Pathological Brain Development Research Articles

Lactiplantibacillus plantarum HEAL9 attenuates cognitive impairment and progression of Alzheimer's disease and related bowel symptoms in SAMP8 mice by modulating microbiota-gut-inflammasome-brain axis.

Background: Growing evidence highlights the relevance of the microbiota-gut-brain axis in Alzheimer's disease (AD). AD patients display gut dysbiosis, altered intestinal barrier and enteric inflammation that, besides bowel symptoms, can contribute to brain pathology. In this context, the modulation of gut microbiota is emerging as a therapeutical option to halt or slow down central pathology. Herein, we examined the effects of Lactiplantibacillus plantarum HEAL9 in a spontaneous mouse model of AD. Methods: Senescence-accelerated mouse prone 8 (SAMP8) mice and control SAMR1 mice were treated orally with HEAL9 1 × 109 CFU per mouse per day or placebo for two months to evaluate the effects of the probiotic during the earliest stages of AD, before the development of brain pathology. Cognitive impairment, in vivo and in vitro colonic motility, astrocyte and microglia reactive response, brain and colonic amyloid-β1-42 (Aβ1-42) levels, and inflammasome components activation (NLRP3, ASC, caspase-1 and interleukin-1β) were assessed. In addition, gut barrier alterations [circulating lipopolysaccharide-binding protein (LBP) levels] and acidic mucus were evaluated. Results: HEAL9 administration significantly attenuated cognitive impairment and counteracted colonic dysmotility in SAMP8 mice. Moreover, HEAL9 decreased astrogliosis and microgliosis, Aβ1-42 accumulation and inflammasome activation in colon and brain and normalized plasma LBP levels and colonic acidic mucus content. Conclusion: HEAL9 intake alleviated cognitive decline and normalized colonic motility in the prodromal phases of AD via the modulation of microbiota-gut-inflammasome-brain signalling. Thus, dietary supplementation with HEAL9 could be considered as a suitable therapeutical option for the treatment of AD and related intestinal symptoms in the early stages of the disease.

Current Findings on the Spectrum of Neuronal Autoantibodies Associated with Psychotic Disorders

Background: Neural autoantibodies are observed in a subtype of psychotic disorders ranging from first-episode psychosis to schizophrenia. The clinical spectrum has so far been incompletely described, as new neuronal autoantibodies are emerging in the context of psychosis. This review is dedicated to describing the current spectrum of neural autoantibodies associated with psychotic disorders.
 Methods: In our narrative review, we searched for neural autoantibodies addressed in the PubMed database in the last 15 years focusing on the last three years after publication of the international guidelines for autoimmune psychosis. We relied on small and large cohort studies and case series descriptions related to neural autoantibodies in psychotic disorders.
 Results: Mainly neural autoantibodies against membrane surface structures such as N-Methyl-D-aspartate receptors (NMDAR) and against intracellular targets are present in psychotic disorders, but also in healthy controls. There is current suspicion that these neuronal autoantibodies (ie., NMDAR autoantibodies) play a potentially relevant role in the development of brain pathologies in psychotic disorders, especially when detected in cerebrospinal fluid. Autoantibodies against cell adhesion molecules and synaptic proteins such as neuronal cell adhesion molecule 1 (NCAM1) and antigen neurexin 1 alpha (NRXN1)-alpha occur in schizophrenia, but not in controls, suggesting that these are highly disease-specific antibodies. These lines of evidence are further supported by animal-model evidence showing a role of these autoantibodies in brain pathology and the development of schizophrenia-like symptoms.
 Conclusions: In recent years, a new landscape of potentially relevant neural autoantibodies has emerged in a subtype of psychotic disorders. Their significance remains unclear. Large-scale investigations should particularly investigate what triggers the pathogenicity of these autoantibodies, as they probably do not cause the psychotic disorder per se, but might be involved as one factor in the immunopathophysiology. Psychotic disorders remain elusive, and differential diagnosis is required to determine the role neural autoantibodies play in the manifestation of psychoses.

Expression of Cytokines and Neurodegeneration in the Rat Hippocampus and Cortex in the Lithium-Pilocarpine Model of Status Epilepticus and the Role of Modulation of Endocannabinoid System.

