Early Blockade of CB1 Receptors Ameliorates Schizophrenia-like Alterations in the Neurodevelopmental MAM Model of Schizophrenia

In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of Sprague-Dawley rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produces long-lasting behavioral alterations such as social withdrawal and cognitive impairment in adulthood, mimicking a schizophrenia-like phenotype. These abnormalities were preceded at neonatal age both by the delayed appearance of neonatal reflexes, an index of impaired brain maturation, and by higher 2-arachidonoylglycerol (2-AG) brain levels. Schizophrenia-like deficits were reversed by early treatment [from postnatal day (PND) 2 to PND 8] with the CB1 antagonist/inverse agonist AM251 (0.5 mg/kg/day). By contrast, early CB1 blockade affected the behavioral performance of control rats which was paralleled by enhanced 2-AG content in the prefrontal cortex (PFC). These results suggest that prenatal MAM insult leads to premorbid anomalies at neonatal age via altered tone of the endocannabinoid system, which may be considered as an early marker preceding the development of schizophrenia-like alterations in adulthood.

Iron deficiency and internalizing symptom severity in unmedicated adolescents: a pilot study

Background Iron plays a key role in a broad set of metabolic processes. Iron deficiency is the most common nutritional deficiency in the world, but its neuropsychiatric implications in adolescents have not been examined. Methods Twelve- to 17-year-old unmedicated females with major depressive or anxiety disorders or with no psychopathology underwent a comprehensive psychiatric assessment for this pilot study. A T1-weighted magnetic resonance imaging scan was obtained, segmented using Freesurfer. Serum ferritin concentration (sF) was measured. Correlational analyses examined the association between body iron stores, psychiatric symptom severity, and basal ganglia volumes, accounting for confounding variables. Results Forty females were enrolled, 73% having a major depressive and/or anxiety disorder, 35% with sF < 15 ng/mL, and 50% with sF < 20 ng/mL. Serum ferritin was inversely correlated with both anxiety and depressive symptom severity (r = −0.34, p < 0.04 and r = −0.30, p < 0.06, respectively). Participants with sF < 15 ng/mL exhibited more severe depressive and anxiety symptoms as did those with sF < 20 ng/mL. Moreover, after adjusting for age and total intracranial volume, sF was inversely associated with left caudate (Spearman's r = −0.46, p < 0.04), left putamen (r = −0.58, p < 0.005), and right putamen (r = −0.53, p < 0.01) volume. Conclusions Brain iron may become depleted at a sF concentration higher than the established threshold to diagnose iron deficiency (i.e. 15 ng/mL), potentially disrupting brain maturation and contributing to the emergence of internalizing disorders in adolescents.

On Neuroeducation: Why and How to Improve Neuroscientific Literacy in Educational Professionals

New findings from the neurosciences receive much interest for use in the applied field of education. For the past 15 years, neuroeducation and the application of neuroscience knowledge were seen to have promise, but there is presently some lack of progress. The present paper states that this is due to several factors. Neuromyths are still prevalent, and there is a confusion of tongues between the many neurodisciplines and the domains of behavioral and educational sciences. Second, a focus upon cognitive neuroimaging research has yielded findings that are scientifically relevant, but cannot be used for direct application in the classroom. A third factor pertains to the emphasis which has been on didactics and teaching, whereas the promise of neuroeducation for the teacher may lie more on pedagogical inspiration and support. This article states that the most important knowledge and insights have to do with the notion of brain plasticity; the vision that development is driven by an interaction between a person’s biology and the social system. This helps individuals to select and process information, and to adapt to the personal environment. The paper describes how brain maturation and neuropsychological development extend through the important period of adolescence and emergent adulthood. Over this long period, there is a major development of the Executive Functions (EFs) that are essential for both cognitive learning, social behavior and emotional processing and, eventually, personal growth. The paper describes the basic neuroscience knowledge and insights – or “neuroscientific literacy” – that the educational professional should have to understand and appreciate the above-described themes. The authors formulate a proposal for four themes of neuroscience content “that every teacher should know.” These four themes are based on the Neuroscience Core Concepts formulated by the Society for Neuroscience. The authors emphasize that integrating neuroscientific knowledge and insights in the field of education should not be a one-way street; attempts directed at improving neuroscientific literacy are a transdisciplinary undertaking. Teacher trainers, experts from the neuroscience fields but also behavioral scientists from applied fields (notable applied neuropsychologists) should all contribute to for the educational innovations needed.

