Human Brain Disorders Research Articles

Human Brain Disorders: A Review

Background: Due to the stressful life, brain disorders are considered as a significant global healthcare problem. It has generated a great need for continuous research for understanding brain structure as well as functions in context to health and diseases. Scope and Approach: The structure and functions of the brain were questioned and studied since Ancient Greek times and led to the compilation of enormous information on the subject globally. With the advent of new technology, the researchers are able to discover the causes of brain diseases/disorders. Conclusion: In the present review, we have compiled various diseases and disorders related to the brain, along with their symptoms and the treatment strategies.

Quantifying Genomic Imprinting at Tissue and Cell Resolution in the Brain.

Imprinted genes are a group of ~150 genes that are preferentially expressed from one parental allele owing to epigenetic marks asymmetrically distributed on inherited maternal and paternal chromosomes. Altered imprinted gene expression causes human brain disorders such as Prader-Willi and Angelman syndromes and additional rare brain diseases. Research data principally obtained from the mouse model revealed how imprinted genes act in the normal and pathological brain. However, a better understanding of imprinted gene functions calls for building detailed maps of their parent-of-origin-dependent expression and of associated epigenetic signatures. Here we review current methods for quantifying genomic imprinting at tissue and cell resolutions, with a special emphasis on methods to detect parent-of-origin dependent expression and their applications to the brain. We first focus on bulk RNA-sequencing, the main method to detect parent-of-origin-dependent expression transcriptome-wide. We discuss the benefits and caveats of bulk RNA-sequencing and provide a guideline to use it on F1 hybrid mice. We then review methods for detecting parent-of-origin-dependent expression at cell resolution, including single-cell RNA-seq, genetic reporters, and molecular probes. Finally, we provide an overview of single-cell epigenomics technologies that profile additional features of genomic imprinting, including DNA methylation, histone modifications and chromatin conformation and their combination into sc-multimodal omics approaches, which are expected to yield important insights into genomic imprinting in individual brain cells.

Opportunities and limitations of genetically modified nonhuman primate models for neuroscience research

The recently developed new genome-editing technologies, such as the CRISPR/Cas system, have opened the door for generating genetically modified nonhuman primate (NHP) models for basic neuroscience and brain disorders research. The complex circuit formation and experience-dependent refinement of the human brain are very difficult to model in vitro, and thus require use of in vivo whole-animal models. For many neurodevelopmental and psychiatric disorders, abnormal circuit formation and refinement might be at the center of their pathophysiology. Importantly, many of the critical circuits and regional cell populations implicated in higher human cognitive function and in many psychiatric disorders are not present in lower mammalian brains, while these analogous areas are replicated in NHP brains. Indeed, neuropsychiatric disorders represent a tremendous health and economic burden globally. The emerging field of genetically modified NHP models has the potential to transform our study of higher brain function and dramatically facilitate the development of effective treatment for human brain disorders. In this paper, we discuss the importance of developing such models, the infrastructure and training needed to maximize the impact of such models, and ethical standards required for using these models.

Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation.

During embryonic development and adulthood, Reelin exerts several important functions in the brain including the regulation of neuronal migration, dendritic growth and branching, dendritic spine formation, synaptogenesis and synaptic plasticity. As a consequence, the Reelin signaling pathway has been associated with several human brain disorders such as lissencephaly, autism, schizophrenia, bipolar disorder, depression, mental retardation, Alzheimer’s disease and epilepsy. Several elements of the signaling pathway are known. Core components, such as the Reelin receptors very low-density lipoprotein receptor (VLDLR) and Apolipoprotein E receptor 2 (ApoER2), Src family kinases Src and Fyn, and the intracellular adaptor Disabled-1 (Dab1), are common to most but not all Reelin functions. Other downstream effectors are, on the other hand, more specific to defined tasks. Reelin is a large extracellular protein, and some aspects of the signal are regulated by its processing into smaller fragments. Rather than being inhibitory, the processing at two major sites seems to be fulfilling important physiological functions. In this review, I describe the various cellular events regulated by Reelin and attempt to explain the current knowledge on the mechanisms of action. After discussing the shared and distinct elements of the Reelin signaling pathway involved in neuronal migration, dendritic growth, spine development and synaptic plasticity, I briefly outline the data revealing the importance of Reelin in human brain disorders.