A significant body of evidence shows that neuroinflammation is one of the key processes in the development of brain pathology in trauma, neurodegenerative disorders, and epilepsy. Various brain insults, including severe and prolonged seizure activity during status epilepticus (SE), trigger proinflammatory cytokine release. We investigated the expression of the proinflammatory cytokines interleukin-1β (Il1b) and interleukin-6 (Il6), and anti-inflammatory fractalkine (Cx3cl1) in the hippocampus, entorhinal cortex, and neocortex of rats 24 h, 7 days, and 5 months after lithium-pilocarpine SE. We studied the relationship between cytokine expression and neuronal death in the hippocampus and evaluated the effect of modulation of endocannabinoid receptors on neuroinflammation and neurodegeneration after SE. The results of the present study showed that inhibition of endocannabinoid CB1 receptors with AM251 early after SE had a transient neuroprotective effect that was absent in the chronic period and did not affect the development of spontaneous seizures after SE. At the same time, AM251 reduced the expression of Il6 in the chronic period after SE. Higher Cx3cl1 levels were found in rats with more prominent hippocampal neurodegeneration.

Dual Role of the P2X7 Receptor in Dendritic Outgrowth during Physiological and Pathological Brain Development.

At high levels, extracellular ATP operates as a "danger" molecule under pathologic conditions through purinergic receptors, including the ionotropic P2X7 receptor (P2X7R). Its endogenous activation is associated with neurodevelopmental disorders; however, its function during early embryonic stages remains largely unclear. Our objective was to determine the role of P2X7R in the regulation of neuronal outgrowth. For this purpose, we performed Sholl analysis of dendritic branches on primary hippocampal neurons and in acute hippocampal slices from WT mice and mice with genetic deficiency or pharmacological blockade of P2X7R. Because abnormal dendritic branching is a hallmark of certain neurodevelopmental disorders, such as schizophrenia, a model of maternal immune activation (MIA)-induced schizophrenia, was used for further morphologic investigations. Subsequently, we studied MIA-induced behavioral deficits in young adult mice females and males. Genetic deficiency or pharmacological blockade of P2X7R led to branching deficits under physiological conditions. Moreover, pathologic activation of the receptor led to deficits in dendritic outgrowth on primary neurons from WT mice but not those from P2X7R KO mice exposed to MIA. Likewise, only MIA-exposed WT mice displayed schizophrenia-like behavioral and cognitive deficits. Therefore, we conclude that P2X7R has different roles in the development of hippocampal dendritic arborization under physiological and pathologic conditions.SIGNIFICANCE STATEMENT Our main finding is a novel role for P2X7R in neuronal branching in the early stages of development under physiological conditions. We show how a decrease in the expression of P2X7R during brain development causes the receptor to play pathologic roles in adulthood. Moreover, we studied a neurodevelopmental model of schizophrenia and found that, at higher ATP concentrations, endogenous activation of P2X7R is necessary and sufficient for the development of positive and cognitive symptoms.

Amorfrutin B Protects Mouse Brain Neurons from Hypoxia/Ischemia by Inhibiting Apoptosis and Autophagy Processes Through Gene Methylation- and miRNA-Dependent Regulation

Amorfrutin B is a selective modulator of the PPARγ receptor, which has recently been identified as an effective neuroprotective compound that protects brain neurons from hypoxic and ischemic damage. Our study demonstrated for the first time that a 6-h delayed post-treatment with amorfrutin B prevented hypoxia/ischemia-induced neuronal apoptosis in terms of the loss of mitochondrial membrane potential, heterochromatin foci formation, and expression of specific genes and proteins. The expression of all studied apoptosis-related factors was decreased in response to amorfrutin B, both during hypoxia and ischemia, except for the expression of anti-apoptotic BCL2, which was increased. After post-treatment with amorfrutin B, the methylation rate of the pro-apoptotic Bax gene was inversely correlated with the protein level, which explained the decrease in the BAX/BCL2 ratio as a result of Bax hypermethylation. The mechanisms of the protective action of amorfrutin B also involved the inhibition of autophagy, as evidenced by diminished autophagolysosome formation and the loss of neuroprotective properties of amorfrutin B after the silencing of Becn1 and/or Atg7. Although post-treatment with amorfrutin B reduced the expression levels of Becn1, Nup62, and Ambra1 during hypoxia, it stimulated Atg5 and the protein levels of MAP1LC3B and AMBRA1 during ischemia, supporting the ambiguous role of autophagy in the development of brain pathologies. Furthermore, amorfrutin B affected the expression levels of apoptosis-focused and autophagy-related miRNAs, and many of these miRNAs were oppositely regulated by amorfrutin B and hypoxia/ischemia. The results strongly support the position of amorfrutin B among the most promising anti-stroke and wide-window therapeutics.

