Using IMS CID MS/MS, applied here for the first time to gangliosides, a novel, tetrasialylated O-GalNAc modified species with a potential biomarker role in brain development was structurally characterized. Under variable collision energy, a high number of sequence ions was generated for the investigated GalNAc-GQ1(d18:1/18:0) species. Several fragment ions documented the presence of the tetrasialo element attached to the inner Gal, indicating that GalNAc-GQ1(d18:1/18:0) belongs to the d series.

Evaluation of the Effect of Nest Posture on the Sleep-wake State of Premature Infants

Background: Premature birth is a major cause of infant mortality in developed countries. Newborns confined to neonatal intensive care units (NICUs) are in a rapid stage of brain development. As such, sleep plays a pivotal role in the proper brain development of newborns. However, this developmental aspect is often disregarded due to the lack of information. Aim: This study aimed to evaluate the effect of nest posture on the sleep-wake state of premature infants. Method: This cross-over clinical trial was conducted on 60 premature infants admitted in the NICU of Ghaem Hospital in Mashhad, Iran in 2015. Infants were divided into two groups of experimental and control. Data were collected using the Assessment of Premature Infants' Behavior (APIB). Neonates in the control group were placed in an incubator, and neonates in the experimental group were positioned in a nest. Between-group comparison was performed using paired-samples T-test for normal variables and Wilcoxon test for non-normal variables. Results: In this study, no statistically significant differences were observed between the two groups in terms of the scores of deep sleep state before (P=0.50) and after the intervention (P=0.59). However, during the intervention, mean score of deep sleep was higher in the experimental group (P=0.08). Moreover, mean score of slow wake state had no significant difference between the study groups before (P=0.67), after (P=0.86), and during the intervention (P=0.81). Implications for Practice: According to the results of this study, nest posture increased the deep sleep hours of premature infants as the most imperative state of brain development. Therefore, it is recommended that nest posture be used to improve the deep sleep state of premature infants.

The optimum context for learning; drawing on neuroscience to inform best practice in the classroom

Aims:As our understanding of neuroscience and the developing brain continues to grow, there is a worldwide move to use this information to inform educational practice. This paper attempts to draw together several convergent but complementary ideas in neuroscience to produce a model outlining the optimum context for a child to learn in a classroom.Method:A general outline of brain development is presented, highlighting key areas of brain functioning and cell connection. The positive cycle of learning shows how brain circuits are formed which require the child to be engaged in ‘doing’ a task.Findings:Two key situations which mitigate against a child entering the positive cycle of learning are highlighted: where the child is stressed, and where they are not at their achievable challenge level. Both situations might emphasise activity in the midbrain, which is believed to reduce connections to the forebrain (primarily considered the ‘thinking brain’, which is essential for learning). The importance of a student’s beliefs and mindset are also described which are strong contributors to learning behaviour. Finally, the importance of maintaining a developmental perspective within education is outlined, given what is known about stages of brain development and in particular given the significant changes that take place during adolescence in terms of brain reorganisation. A final model is proposed to guide teacher’s behaviour as a model to be empirically tested in the future.Limitations:Although an emerging area, this field is in its infancy. Many of the studies included in the model have yet to be replicated and the degree to which a cohesive model such as this can offer a testable means for approaching individual needs is unknown. Merging paradigms from different fields such neuroscience, attachment research and education is a fairly recent endeavour and will require further empirical investigation in a collaborative manner.

Assessing knowledge differences between daycare staff and parents


 Background and Purpose: Most Canadians have lead in their blood and it has been shown that even low levels of lead can cause harm. Children are the most susceptible population to the harmful effects of lead due to their increased absorption and earlier stages of brain development. Lead exposure in children has been shown to have negative and irreversible effects, including delayed development and reduced neurological function. As parents and daycare staff have the most interaction with young children, their health knowledge is important for minimizing day-to-day exposures. This research project assessed the level of knowledge of daycare staff and parents of young children on lead sources and health risks. Methods: An in-person, self-administered knowledge survey was given to parents and Early Childhood Educators (ECEs) at daycare centres located in Surrey, BC and Burnaby, BC. The data was then analyzed using SAS statistical software to compare the two groups using a chi square test. Results: Daycare staff and parents showed no significant differences in knowledge levels. The mean score on the knowledge test for daycare workers was 39.98 +14.77% and for parents was 30.73 +16.53%. Both groups had significant gaps in knowledge on lead, its sources, its risks for children, and preventive measures. Conclusion: Daycare staff and parents have an important role in minimizing children’s exposure to lead. Identifying knowledge gaps in these groups can lead to more targeted health promotion projects as well as changes to education and training.

