Deleting Neurons: A closer look at Synaptic Pruning

Brain Plasticity ◽

Critical Role ◽

Current Data ◽

Potential Contribution ◽

Synapse Elimination ◽

Synaptic Contacts ◽

Developmental Neuroscience ◽

The Brain ◽

Synaptic Pruning

The overproduction of neural elements, including neurons, axons, and synapses, is a tool commonly used in developmental neuroscience to reconstruct nervous systems. This generation and maturation of these neuronal synapses are accompanied by a so-called "pruning" process, marking a peak in synapse elimination (synaptic pruning) which is a final stage in the development of the human brain. Analogous to cleaning up of the brain, synaptic pruning eliminates extra neurons and synaptic connections to increase the efficiency of neuronal transmissions along with eliminating weaker synaptic contacts while stronger connections are kept and strengthened. Brain plasticity is a result of this neural "pruning"; neurons that are more frequently activated are preserved, while those forming weaker synaptic contacts are "trimmed away." Research in zebrafish and rat models have shown pruning occurring in about 80 per cent of the synapses, barring the largest ones. These larger synapses were found to be associated with the most stable and crucial memories residing in the brain. Recent studies indicate that glial cells(microglia and astrocytes) play a critical role in synaptic pruning, mediated by a set of signalling pathways between neurons and glia, identifying and removing unnecessary neural connections. This loss of redundant pathways may explain the arduous task of recovering from a traumatic brain injury; eliminating synaptic redundancies diminishes our ability to develop alternative pathways to bypass the damaged regions. Brain imaging and postmortem anatomical studies have pointed to insufficient or excessive synaptic pruning that may underlie several neurodevelopmental disorders, including autism, schizophrenia, and epilepsy. In this review, we explore the brains innate delete button and present current data on the mechanisms of glial-cell-dependent synaptic pruning by outlining their potential contribution to neurodevelopmental disorders.

Changes in expression of GFAP, ApoE and APP mRNA and protein levels in the adult rat brain following cortical injury

Archives of Biological Sciences ◽

10.2298/abs1301255l ◽

2013 ◽

Vol 65 (1) ◽

pp. 255-264

Author(s):

Natasa Loncarevic-Vasiljkovic ◽

Vesna Pesic ◽

N. Tanic ◽

Desanka Milanovic ◽

Aleksandra Mladenovic-Djordjevic ◽

...

Keyword(s):

Brain Plasticity ◽

Recovery Period ◽

Potential Contribution ◽

Cortical Injury ◽

Adult Rat ◽

Protein Levels ◽

Adult Rat Brain ◽

Apoe Protein ◽

The recovery period following cortical injury (CI) is characterized by a dynamic and highly complex interplay between beneficial and detrimental events. The aim of this study was to examine the expressions of Glial Fibrillary Acidic Protein (GFAP), Apolipoprotein E (ApoE) and Amyloid Precursor Protein (APP), all of which are involved in brain plasticity and neurodegeneration. Our results reveal that CI strongly influenced GFAP, ApoE and APP mRNA expression, as well as GFAP and ApoE protein expression. Considering the pivotal role of these proteins in the brain, the obtained results point to their potential contribution in neurodegeneration and consequent Alzheimer?s disease development.

Pengaruh Stres Kronik terhadap Otak: Kajian Biomolekuler Hormon Glukokortikoid dan Regulasi Brain-Derived Neurotrophic Factor (BDNF) Pascastres di Cerebellum

Jurnal Ilmu Kedokteran ◽

10.26891/jik.v9i2.2015.65-70 ◽

2017 ◽

Vol 9 (2) ◽

pp. 65

Author(s):

Desby Juananda ◽

Dwi Cahyani Ratna Sari ◽

Djoko Prakosa2, ◽

Nur Arfian ◽

Mansyur Romi

Keyword(s):

Chronic Stress ◽

Brain Plasticity ◽

Critical Role ◽

Synaptic Function ◽

Bdnf Expression ◽

Acute And Chronic Stress ◽

Repetitive Stress ◽

Central Organ ◽

The Impact ◽

The brain is the central organ of stress adaptation, and is also a target of stress. Chronic stress may result in abnormalchanges in brain plasticity; include dendritic retraction, neuronal toxicity, and suppression of neurogenesis andaxospinous synaptic plasticity. Repetitive stress exposure will gradually change the electrical characteristic, morphologyand proliferative capacity of neurons. Among brain region, the cerebellum is known to be severely affected by oxidativedamage associated with glucocorticoids level. It is believed due to the highest levels of glucocorticoid receptorslocalized in the external granular layer. BDNF, a member of neurotrophin family, is known to be a strong survivalpromoting factor, and plays a critical role in cell proliferation and differentiation, neuronal protection, and the regulationof synaptic function in the central nervous system. BDNF is highly expressed in the cerebellum, mainly in granulecells. Both acute and chronic stress change BDNF expression in the brain. Although the impact of stress on BDNFlevels showed the different results, BDNF is believed to protect neurons from injuries caused by stress.