The immune cell profile of the developing rat brain

Little is known about the peripheral immune cell (PIC) profile of the developing brain despite growing appreciation for these cells in the mature nervous system. To address this gap, the PIC profile, defined as which cells are present, where they are located, and for how long, was examined in the developing rat using spectral flow cytometry. Select regions of the rat brain (cerebellum, hippocampus, and hypothalamus) were examined at embryonic day 20, and postnatal days 0, 7 and 16. At their peak (E20), PICs were most abundant in the cerebellum, then the hippocampus and hypothalamus. Within the PIC pool, monocytes were most prevalent in all regions and time points, and shifted from being majority classical at E20 to non-classical by PN7. T cells increased over time, and shifted from majority cytotoxic to T-helper cells by PN7. This suggests the PIC profile transitions from reactive to adaptive and surveilling in the second postnatal week. NK cells and mast cells increased temporarily, and mast cells were restricted to the hippocampus and hypothalamus, suggesting they may play a specific role in the development of those regions. Mimicking a viral infection by administration of Poly I:C increased the influx of PICs into the neonatal brain, particularly of NK cells and in the case of males only, non-classical monocytes. This work provides a map for researchers as they study immune cell contributions to healthy and pathological brain development.

Neurobiological, familial and genetic risk factors for dimensional psychopathology in the Adolescent Brain Cognitive Development study.

Adolescence is a key period for brain development and the emergence of psychopathology. The Adolescent Brain Cognitive Development (ABCD) study was created to study the biopsychosocial factors underlying healthy and pathological brain development during this period, and comprises the world's largest youth cohort with neuroimaging, family history and genetic data. We examined 9856 unrelated 9-to-10-year-old participants in the ABCD study drawn from 21 sites across the United States, of which 7662 had multimodalmagnetic resonance imaging scans passing quality control, and 4447 were non-Hispanic white and used for polygenic risk score analyses. Using data available at baseline, we associated eight 'syndrome scale scores' from the Child Behavior Checklist-summarizing anxious/depressed symptoms, withdrawn/depressed symptoms, somatic complaints, social problems, thought problems, attention problems, rule-breaking behavior, and aggressive behavior-with resting-state functional and structural brain magnetic resonance imaging measures; eight indicators of family history of psychopathology; and polygenic risk scores for major depression, bipolar disorder, schizophrenia, attention deficit hyperactivity disorder (ADHD) and anorexia nervosa. As a sensitivity analysis, we excluded participants with clinically significant (>97th percentile) or borderline (93rd-97th percentile) scores for each dimension. Most Child Behavior Checklist dimensions were associated with reduced functional connectivity within one or more of four large-scale brain networks-default mode, cingulo-parietal, dorsal attention, and retrosplenial-temporal. Several dimensions were also associated with increased functional connectivity between the default mode, dorsal attention, ventral attention and cingulo-opercular networks. Conversely, almost no global or regional brain structural measures were associated with any of the dimensions. Every family history indicator was associated with every dimension. Major depression polygenic risk was associated with six of the eight dimensions, whereas ADHD polygenic risk was exclusively associated with attention problems and externalizing behavior (rule-breaking and aggressive behavior). Bipolar disorder, schizophrenia and anorexia nervosa polygenic risk were not associated with any of the dimensions. Many associations remained statistically significant even after excluding participants with clinically significant or borderline psychopathology, suggesting that the same risk factors that contribute to clinically significant psychopathology also contribute to continuous variation within the clinically normal range. This study codifies neurobiological, familial and genetic risk factors for dimensional psychopathology across a population-scale cohort of community-dwelling preadolescents. Future efforts are needed to understand how these multiple modalities of risk intersect to influence trajectories of psychopathology into late adolescence and adulthood.

Multidimensional brain-age prediction reveals altered brain developmental trajectory in psychiatric disorders.