Zika Virus: More Questions Than Answers

The recent Zika virus (ZIKV) outbreak has been declared a Public Health Emergency of International Concern (PHEIC) by the World Health Organization in February 2016. It started in Brazil in 2015, rapidly spread through South and Central America, and is expected to reach the continental US in the summer of 2016. The appearance of ZIKV has been connected with an increase in cases of microcephaly in newborns of the affected areas and Guillain–Barre Syndrome (GBS) (WHO, 2016). Since the virus' first isolation in Uganda in 1947, the two major outbreaks happened in Micronesia (2007) and in French Polynesia (2013). The 2013 outbreak is the only precedent where ZIKV was associated with serious complications (GBS) and a causal link between ZIKV infection and GBS was suggested based on a large study (Cao-Lormeau et al., 2016). The mechanism of ZIKV-induced GBS is not clear, but one possibility is cross-reactivity between a viral antigen and the self-peptide myelin. The evidence for ZIKV causing fetal microcephaly has been under debate due to the small number of studies reported, but as new reports appear every week the evidence seems clearer, although it has not been scientifically proven yet. A recent cohort study of 88 pregnant women in Brazil showed that 29% of infected mothers delivered babies with fetal abnormalities (Brasil et al., 2016). Furthermore, from nine current reported cases of ZIKV-positive pregnant women in the US that traveled to ZIKV endemic areas, five pregnancies resulted in fetal abnormalities or death, two in healthy babies while two women are still pregnant (Meaney-Delman et al., 2016). ZIKV has also been found both in the amniotic fluid and in fetal brain after pregnant mothers were infected, supporting the causal link between ZIKV-infected mothers and fetal microcephaly (Marrs et al., 2016). There are precedents of closely related neutrotropic flaviviruses that cause neurological diseases. West Nile Virus (WNV) can cause encephalitis and meningitis, and chikungunya virus (CHIKV) can cause neonatal encephalopathy and microcephaly (Gerardin et al., 2014). Additionally, other viruses causing congenitally acquired infections (TORCH) like rubella virus, cytomegalovirus, herpes simplex virus, varicella zoster virus or HIV have been associated with microcephaly in neonates. ZIKV can bind different cell receptors (Hamel et al., 2015), some of them present in neurons, and can infect and replicate in murine neurons and astroglia (Bell et al., 1971). Although pregnant women infected with ZIKV do not show neurological disease, hormonal-induced changes in immune responses, infections in ZIKV-naive women or specific genetic factors might facilitate increased replication of the virus in the mother, cross-placental barrier accessibility and ultimately ZIKV presence in the fetus during early stages of brain development. Nevertheless, the neuropathogenic effect of ZIKV is unknown. Similarly to GBS, the induction of mimicry, where antibodies produced against a viral protein by the mother will recognize a self-protein in the fetus (i.e. during brain development), is possible, or the presence of ZIKV in the brain could also cause tissue damage. ZIKV is a mosquito-borne virus of the family Flaviviridae, genus Flavivirus. The natural vector for ZIKV transmission is Aedes sp. mosquitoes, mainly A. aegypti and A. albopictus species, which also transmit other flaviviruses as dengue virus (DENV) and CHIKV. This mosquito is endemic in tropical areas, and may have facilitated ZIKV dispersion during outbreaks. ZIKV has been also reported to be transmitted by blood transfusion and sporadically by sexual contact, from a sexual partner infected while traveling to ZIKV areas. Detection of infective ZIKV in semen has been confirmed, and an increasing number of potential sexual transmission cases are currently being investigated by the CDC (Hills et al., 2016). This poses new challenges to control the epidemic. ZIKV infection is asymptomatic in 80% of the cases and the remainder 20% suffer mild symptoms similar to those induced by DENV: fever, headache, red eyes, rash, fatigue, muscle and joint pain. In the current outbreak, cross-reactivity with antibodies from DENV and CHIKV in the affected areas has stalled the use of ELISA to detect ZIKV antibodies. The only reliable diagnostic technique available is RT-PCR testing of serum, but is only positive during the viremia, usually 3–7 days, and of urine, where virus can be detected from 4 up to 30 days after the onset of infection. Tests for semen and saliva are still under development. Amniotic fluid sampling for PCR has been recommended for pregnant women, especially when the blood test results are negative. Ultrasound testing can confirm fetal microcephaly, and additional testing may be performed on fetal tissue, like RT-PCR on tissue and electron microscopy to detect virus particles, and direct immunofluorescence suggestive of viral infection within neurons.