Gene regulatory networks underlying human microglia maturation

10.1101/2021.06.02.446636 ◽

2021 ◽

Author(s):

Nicole G Coufal ◽

Christopher Glass ◽

Claudia Han ◽

Rick Z. Li ◽

Emily Hansen ◽

...

Keyword(s):

Brain Development ◽

Single Cell ◽

Gene Regulatory Networks ◽

Regulatory Networks ◽

Critical Time ◽

Open Chromatin ◽

Potential Contribution ◽

Gene Regulatory ◽

The fetal period is a critical time for brain development, characterized by neurogenesis, neural migration, and synaptogenesis(1-3). Microglia, the tissue resident macrophages of the brain, are observed as early as the fourth week of gestation4 and are thought to engage in a variety of processes essential for brain development and homeostasis(5-11). Conversely, microglia phenotypes are highly regulated by the brain environment(12-14). Mechanisms by which human brain development influences the maturation of microglia and microglia potential contribution to neurodevelopmental disorders remain poorly understood. Here, we performed transcriptomic analysis of human fetal and postnatal microglia and corresponding cortical tissue to define age-specific brain environmental factors that may drive microglia phenotypes. Comparative analysis of open chromatin profiles using bulk and single-cell methods in conjunction with a new computational approach that integrates epigenomic and single-cell RNA-seq data allowed decoding of cellular heterogeneity with inference of subtype- and development stage-specific transcriptional regulators. Interrogation of in vivo and in vitro iPSC-derived microglia models provides evidence for roles of putative instructive signals and downstream gene regulatory networks which establish human-specific fetal and postnatal microglia gene expression programs and potentially contribute to neurodevelopmental disorders.

New insights into nutrition and cognitive neuroscience

Proceedings of The Nutrition Society ◽

10.1017/s0029665109990188 ◽

2009 ◽

Vol 68 (4) ◽

pp. 408-415 ◽

Cited By ~ 58

Author(s):

M. J. Dauncey

Keyword(s):

Mental Health ◽

Brain Plasticity ◽

Critical Role ◽

Short Review ◽

Neural Pathways ◽

Brain Health ◽

Brain Structure And Function ◽

And Function ◽

Nutrition can affect the brain throughout the life cycle, with profound implications for mental health and degenerative disease. Many aspects of nutrition, from entire diets to specific nutrients, affect brain structure and function. The present short review focuses on recent insights into the role of nutrition in cognition and mental health and is divided into four main sections. First, the importance of nutritional balance and nutrient interactions to brain health are considered by reference to the Mediterranean diet, energy balance, fatty acids and trace elements. Many factors modulate the effects of nutrition on brain health and inconsistencies between studies can be explained in part by differences in early environment and genetic variability. Thus, these two factors are considered in the second and third parts of the present review. Finally, recent findings on mechanisms underlying the actions of nutrition on the brain are considered. These mechanisms involve changes in neurotrophic factors, neural pathways and brain plasticity. Advances in understanding the critical role of nutrition in brain health will help to fulfil the potential of nutrition to optimise brain function, prevent dysfunction and treat disease.

A new method to predict anomaly in brain network based on graph deep learning

Reviews in the Neurosciences ◽

10.1515/revneuro-2019-0108 ◽

2020 ◽

Vol 31 (6) ◽

pp. 681-689

Author(s):

Jalal Mirakhorli ◽

Hamidreza Amindavar ◽

Mojgan Mirakhorli

Keyword(s):