Oligodendrocytes are a lifelong source of nuclear and ribosomal material for neurons in the mouse brain

Nuclear and ribosomal components define cell identity and function by regulating chromatin dynamics, gene expression, and protein turnover. Here we report that in the mouse central nervous system (CNS) under normal conditions, neurons accumulate nuclear and ribosomal material of oligodendrocyte (OL) origin. We show that neuronal accumulation of OL-derived nuclear and ribosomal material is brain area-specific, and in the cortex and hippocampal dentate gyrus gradually propagates during postnatal brain maturation. We further demonstrate that OL-to-neuron material transfer persists throughout adulthood and responds to neuroinflammation. We found that satellite OL of the gray matter form internuclear contacts with receiving neurons in the mouse brain. Similar close internuclear associations between satellite OL and neurons are present in the adult human cortex. Our findings provide the first evidence of wide-spread dynamic and selective OL-to-neuron nuclear and ribosomal material transfer in the mouse CNS and indicate that satellite OL serve as powerful mediators of neuronal function. Equivalent processes may occur in the human CNS and cause neurological disorders when dysregulated.

Analysis of deep grey nuclei susceptibility in early childhood: a quantitative susceptibility mapping and R2* study at 3 Tesla

Purpose Aging is the most significant determinant for brain iron accumulation in the deep grey matter. Data on brain iron evolution during brain maturation in early childhood are limited. The purpose of this study was to investigate age-related iron deposition in the deep grey matter in children using quantitative susceptibility (QSM) and R2* mapping. Methods We evaluated brain MRI scans of 74 children (age 6–154 months, mean 40 months). A multi-echo gradient-echo sequence obtained at 3 Tesla was used for the QSM and R2* calculation. Susceptibility of the pallidum, head of caudate nucleus, and putamen was correlated with age and compared between sexes. Results Susceptibility changes in all three nuclei correlated with age (correlation coefficients for QSM/R2*: globus pallidus 0.955/0.882, caudate nucleus 0.76/0.65, and putamen 0.643/0.611). During the first 2 years, the R2* values increased more rapidly than the QSM values, indicating a combined effect of iron deposition and myelination, followed by a likely dominating effect of iron deposition. There was no significant gender difference. Conclusion QSM and R2* can monitor myelin maturation processes and iron accumulation in the deep grey nuclei of the brain in early life and may be a promising tool for the detection of deviations of this normal process. Susceptibility in the deep nuclei is almost similar early after birth and increases more quickly in the pallidum. The combined use of QSM and R2* analysis is beneficial.

Effects of Post-natal Dietary Milk Fat Globule Membrane Polar Lipid Supplementation on Motor Skills, Anxiety, and Long-Term Memory in Adulthood

Early life nutrition critically impacts post-natal brain maturation and cognitive development. Post-natal dietary deficits in specific nutrients, such as lipids, minerals or vitamins are associated with brain maturation and cognitive impairments. Specifically, polar lipids (PL), such as sphingolipids and phospholipids, are important cellular membrane building blocks and are critical for brain connectivity due to their role in neurite outgrowth, synaptic formation, and myelination. In this preclinical study, we assessed the effects of a chronic supplementation with a source of PL extracted from an alpha-lactalbumin enriched whey protein containing 10% lipids from early life (post-natal day (PND) 7) to adulthood (PND 72) on adult motor skills, anxiety, and long-term memory. The motor skills were assessed using open field and rotarod test. Anxiety was assessed using elevated plus maze (EPM). Long-term object and spatial memory were assessed using novel object recognition (NOR) and Morris water maze (MWM). Our results suggest that chronic PL supplementation improved measures of spatial long-term memory accuracy and cognitive flexibility in the MWM in adulthood, with no change in general mobility, anxiety and exploratory behavior. Our results indicate memory specific functional benefits of long-term dietary PL during post-natal brain development.