Atypical functional connectivity in resting-state networks of individuals with 22q11.2 deletion syndrome: associations with neurocognitive and psychiatric functioning.

Background22q11.2 deletion syndrome (22q11DS) is a neurogenetic condition associated with deficits in neuropsychological functioning and psychiatric disorders. This deletion confers a high risk for the development of psychosis, as approximately 30–45 % of individuals develop psychosis in adulthood. Previous reports of resting-state functional magnetic resonance imaging (rs-fMRI) functional connectivity patterns in 22q11DS have demonstrated that atypical connectivity is associated with both the emergence and severity of psychotic symptoms. However, due to sample overlap and large age ranges of samples spanning multiple critical periods of brain maturation, more independent studies with samples within the window of time when psychotic symptoms have been shown to emerge (ages 17–26) are needed. Resting-state networks (RSNs) in 22q11DS during this stage of brain development may thus provide insight into the dynamic changes in functional integration that influence the incidence of prodromal symptoms and neurocognitive deficits characteristic of this syndrome.MethodsIndependent component analysis (ICA) was performed to identify RSNs in a combined sample of 55 individuals with 22q11DS (27 males; age range 17–26) and 29 controls (17 males; age range 17–23, consisting of 8 siblings without the deletion and 21 typically developed individuals) from two research sites. We conducted a full factorial analysis to determine group differences between 22q11DS and controls. A Poisson regression analysis was conducted in the 22q11DS group to determine relationships of rs-fMRI network connectivity with psychiatric symptoms based on factors of the 18-item Brief Psychiatric Rating Scale. Nonparametric Spearman correlations were performed to test associations between within-network functional connectivity (FC) and performance on measures of verbal memory (California Verbal Learning Test) and executive function (Behavior Rating Inventory of Executive Function Adult version) in 22q11DS.ResultsBetween-group network connectivity analyses revealed significant differences in 9 RSNs. Decreased network FC in 22q11DS was observed in the following networks: high-level visual processing network (HLVPN), low-level visual processing network (LLVPN), visual/precuneus network, left frontal-parietal network (LFPN), right frontal-parietal network (RFPN), and self-referential network (SRN). In contrast, greater network FC in 22q11DS was observed in subclusters of the LLVPN, visual/precuneus network, limbic network (LN), default mode network (DMN), and visuospatial processing network (VSPN). Increased functional connectivity of the right cuneus (visual/precuneus network) and right superior parietal lobule (DMN) in 22q11DS was positively associated with both thought disturbance and disorganization factors of the Brief Psychiatric Rating Scale (BPRS). Decreased functional connectivity in the left posterior cingulate (LLVPN) was associated with higher thought disturbance scores in 22q11DS. No associations with our neurocognitive measures passed correction for multiple comparisons (Bonferroni-corrected p ≤ 0.0014).ConclusionsOur findings suggest that atypical network connectivity within RSNs may be indicative of increased risk for developing psychosis and supports the utility of RSNs as biomarkers of prodromal symptoms in 22q11DS.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-016-9135-z) contains supplementary material, which is available to authorized users.