Brain-age prediction has emerged as a novel approach for studying brain development. However, brain regions change in different ways and at different rates. Unitary brain-age indices represent developmental status averaged across the whole brain and therefore do not capture the divergent developmental trajectories of various brain structures. This staggered developmental unfolding, determined by genetics and postnatal experience, is implicated in the progression of psychiatric and neurological disorders. We propose a multidimensional brain-age index (MBAI) that provides regional age predictions. Using a database of 556 individuals, we identified clusters of imaging features with distinct developmental trajectories and built machine learning models to obtain brain-age predictions from each of the clusters. Our results show that the MBAI provides a flexible analysis of region-specific brain-age changes that are invisible to unidimensional brain-age. Importantly, brain-ages computed from region-specific feature clusters contain complementary information and demonstrate differential ability to distinguish disorder groups (e.g., depression and oppositional defiant disorder) from healthy controls. In summary, we show that MBAI is sensitive to alterations in brain structures and captures distinct regional change patterns that may serve as biomarkers that contribute to our understanding of healthy and pathological brain development and the characterization and diagnosis of psychiatric disorders.

Choline, folic acid, Vitamin D, and fetal brain development in the psychosis spectrum

Choline, folic acid, and Vitamin D are essential for fetal brain development that may be the first steps in the pathogenesis of the psychotic spectrum. Micronutrient deficiencies have been associated with changes in fetal brain development, manifest as early problems in childhood behavior, and cognition, and later as increased incidence of psychotic and autism spectrum disorders. Micronutrient supplements may not only prevent deficiency, but they may also positively affect brain development in the context of other maternal risk factors, including maternal infection, stress, inflammation, and substance abuse. Many genes associated with later psychotic illness are highly expressed in the fetal brain, where they are responsible for various neurodevelopmental mechanisms. Interaction of micronutrient vitamins with these genetically programmed mechanisms to prevent pathological brain development associated with later psychosis is under active investigation. In addition to their effects on brain development, micronutrient vitamins have effects on other aspects of gestation and fetal development, including the prevention of premature delivery and other developmental abnormalities. Supplemental micronutrient vitamins should be part of good prenatal care, as has already happened for folic acid and Vitamin D and is now advocated by the American Medical Association for choline. The benefits of these micronutrient supplements include protection of brain development and the possibility of decreased risk for future psychotic disorders in those children who are either genetically or environmentally vulnerable. The purpose of this review is to present the current evidence supporting the safety and effectiveness of micronutrients in gestation and to suggest areas for future research.

Specific immune modulation of experimental colitis drives enteric alpha-synuclein accumulation and triggers age-related Parkinson-like brain pathology.

Background: In some people with Parkinson's disease (PD), α-synuclein (αSyn) accumulation may begin in the enteric nervous system (ENS) decades before development of brain pathology and disease diagnosis. Objective: To determine how different types and severity of intestinal inflammation could trigger αSyn accumulation in the ENS and the subsequent development of αSyn brain pathology. Methods: We assessed the effects of modulating short- and long-term experimental colitis on αSyn accumulation in the gut of αSyn transgenic and wild type mice by immunostaining and gene expression analysis. To determine the long-term effect on the brain, we induced dextran sulfate sodium (DSS) colitis in young αSyn transgenic mice and aged them under normal conditions up to 9 or 21 months before tissue analyses. Results: A single strong or sustained mild DSS colitis triggered αSyn accumulation in the submucosal plexus of wild type and αSyn transgenic mice, while short-term mild DSS colitis or inflammation induced by lipopolysaccharide did not have such an effect. Genetic and pharmacological modulation of macrophage-associated pathways modulated the severity of enteric αSyn. Remarkably, experimental colitis at three months of age exacerbated the accumulation of aggregated phospho-Serine 129 αSyn in the midbrain (including the substantia nigra), in 21- but not 9-month-old αSyn transgenic mice. This increase in midbrain αSyn accumulation is accompanied by the loss of tyrosine hydroxylase-immunoreactive nigral neurons. Conclusions: Our data suggest that specific types and severity of intestinal inflammation, mediated by monocyte/macrophage signaling, could play a critical role in the initiation and progression of PD.

Prenatal Alcohol Exposure Results in Sex-Specific Alterations in Circular RNA Expression in the Developing Mouse Brain.