Deep Learning ◽

Large Scale ◽

Brain Plasticity ◽

Brain Network ◽

High Order ◽

Brain Diseases ◽

Simultaneous Occurrence ◽

Generative Adversarial Network ◽

The Brain ◽

Brain Connections

AbstractFunctional magnetic resonance imaging a neuroimaging technique which is used in brain disorders and dysfunction studies, has been improved in recent years by mapping the topology of the brain connections, named connectopic mapping. Based on the fact that healthy and unhealthy brain regions and functions differ slightly, studying the complex topology of the functional and structural networks in the human brain is too complicated considering the growth of evaluation measures. One of the applications of irregular graph deep learning is to analyze the human cognitive functions related to the gene expression and related distributed spatial patterns. Since a variety of brain solutions can be dynamically held in the neuronal networks of the brain with different activity patterns and functional connectivity, both node-centric and graph-centric tasks are involved in this application. In this study, we used an individual generative model and high order graph analysis for the region of interest recognition areas of the brain with abnormal connection during performing certain tasks and resting-state or decompose irregular observations. Accordingly, a high order framework of Variational Graph Autoencoder with a Gaussian distributer was proposed in the paper to analyze the functional data in brain imaging studies in which Generative Adversarial Network is employed for optimizing the latent space in the process of learning strong non-rigid graphs among large scale data. Furthermore, the possible modes of correlations were distinguished in abnormal brain connections. Our goal was to find the degree of correlation between the affected regions and their simultaneous occurrence over time. We can take advantage of this to diagnose brain diseases or show the ability of the nervous system to modify brain topology at all angles and brain plasticity according to input stimuli. In this study, we particularly focused on Alzheimer’s disease.

LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models

Science Advances ◽

10.1126/sciadv.aba1187 ◽

2021 ◽

Vol 7 (11) ◽

pp. eaba1187

Author(s):

Rina Baba ◽

Satoru Matsuda ◽

Yuuichi Arakawa ◽

Ryuji Yamada ◽

Noriko Suzuki ◽

...

Keyword(s):

Gene Expression ◽

Enzyme Activity ◽

Neurodevelopmental Disorder ◽

Specific Inhibitor ◽

Autism Spectrum ◽

Poly I:C ◽

Control Of Gene Expression ◽

Epigenetic Machinery ◽

Persistent epigenetic dysregulation may underlie the pathophysiology of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show that the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity normalizes aberrant epigenetic control of gene expression in neurodevelopmental disorders. Maternal exposure to valproate or poly I:C caused sustained dysregulation of gene expression in the brain and ASD-like social and cognitive deficits after birth in rodents. Unexpectedly, a specific inhibitor of LSD1 enzyme activity, 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide hydrochloride (TAK-418), almost completely normalized the dysregulated gene expression in the brain and ameliorated some ASD-like behaviors in these models. The genes modulated by TAK-418 were almost completely different across the models and their ages. These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders.

The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour

Cellular and Molecular Life Sciences ◽

10.1007/s00018-020-03721-6 ◽

2020 ◽

Author(s):

Enrico Castroflorio ◽

Joery den Hoed ◽

Daria Svistunova ◽

Mattéa J. Finelli ◽

Alberto Cebrian-Serrano ◽

...

Keyword(s):

Regulatory Protein ◽

Molecular Function ◽

Neuronal Connectivity ◽

Nuclear Receptor Coactivator ◽

Lysm Domain ◽

Behavioural Assessment ◽

And Function ◽

Abstract Members of the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) protein family are associated with multiple neurodevelopmental disorders, although their exact roles in disease remain unclear. For example, nuclear receptor coactivator 7 (NCOA7) has been associated with autism, although almost nothing is known regarding the mode-of-action of this TLDc protein in the nervous system. Here we investigated the molecular function of NCOA7 in neurons and generated a novel mouse model to determine the consequences of deleting this locus in vivo. We show that NCOA7 interacts with the cytoplasmic domain of the vacuolar (V)-ATPase in the brain and demonstrate that this protein is required for normal assembly and activity of this critical proton pump. Neurons lacking Ncoa7 exhibit altered development alongside defective lysosomal formation and function; accordingly, Ncoa7 deletion animals exhibited abnormal neuronal patterning defects and a reduced expression of lysosomal markers. Furthermore, behavioural assessment revealed anxiety and social defects in mice lacking Ncoa7. In summary, we demonstrate that NCOA7 is an important V-ATPase regulatory protein in the brain, modulating lysosomal function, neuronal connectivity and behaviour; thus our study reveals a molecular mechanism controlling endolysosomal homeostasis that is essential for neurodevelopment. Graphic abstract

Reactive Oxygen Species: Beyond Their Reactive Behavior

Neurochemical Research ◽

10.1007/s11064-020-03208-7 ◽

2021 ◽

Vol 46 (1) ◽

pp. 77-87

Author(s):