Nicotine administration enhances negative occasion setting in adolescent rats

Substantial research has established that exposure to nicotine during adolescence can lead to long-term changes in neural circuitry and behavior. However, relatively few studies have considered the effects of nicotine use on cognition during this critical stage of brain development. This is significant because the influence of nicotine on cognitive performance during adolescence may contribute to the development of regular nicotine use. For example, improvements in cognitive functioning may increase the perceived value of smoking and facilitate impulses to smoke. To address this, the present research tested the effects of nicotine on a form of inhibitory learning during adolescence. Specifically, adolescent rats were exposed to nicotine as they were trained in a negative occasion setting paradigm, in which successful performance depends on learning the conditions under which it is, or is not, appropriate to respond to a target stimulus. Here, we found that nicotine administration enhances negative occasion setting in adolescents. In addition, nicotine increased the amount of orienting behavior directed toward the inhibitory stimulus, suggesting that improvements in this form of behavioral inhibition may be attributed to nicotine-induced increases in attentional processing. These results may help elucidate the factors that contribute to the onset as well as continued use of products containing nicotine during adolescence and provide insight to increase the effectiveness of interventions targeted at reducing the prevalence of adolescent smoking.

Neuronal apoptosis of the developing brain: Influence of anesthetics

Surgeries and multiple procedures are undertaken on millions of children all over the world which involves exposure of these children to anesthetics during the stage of brain development. There is an increasing concern regarding the risk of anaesthetic neurotoxicity in children. Evidence has shown that exposure to all commonly used anaesthetics and sedatives can cause neurodegeneration in the developing brain with the possible exception of α 2-adrenergic agonists. Anaesthetic effects on the brain during its growth spurt can initiate a cascade of alterations in neurodevelopment which have been detected structurally or functionally in preclinical experiments. The studies are ongoing to gather clinical evidence.

Spatiotemporal Expression and Molecular Characterization of miR-344b and miR-344c in the Developing Mouse Brain.

MicroRNAs (miRNAs) are small noncoding RNA known to regulate brain development. The expression of two novel miRNAs, namely, miR-344b and miR-344c, was characterized during mouse brain developmental stages in this study. In situ hybridization analysis showed that miR-344b and miR-344c were expressed in the germinal layer during embryonic brain developmental stages. In contrast, miR-344b was not detectable in the adult brain while miR-344c was expressed exclusively in the adult olfactory bulb and cerebellar granular layer. Stem-loop RT-qPCR analysis of whole brain RNAs showed that expression of the miR-344b and miR-344c was increased as brain developed throughout the embryonic stage and maintained at adulthood. Further investigation showed that these miRNAs were expressed in adult organs, where miR-344b and miR-344c were highly expressed in pancreas and brain, respectively. Bioinformatics analysis suggested miR-344b and miR-344c targeted Olig2 and Otx2 mRNAs, respectively. However, luciferase experiments demonstrated that these miRNAs did not target Olig2 and Otx2 mRNAs. Further investigation on the locality of miR-344b and miR-344c showed that both miRNAs were localized in nuclei of immature neurons. In conclusion, miR-344b and miR-344c were expressed spatiotemporally during mouse brain developmental stages.

Developmental Dynamics of Rett Syndrome.

Rett Syndrome was long considered to be simply a disorder of postnatal development, with phenotypes that manifest only late in development and into adulthood. A variety of recent evidence demonstrates that the phenotypes of Rett Syndrome are present at the earliest stages of brain development, including developmental stages that define neurogenesis, migration, and patterning in addition to stages of synaptic and circuit development and plasticity. These phenotypes arise from the pleotropic effects of MeCP2, which is expressed very early in neuronal progenitors and continues to be expressed into adulthood. The effects of MeCP2 are mediated by diverse signaling, transcriptional, and epigenetic mechanisms. Attempts to reverse the effects of Rett Syndrome need to take into account the developmental dynamics and temporal impact of MeCP2 loss.

Maternal antibodies and developing blood-brain barrier.

We briefly review the protective role of maternal antibodies during fetal development and at early postnatal stages. We describe antibody delivery to fetuses, particularly in the context of the developing blood-brain barrier (BBB), and present the essential concepts regarding the adult BBB, together with existing information on the prenatal developing BBB. We focus on maternal antibody transfer to the developing brain and the consequences of the presence of pathogenic antibodies at early stages of brain development on subsequent brain dysfunction.