Fetal alcohol spectrum disorders (FASD) are heterogeneous disorders associated with alcohol exposure to the developing fetus that are characterized by a range of adverse neurodevelopmental deficits. Despite the numerous genomics and genetic studies on FASD models, the comprehensive molecular understanding of the mechanisms that underlie FASD-related neurodevelopmental deficits remains elusive. Circular RNAs (circRNAs) are a subtype of long non-coding RNAs that are derived from back-splicing and covalent joining of exons and/or introns of protein-coding genes. Recent studies have shown that circRNAs are highly enriched in the brain, where they are developmentally regulated. However, the role of the majority of brain-enriched circRNAs in normal and pathological brain development and function has not been explored yet. Here we carried out the first systematic profiling of circRNA expression in response to prenatal alcohol exposure (PAE) in male and female embryonic day 18 (E18) whole brains. We observed that the changes in circRNA expression in response to PAE were notably sex-specific and that PAE tended to erase most of the sex-specificity in circRNA expression present in control (saccharin-treated) mice. On the other hand, RNA sequencing (RNA-seq) in the same samples showed that changes in protein-coding gene expression were not predominantly sex-specific. Using circRNA quantitative real-time PCR (qRT-PCR), we validated that circSatb2, which is generated from the special AT-rich sequence-binding protein 2 (Satb2) gene, is significantly upregulated in the brain of E18 male PAE mice. We also show that circPtchd2, a circRNA synthesized from dispatched RND transporter family member 3 (Disp3, also known as Ptchd2), exhibits significantly higher expression in E18 control but not PAE female mouse brain relative to males. Taken together, our results demonstrate that PAE differentially alters circRNA expression in the developing brain in a sex-specific manner.

Microglial and peripheral immune priming is partially sexually dimorphic in adolescent mouse offspring exposed to maternal high-fat diet

BackgroundMaternal nutrition is critical for proper fetal development. While increased nutrient intake is essential during pregnancy, an excessive consumption of certain nutrients, like fat, can lead to long-lasting detrimental consequences on the offspring. Animal work investigating the consequences of maternal high-fat diet (mHFD) revealed in the offspring a maternal immune activation (MIA) phenotype associated with increased inflammatory signals. This inflammation was proposed as one of the mechanisms causing neuronal circuit dysfunction, notably in the hippocampus, by altering the brain-resident macrophages—microglia. However, the understanding of mechanisms linking inflammation and microglial activities to pathological brain development remains limited. We hypothesized that mHFD-induced inflammation could prime microglia by altering their specific gene expression signature, population density, and/or functions.MethodsWe used an integrative approach combining molecular (i.e., multiplex-ELISA, rt-qPCR) and cellular (i.e., histochemistry, electron microscopy) techniques to investigate the effects of mHFD (saturated and unsaturated fats) vs control diet on inflammatory priming, as well as microglial transcriptomic signature, density, distribution, morphology, and ultrastructure in mice. These analyses were performed on the mothers and/or their adolescent offspring at postnatal day 30.ResultsOur study revealed that mHFD results in MIA defined by increased circulating levels of interleukin (IL)-6 in the mothers. This phenotype was associated with an exacerbated inflammatory response to peripheral lipopolysaccharide in mHFD-exposed offspring of both sexes. Microglial morphology was also altered, and there were increased microglial interactions with astrocytes in the hippocampus CA1 of mHFD-exposed male offspring, as well as decreased microglia-associated extracellular space pockets in the same region of mHFD-exposed offspring of the two sexes. A decreased mRNA expression of the inflammatory-regulating cytokine Tgfb1 and microglial receptors Tmem119, Trem2, and Cx3cr1 was additionally measured in the hippocampus of mHFD-exposed offspring, especially in males.ConclusionsHere, we described how dietary habits during pregnancy and nurturing, particularly the consumption of an enriched fat diet, can influence peripheral immune priming in the offspring. We also found that microglia are affected in terms of gene expression signature, morphology, and interactions with the hippocampal parenchyma, in a partially sexually dimorphic manner, which may contribute to the adverse neurodevelopmental outcomes on the offspring.

Ubiquitin and Ubiquitin-Like Proteins in the Critical Equilibrium between Synapse Physiology and Intellectual Disability.