Cholesterol in Brain Development and Perinatal Brain Injury: more than a Building Block

: The central nervous system (CNS) is enriched with important classes of lipids, in which cholesterol is known to make up a major portion of myelin sheaths, besides being a structural and functional unit of CNS cell membranes. Unlike in the adult brain where the cholesterol pool is relatively stable, cholesterol is synthesized and accumulated at the highest rate in the developing brain to meet the needs of rapid brain growth at this stage, which is also a critical period for neuroplasticity. In addition to its biophysical role in membrane organization, cholesterol is crucial for brain development due to its involvement in brain patterning, myelination, neuronal differentiation and synaptogenesis. Thus any injuries to the immature brain that affect cholesterol homeostasis may have long-term adverse neurological consequences. In this review, we describe the unique features of brain cholesterol biosynthesis and metabolism, cholesterol trafficking between different cell types, and highlight cholesterol-dependent biological processes during brain maturation. We also discuss the association of impaired cholesterol homeostasis with several forms of perinatal brain disorders in term and preterm newborns, including hypoxic-ischemic encephalopathy. Strategies targeting the cholesterol pathways may open new avenues for diagnosis and treatment of developmental brain injury.

EEG Signal Complexity Is Reduced During Resting-State in Fragile X Syndrome

Introduction: Fragile X syndrome (FXS) is a genetic disorder caused by a mutation of the fragile X mental retardation 1 gene (FMR1). FXS is associated with neurophysiological abnormalities, including cortical hyperexcitability. Alterations in electroencephalogram (EEG) resting-state power spectral density (PSD) are well-defined in FXS and were found to be linked to neurodevelopmental delays. Whether non-linear dynamics of the brain signal are also altered remains to be studied.Methods: In this study, resting-state EEG power, including alpha peak frequency (APF) and theta/beta ratio (TBR), as well as signal complexity using multi-scale entropy (MSE) were compared between 26 FXS participants (ages 5–28 years), and 7 neurotypical (NT) controls with a similar age distribution. Subsequently a replication study was carried out, comparing our cohort to 19 FXS participants independently recorded at a different site.Results: PSD results confirmed the increased gamma, decreased alpha power and APF in FXS participants compared to NT controls. No alterations in TBR were found. Importantly, results revealed reduced signal complexity in FXS participants, specifically in higher scales, suggesting that altered signal complexity is sensitive to brain alterations in this population. The replication study mostly confirmed these results and suggested critical points of stagnation in the neurodevelopmental curve of FXS.Conclusion: Signal complexity is a powerful feature that can be added to the electrophysiological biomarkers of brain maturation in FXS.

EEG sleep macrostructure and sleep spindles in early infancy

Study Objectives Sleep features in infancy are potential biomarkers for brain maturation but poorly characterised. We describe normative values for sleep macrostructure and sleep spindles at 4-5 months of age. Methods Healthy term infants were recruited at birth and had daytime sleep EEGs at 4-5 months. Sleep staging was performed and 5 features were analysed. Sleep spindles were annotated and 7 quantitative features were extracted. Features were analysed across sex, recording time (am/pm), infant age and from first to second sleep cycles. Results We analysed sleep recordings from 91 infants, 41% girls. Median (IQR) macrostructure results: sleep duration 49.0 (37.8-72.0) minutes (n=77); first sleep cycle duration 42.8 (37.0 – 51.4) minutes; REM percentage 17.4 (9.5 - 27.7)% (n=68); latency to REM 36.0 (30.5-41.1) minutes (n=66). First cycle median (IQR) values for spindle features: number 241.0 (193.0-286.5), density 6.6 (5.7-8.0) spindles.min -1(n=77); mean frequency 13.0 (12.8-13.3) Hz, mean duration 2.9 (2.6-3.6)s, spectral power 7.8 (4.7-11.4)µV 2, brain symmetry index 0.20 (0.16-0.29), synchrony 59.5 (53.2-63.8)% (n=91). In males, spindle spectral power (µV 2) is 24.5% lower (p=0.032) and brain symmetry index 24.2% higher than females (p=0.011) when controlling for gestational and postnatal age and timing of the nap. We found no other significant associations between studied sleep features and sex, recording time (am/pm), or age. Spectral power decreased (p&lt;0.001) on the second cycle. Conclusion This normative data may be useful for comparison with future studies of sleep dysfunction and atypical neurodevelopment in infancy.