Age at First Episode Modulates Diagnosis-Related Structural Brain Abnormalities in Psychosis.

Brain volume and thickness abnormalities have been reported in first-episode psychosis (FEP). However, it is unclear if and how they are modulated by brain developmental stage (and, therefore, by age at FEP as a proxy). This is a multicenter cross-sectional case-control brain magnetic resonance imaging (MRI) study. Patients with FEP (n = 196), 65.3% males, with a wide age at FEP span (12-35 y), and healthy controls (HC) (n = 157), matched for age, sex, and handedness, were scanned at 6 sites. Gray matter volume and thickness measurements were generated for several brain regions using FreeSurfer software. The nonlinear relationship between age at scan (a proxy for age at FEP in patients) and volume and thickness measurements was explored in patients with schizophrenia spectrum disorders (SSD), affective psychoses (AFP), and HC. Earlier SSD cases (ie, FEP before 15-20 y) showed significant volume and thickness deficits in frontal lobe, volume deficits in temporal lobe, and volume enlargements in ventricular system and basal ganglia. First-episode AFP patients had smaller cingulate cortex volume and thicker temporal cortex only at early age at FEP (before 18-20 y). The AFP group also had age-constant (12-35-y age span) volume enlargements in the frontal and parietal lobe. Our study suggests that age at first episode modulates the structural brain abnormalities found in FEP patients in a nonlinear and diagnosis-dependent manner. Future MRI studies should take these results into account when interpreting samples with different ages at onset and diagnosis.

Lack of the scavenger receptor CD36 alters microglial phenotypes after neonatal stroke.

The stage of brain development at the time of stroke has a major impact on the pathophysiological mechanisms of ischemic damage, including the neuroinflammatory response. Microglial cells have been shown to contribute to acute and subchronic injury in adult stroke models, whereas in neonatal rodents we showed that microglial cells serve as endogenous neuroprotectants early following transient middle cerebral artery occlusion, limiting neuroinflammation and injury. In the neonate, microglial depletion or lack of the scavenger receptor CD36 exacerbates injury. In this study we asked if lack of CD36 affects microglial phenotypes after neonatal stroke. Using RT-PCR we characterized the patterns of gene expression in microglia isolated from injured regions following acute transient middle cerebral artery occlusion in postnatal day 10 mice and showed that expression of several pro-inflammatory genes, including Toll-like receptors, remains largely unaffected in activated microglia in injured regions. Using multiple biochemical assays we demonstrated that lack of CD36 alters several functions of microglia in acutely injured neonatal brain: it further enhances accumulation of the chemokine MCP-1, affects the number of CD11b(+) /CD45(+) cells, along with protein expression of its co-receptor, Toll-like receptor 2, but does not affect accumulation of superoxide in microglia or the cytokines TNFα and IL-1β in injured regions.

Clinical characteristics and post-surgical outcomes of focal cortical dysplasia subtypes

We retrospectively studied 105 patients with a focal cortical dysplasia (FCD) diagnosed on pathological examination, and investigated the long term postoperative seizure outcomes, different clinical characteristics of the three FCD subtypes, particularly type I and II, and surgical outcomes for each group. FCD is a common cause of drug-resistant epilepsy, which is divided into three different subtypes according to its involvement at different stages of brain development. Each of these groups may have different characteristics and may even have different surgical outcomes. After treatment, 55% of patients were completely seizure-free, with two significant predictive variables for poorer outcomes: focal MRI findings and electrode implantation. FCD type I had relatively poor surgical outcomes compared to FCD type II and type IIIa. Compared with FCD type I, type II, particularly IIb, had a higher frequency of seizure attacks, predominantly located in the extratemporal lobes, and was more readily detected and diagnosed via focal lesions on MRI and localized electroencephalogram abnormalities. FCD type II patients seem to show better surgical outcomes than FCD type I, but the difference was not significant. Larger cohort studies are needed for further evaluation of the seizure outcomes of different FCD subtypes.

Editorial: "Thyroid Hormone in Brain and Brain Cells".