Posttranslational modifications (PTMs) represent a dynamic regulatory system that precisely modulates the functional organization of synapses. PTMs consist in target modifications by small chemical moieties or conjugation of lipids, sugars or polypeptides. Among them, ubiquitin and a large family of ubiquitin-like proteins (UBLs) share several features such as the structure of the small protein modifiers, the enzymatic cascades mediating the conjugation process, and the targeted aminoacidic residue. In the brain, ubiquitination and two UBLs, namely sumoylation and the recently discovered neddylation orchestrate fundamental processes including synapse formation, maturation and plasticity, and their alteration is thought to contribute to the development of neurological disorders. Remarkably, emerging evidence suggests that these pathways tightly interplay to modulate the function of several proteins that possess pivotal roles for brain homeostasis as well as failure of this crosstalk seems to be implicated in the development of brain pathologies. In this review, we outline the role of ubiquitination, sumoylation, neddylation, and their functional interplay in synapse physiology and discuss their implication in the molecular pathogenesis of intellectual disability (ID), a neurodevelopmental disorder that is frequently comorbid with a wide spectrum of brain pathologies. Finally, we propose a few outlooks that might contribute to better understand the complexity of these regulatory systems in regard to neuronal circuit pathophysiology.

Effect of Sleep Deprivation on the Hippocampus of Adult and Senile Male Albino Rat: A Histological and Histochemical Study

Abstract Background The importance of sleep and the impact of its deprivation on development of brain pathology became a recent subject of interest in medicine. The restorative effect of sleep on the brain and the harmful effects of insomnia have been recently revealed through the discovery of the glymphatic system and its association with sleep. Aim of work Specific objectives are: To detect histological and apoptotic changes in the neurons and dendrites of the cornu Amonis and the dentate gyrus in sleep deprived rats in comparison to rats with undisturbed sleep pattern (control). To detect deposition of neurotoxic metabolites in comu Amonis and dentate gyrus in sleep deprived rats in comparison to controls. Methods Twenty four adult male Albino rats were used in the present experiment. randomly categorized into four equal groups; Group A1 served as the control group, Group .A2 one day sleep deprivation, Group A3 three days sleep deprivation and Group A4 seven days sleep deprivation. They were deprived of sleep using grid over water method where the animals placed over a grid suspended above tank filled with water with free access to food (rat chew) and water. Hippocampai specimens were collected, processed for paraffin blocks and examined by light microscopy. Results there were neurodegenerative signs appeared from day one sleep deprivation, increased by day three and prevailed by day seven. It was confirmed by apoptotic changes detected by caspase 3 immunohistochemical staining. Furthermore, deposition of beta amyloid appeared in rats deprived of sleep and confirmed by congo red stain. Conclusion Adequate sleep is essential for integrity of the newly discovered glymphatic system responsible for clearance of the brain from waste products including the area most involved in learning and memory function; the hippocampus. Correction of SD could be a viable therapeutic strategy to prevent the onset or slow the progression of AD. Recommendations Further characterization of the glymphatic system in humans are required, it may lead to new therapies and methods of prevention of neurodegenerative diseases. Correction of SD could be a viable therapeutic strategy to prevent the onset or slow the progression of AD.

Developmental Pathoconnectomics and Advanced Fetal MRI.

Developmental pathoconnectomics is an emerging field that aims to unravel the events leading to and outcome from disrupted brain connectivity development. Advanced magnetic resonance imaging (MRI) technology enables the portrayal of human brain connectivity before birth and has the potential to offer novel insights into normal and pathological human brain development. This review gives an overview of the currently used MRI techniques for connectomic imaging, with a particular focus on recent studies that have successfully translated these to the in utero or postmortem fetal setting. Possible mechanisms of how pathologies, maternal, or environmental factors may interfere with the emergence of the connectome are considered. The review highlights the importance of advanced image post processing and the need for reproducibility studies for connectomic imaging. Further work and novel data-sharing efforts would be required to validate or disprove recent observations from in utero connectomic studies, which are typically limited by low case numbers and high data drop out. Novel knowledge with regard to the ontogenesis, architecture, and temporal dynamics of the human brain connectome would lead to the more precise understanding of the etiological background of neurodevelopmental and mental disorders. To achieve this goal, this review considers the growing evidence from advanced fetal connectomic imaging for the increased vulnerability of the human brain during late gestation for pathologies that might lead to impaired connectome development and subsequently interfere with the development of neural substrates serving higher cognition.