Arnaud Tauffenberger ◽

Pierre J. Magistretti

Keyword(s):

Reactive Oxygen Species ◽

Second Messengers ◽

Critical Role ◽

Complex Function ◽

Reactive Oxygen ◽

High Reactivity ◽

Oxygen Species ◽

Health And Disease ◽

Cellular Dysfunction ◽

AbstractCellular homeostasis plays a critical role in how an organism will develop and age. Disruption of this fragile equilibrium is often associated with health degradation and ultimately, death. Reactive oxygen species (ROS) have been closely associated with health decline and neurological disorders, such as Alzheimer’s disease or Parkinson’s disease. ROS were first identified as by-products of the cellular activity, mainly mitochondrial respiration, and their high reactivity is linked to a disruption of macromolecules such as proteins, lipids and DNA. More recent research suggests more complex function of ROS, reaching far beyond the cellular dysfunction. ROS are active actors in most of the signaling cascades involved in cell development, proliferation and survival, constituting important second messengers. In the brain, their impact on neurons and astrocytes has been associated with synaptic plasticity and neuron survival. This review provides an overview of ROS function in cell signaling in the context of aging and degeneration in the brain and guarding the fragile balance between health and disease.

Complex Network Modelling of Origin–Destination Commuting Flows for the COVID-19 Epidemic Spread Analysis in Italian Lombardy Region

Applied Sciences ◽

10.3390/app11104381 ◽

2021 ◽

Vol 11 (10) ◽

pp. 4381

Author(s):

Angela Lombardi ◽

Nicola Amoroso ◽

Alfonso Monaco ◽

Sabina Tangaro ◽

Roberto Bellotti

Keyword(s):

Urban Areas ◽

Large Scale ◽

Critical Role ◽

Potential Contribution ◽

Epidemic Spread ◽

Network Modelling ◽

Lombardy Region ◽

Commuting Flows ◽

Dynamic Growth ◽

Spread Analysis

Currently the whole world is affected by the COVID-19 disease. Italy was the first country to be seriously affected in Europe, where the first COVID-19 outbreak was localized in the Lombardy region. The further spreading of the cases led to the lockdown of the most affected regions in northern Italy and then the entire country. In this work we investigated an epidemic spread scenario in the Lombardy region by using the origin–destination matrix with information about the commuting flows among 1450 urban areas within the region. We performed a large-scale simulation-based modeling of the epidemic spread over the networks related to three main motivations, i.e., work, study and occasional transfers to quantify the potential contribution of each category of travellers to the spread of the epidemic process. Our findings outline that the three networks are characterised by different weight dynamic growth rates and that the network “work” has a critical role in the diffusion phenomenon showing the greatest contribution to the epidemic spread.

Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders

Scientific Reports ◽

10.1038/s41598-021-86041-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Joseph J. Rossi ◽

Jill A. Rosenfeld ◽

Katie M. Chan ◽

Haley Streff ◽

Victoria Nankivell ◽

...

Keyword(s):

Protein Function ◽

Transcriptional Activity ◽

Neurodevelopmental Disorder ◽

Complete Loss ◽

Loss Of Function ◽

Targeted Disruption ◽

Clinical Exome Sequencing ◽

Partner Protein ◽

AbstractAberrations in the excitatory/inhibitory balance within the brain have been associated with both intellectual disability (ID) and schizophrenia (SZ). The bHLH-PAS transcription factors NPAS3 and NPAS4 have been implicated in controlling the excitatory/inhibitory balance, and targeted disruption of either gene in mice results in a phenotype resembling ID and SZ. However, there are few human variants in NPAS3 and none in NPAS4 that have been associated with schizophrenia or neurodevelopmental disorders. From a clinical exome sequencing database we identified three NPAS3 variants and four NPAS4 variants that could potentially disrupt protein function in individuals with either developmental delay or ID. The transcriptional activity of the variants when partnered with either ARNT or ARNT2 was assessed by reporter gene activity and it was found that variants which truncated the NPAS3/4 protein resulted in a complete loss of transcriptional activity. The ability of loss-of-function variants to heterodimerise with neuronally enriched partner protein ARNT2 was then determined by co-immunoprecipitation experiments. It was determined that the mechanism for the observed loss of function was the inability of the truncated NPAS3/4 protein to heterodimerise with ARNT2. This further establishes NPAS3 and NPAS4 as candidate neurodevelopmental disorder genes.