Editorial: "Thyroid Hormone in Brain and Brain Cells".

Early Exposure to General Anesthesia Disrupts Spatial Organization of Presynaptic Vesicles in Nerve Terminals of the Developing Rat Subiculum.

Exposure to general anesthesia (GA) during critical stages of brain development induces widespread neuronal apoptosis and causes long-lasting behavioral deficits in numerous animal species. Although several studies have focused on the morphological fate of neurons dying acutely by GA-induced developmental neuroapoptosis, the effects of an early exposure to GA on the surviving synapses remain unclear. The aim of this study is to study whether exposure to GA disrupts the fine regulation of the dynamic spatial organization and trafficking of synaptic vesicles in presynaptic terminals. We exposed postnatal day 7 (PND7) rat pups to a clinically relevant anesthetic combination of midazolam, nitrous oxide, and isoflurane and performed a detailed ultrastructural analysis of the synaptic vesicle architecture at presynaptic terminals in the subiculum of rats at PND 12. In addition to a significant decrease in the density of presynaptic vesicles, we observed a reduction of docked vesicles, as well as a reduction of vesicles located within 100 nm from the active zone, in animals 5 days after an initial exposure to GA. We also found that the synaptic vesicles of animals exposed to GA are located more distally with respect to the plasma membrane than those of sham control animals and that the distance between presynaptic vesicles is increased in GA-exposed animals compared to sham controls. We report that exposure of immature rats to GA during critical stages of brain development causes significant disruption of the strategic topography of presynaptic vesicles within the nerve terminals of the subiculum.

Induction of TNF-α signaling cascade in neonatal rat brain during propofol anesthesia

Propofol anesthesia can trigger pro- and anti-apoptotic signaling pathways in the rat brain. In our previous work, we demonstrated that propofol causes widespread apoptotic neurodegeneration in 7-postnatal-day-old (PND7) but not in PND14 rat neurons. The mechanism responsible for these opposing outcomes is unknown, apparently linked to the specific stage of brain development. The present study aims to elucidate the anti-apoptotic process that is activated in the cortex and thalamus of PND14 Wistar rats during the first 48h after the onset of propofol anesthesia. We showed that the expression of tumor necrosis factor-α (TNF-α) and several components of its pathway, TNFR1 and caspase-8, was significantly increased in the cortex and thalamus. Nuclear factor kappa B (NF-κB) p65 was downregulated in the cortex and upregulated in the thalamus. The expression of c-Fos was upregulated only in the cortex, showing opposed profile compared to NF-κB p65. Double immunofluorescence staining revealed the colocalization of NF-κB p65 with neuronal marker (NeuN), but with predominantly cytoplasmic localization. Finally, X-linked inhibitor of apoptosis protein (XIAP) was upregulated in both examined structures. Immunohistochemical staining with Iba-1 revealed that the treatment did not induce changes in microglial morphology. Our results (i) reveal that the simultaneous activation of pro- and anti-apoptotic signaling occurs after propofol anesthesia, and (ii) pinpoint the potential neuroprotective role of XIAP in anesthesia-induced neurotoxicity.

Lin28 promotes the proliferative capacity of neural progenitor cells in brain development

Neural progenitor cells (NPCs) have distinct proliferation capacities at different stages of brain development. Lin28 is an RNA-binding protein with two homologs in mice: Lin28a and Lin28b. Here we show that Lin28a/b are enriched in early NPCs and their expression declines during neural differentiation. Lin28a single-knockout mice show reduced NPC proliferation, enhanced cell cycle exit and a smaller brain, whereas mice lacking both Lin28a alleles and one Lin28b allele display similar but more severe phenotypes. Ectopic expression of Lin28a in mice results in increased NPC proliferation, NPC numbers and brain size. Mechanistically, Lin28a physically and functionally interacts with Imp1 (Igf2bp1) and regulates Igf2-mTOR signaling. The function of Lin28a/b in NPCs could be attributed, at least in part, to the regulation of their mRNA targets that encode Igf1r and Hmga2. Thus, Lin28a and Lin28b have overlapping functions in temporally regulating NPC proliferation during early brain development.