Emerging Roles of Complement in Psychiatric Disorders.

The complement system consists of more than 30 proteins that have long been known to participate to the immune defence against pathogens and to the removal of damaged cells. Their role, however, extends beyond immunity and clearance of altered “self” components in the periphery. In particular, complement proteins can be induced by all cell types in the brain. Recent discoveries highlight the role of complement in normal and pathological brain development. Specifically, the complement system mediates synaptic pruning, a developmental process whereby supernumerary synapses are eliminated in the immature brain. The complement system has been implicated in pathological synapse elimination in schizophrenia, West Nile virus infection, and lupus, all of which are associated with psychiatric manifestations. Complement also contributes to synapse loss in neurodegenerative conditions. This review provides a brief overview of the well-studied role of complement molecules in immunity. The contribution of complement to embryonic and adult neurogenesis, neuronal migration, and developmental synaptic elimination in the normal brain is reviewed. We discuss the role of complement in synapse loss in psychiatric and neurological diseases and evaluate the therapeutic potential of complement-targeting drugs for brain disorders.

Life span pigmentation changes of the substantia nigra detected by neuromelanin-sensitive MRI.

Background: Neuromelanin is a pigment with strong iron‐chelating properties preferentially found in dopaminergic neurons of the substantia nigra pars compacta (SNpc). Parkinson's disease is characterized by pronounced, MRI‐detectable neuromelanin loss, but the neuroprotective or neurotoxic role of neuromelanin remains debated. Histological studies have demonstrated neuromelanin increases with age, but this has not been confirmed in vivo, and there is uncertainty whether neuromelanin declines, stabilizes, or increases from middle age. Methods: This study aimed to establish physiological changes of pigmentation of the SNpc using a pooled data set of neuromelanin‐sensitive 3T MRI from 134 healthy individuals aged 5‐83 years. Neuromelanin‐related brightness (regional contrast to ratio) and calibrated hyperintense volumes were analyzed using linear and nonlinear regression models to characterize age effects. Laterality, sex, and subregional effects were also assessed. Results: For brightness, age effects were best described as a quadratic trajectory explaining 81.5% of the observed variance in the SNpc showing a strong increase from childhood to adolescence, with plateauing in middle age and a decline in older age. Similar but less pronounced effects were seen in hyperintense volumes. We also show an anterior‐posterior gradient in SNpc contrast, larger normalized neuromelanin‐rich volume in women > 47 years old, but no laterality effect. Conclusions: Using optimized neuromelanin MRI in a life span sample, we demonstrate a strong age effect with inverted U‐shaped SNpc pigmentation‐related contrast from childhood to old age. This age trajectory of physiological SNpc pigmentation needs to be taken into account for diagnostic applications of depigmentation. The study also paves the way for systematic investigations of the mechanisms of neuromelanin in healthy and pathological brain development and aging. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

CERES: A new cerebellum lobule segmentation method

The human cerebellum is involved in language, motor tasks and cognitive processes such as attention or emotional processing. Therefore, an automatic and accurate segmentation method is highly desirable to measure and understand the cerebellum role in normal and pathological brain development. In this work, we propose a patch-based multi-atlas segmentation tool called CERES (CEREbellum Segmentation) that is able to automatically parcellate the cerebellum lobules. The proposed method works with standard resolution magnetic resonance T1-weighted images and uses the Optimized PatchMatch algorithm to speed up the patch matching process. The proposed method was compared with related recent state-of-the-art methods showing competitive results in both accuracy (average DICE of 0.7729) and execution time (around 5 minutes).

Detailed Computational Modeling of the Developmental Self-Organization of Neuronal Structure and Function

Event Abstract Back to Event Detailed Computational Modeling of the Developmental Self-Organization of Neuronal Structure and Function Roman Bauer1* 1 Newcastle University, United Kingdom The structure and function of neuronal networks is the result of a complex developmental process, which is implicitly encoded in the genes. A better understanding of neural development is therefore crucial for a comprehensive picture of the workings of the brain. Computational simulations allow to test models of how neural development occurs, and in particular how it relies on the interaction between genetic instructions and the local, external environment of cells. Hence, these simulations should ideally take into account a number of mechanisms, such as gene regulatory networks, extracellular substance gradients, physical forces and electrical activity. Here, I present work comprising the detailed modeling of neural development in cortex, as well as preliminary results on retinal development. In particular, I show how certain reaction-diffusion systems can give rise to spatial patterns of chemical guidance cues, enabling the development of a patchy motif of clustered axonal projections in the superficial layers of cortex [1]. Furthermore, neuronal outgrowth processes and synaptic learning rules that give rise to realistic synaptic connectivity as well as winner-take-all (WTA) functionality are presented [2]. Finally, simulations of cortical [3] and retinal lamination (i.e. the sequential layering of different cell types) are shown, providing a powerful computational framework for studying normal and pathological brain development. Overall, the results of these computational models emphasize the importance of taking into account genetic encoding as well as the 3D physical space within which cells interact, to study brain development. Moreover, this work highlights the necessity of appropriate software for these kinds of simulations, which also require significant computing resources. Acknowledgements This work was first supported by the EU grant 216593 SECO (http://www.seco-project.eu), and afterwards by the Engineering and Physical Sciences Research Council of the United Kingdom (EP/K026992/1) as part of the Human Brain Development Project (http://www.greenbrainproject.org/) References [1] Bauer R, Zubler F, Hauri A, Muir D, Douglas RJ, 2014. Developmental origin of patchy axonal connectivity in the neocortex: A computational model. Cerebral Cortex. [2] Bauer R, Pfister S, Hauri A, Zubler F, Pfeiffer M, Douglas RJ, 2014. Developmental self-construction and -configuration of functional neocortical neuronal networks. PLoS Computational Biology. [3] Zubler F, Hauri A, Pfister S, Bauer R, Anderson JC, Whatley AM, Douglas RJ, 2013: Simulating cortical development as a self constructing process: a novel multi-scale approach combining molecular and physical aspects. PLoS Computational Biology. Keywords: Guidance cues, Gene Regulatory Networks, neuronal self-organization, computational modeling, neurite growth Conference: Neuroinformatics 2016, Reading, United Kingdom, 3 Sep - 4 Sep, 2016. Presentation Type: Investigator presentations Topic: Normal development / cognition Citation: Bauer R (2016). Detailed Computational Modeling of the Developmental Self-Organization of Neuronal Structure and Function. Front. Neuroinform. Conference Abstract: Neuroinformatics 2016. doi: 10.3389/conf.fninf.2016.20.00004 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Apr 2016; Published Online: 18 Jul 2016. * Correspondence: Dr. Roman Bauer, Newcastle University, Newcastle upon Tyne, United Kingdom, r.bauer@surrey.ac.uk Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Roman Bauer Google Roman Bauer Google Scholar Roman Bauer PubMed Roman Bauer Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

New Insights into Epigenetic and Pharmacological Regulation of Amyloid-Degrading Enzymes.

Currently, deficit of amyloid β-peptide (Aβ) clearance from the brain is considered as one of the possible causes of amyloid accumulation and neuronal death in the sporadic form of Alzheimer's disease (AD). Aβ clearance can involve either specific proteases present in the brain or Aβ-binding/transport proteins. Among amyloid-degrading enzymes the most intensively studied are neprilysin (NEP) and insulin-degrading enzyme (IDE). Since ageing and development of brain pathologies is often accompanied by a deficit in the levels of expression and activity of these enzymes in the brain, there is an urgent need to understand the mechanisms involved in their regulation. We have recently reported that NEP and also an Aβ-transport protein, transthyretin are epigenetically co-regulated by the APP intracellular domain (AICD) and this regulation depends on the cell type and APP695 isoform expression in a process that can be regulated by the tyrosine kinase inhibitor, Gleevec. We have now extended our work and shown that, unlike NEP, another amyloid-degrading enzyme, IDE, is not related to over-expression of APP695 in neuroblastoma SH-SY5Y cells but is up-regulated by APP751 and APP770 isoforms independently of AICD but correlating with reduced HDAC1 binding to its promoter. Studying the effect of the nuclear retinoid X receptor agonist, bexarotene, on NEP and IDE expression, we have found that both enzymes can be up-regulated by this compound but this mechanism is not APP-isoform specific and does not involve AICD but, on the contrary, affects HDAC1 occupancy on the NEP gene promoter. These new insights into the mechanisms of NEP and IDE regulation suggest possible pharmacological targets in developing AD therapies.