Evolution and transition of expression trajectory during human brain development

BackgroundThe remarkable abilities of the human brain are distinctive features that set us apart from other animals. However, our understanding of how the brain has changed in the human lineage remains incomplete, but is essential for understanding cognition, behavior, and brain disorders in humans. Here, we compared the expression trajectory in brain development between humans and rhesus macaques (Macaca mulatta) to explore their divergent transcriptome profiles.ResultsResults showed that brain development could be divided into two stages, with a demarcation date in a range between 25 and 26 postconception weeks (PCW) for humans and 17-23PCWfor rhesus macaques, rather than birth time that have been widely used as a uniform demarcation time of neurodevelopment across species. Dynamic network biomarker (DNB) analysis revealed that the two demarcation dates were transition phases during brain development, after which the brain transcriptome profiles underwent critical transitions characterized by highly fluctuating DNB molecules. We also found that changes between early and later brain developmental stages (as defined by the demarcation points) were substantially greater in the human brain than in the macaque brain. To explore the molecular mechanism underlying prolonged timing during early human brain development, we carried out expression heterochrony tests. Results demonstrated that compared to macaques, more heterochronic genes exhibited neoteny during early human brain development, consistent with the delayed demarcation time in the human lineage, and proving that neoteny in human brain development could be traced to the prenatal period. We further constructed transcriptional networks to explore the profile of early human brain development and identified the hub gene RBFOX1 as playing an important role in regulating early brain development. We also found RBFOX1 evolved rapidly in its non-coding regions, indicating that this gene played an important role in human brain evolution. Our findings provide evidence that RBFOX1 is a likely key hub gene in early human brain development and evolution.ConclusionsBy comparing gene expression profiles between humans and macaques, we found divergent expression trajectories between the two species, which deepens our understanding of the evolution of the human brain.

Brain organoids: an ensemble of bioassays to investigate human neurodevelopment and disease.

Understanding etiology of human neurological and psychiatric diseases is challenging. Genomic changes, protracted development, and histological features unique to human brain development limit the disease aspects that can be investigated using model organisms. Hence, in order to study phenotypes associated with human brain development, function, and disease, it is necessary to use alternative experimental systems that are accessible, ethically justified, and replicate human context. Human pluripotent stem cell (hPSC)-derived brain organoids offer such a system, which recapitulates features of early human neurodevelopment in vitro, including the generation, proliferation, and differentiation of neural progenitors into neurons and glial cells and the complex interactions among the diverse, emergent cell types of the developing brain in three-dimensions (3-D). In recent years, numerous brain organoid protocols and related techniques have been developed to recapitulate aspects of embryonic and fetal brain development in a reproducible and predictable manner. Altogether, these different organoid technologies provide distinct bioassays to unravel novel, disease-associated phenotypes and mechanisms. In this review, we summarize how the diverse brain organoid methods can be utilized to enhance our understanding of brain disorders. FACTS: Brain organoids offer an in vitro approach to study aspects of human brain development and disease. Diverse brain organoid techniques offer bioassays to investigate new phenotypes associated with human brain disorders that are difficult to study in monolayer cultures. Brain organoids have been particularly useful to study phenomena and diseases associated with neural progenitor morphology, survival, proliferation, and differentiation. OPEN QUESTION: Future brain organoid research needs to aim at later stages of neurodevelopment, linked with neuronal activity and connections, to unravel further disease-associated phenotypes. Continued improvement of existing organoid protocols is required to generate standardized methods that recapitulate in vivo-like spatial diversity and complexity.

Application of Fused Organoid Models to Study Human Brain Development and Neural Disorders.

Human brain organoids cultured from human pluripotent stem cells provide a promising platform to recapitulate histological features of the human brain and model neural disorders. However, unlike animal models, brain organoids lack a reproducible topographic organization, which limits their application in modeling intricate biology, such as the interaction between different brain regions. To overcome these drawbacks, brain organoids have been pre-patterned into specific brain regions and fused to form an assembloid that represents reproducible models recapitulating more complex biological processes of human brain development and neurological diseases. This approach has been applied to model interneuron migration, neuronal projections, tumor invasion, oligodendrogenesis, forebrain axis establishment, and brain vascularization. In this review article, we will summarize the usage of this technology to understand the fundamental biology underpinning human brain development and disorders.

Channelrhodopsin Excitation Contracts Brain Pericytes and Reduces Blood Flow in the Aging Mouse Brain in vivo.

Brains depend on blood flow for the delivery of oxygen and nutrients essential for proper neuronal and synaptic functioning. French physiologist Rouget was the first to describe pericytes in 1873 as regularly arranged longitudinal amoeboid cells on capillaries that have a muscular coat, implying that these are contractile cells that regulate blood flow. Although there have been >30 publications from different groups, including our group, demonstrating that pericytes are contractile cells that can regulate hemodynamic responses in the brain, the role of pericytes in controlling cerebral blood flow (CBF) has not been confirmed by all studies. Moreover, recent studies using different optogenetic models to express light-sensitive channelrhodopsin-2 (ChR2) cation channels in pericytes were not conclusive; one, suggesting that pericytes expressing ChR2 do not contract after light stimulus, and the other, demonstrating contraction of pericytes expressing ChR2 after light stimulus. Since two-photon optogenetics provides a powerful tool to study mechanisms of blood flow regulation at the level of brain capillaries, we re-examined the contractility of brain pericytes in vivo using a new optogenetic model developed by crossing our new inducible pericyte-specific CreER mouse line with ChR2 mice. We induced expression of ChR2 in pericytes with tamoxifen, excited ChR2 by 488 nm light, and monitored pericyte contractility, brain capillary diameter changes, and red blood cell (RBC) velocity in aged mice by in vivo two-photon microscopy. Excitation of ChR2 resulted in pericyte contraction followed by constriction of the underlying capillary leading to approximately an 8% decrease (p = 0.006) in capillary diameter. ChR2 excitation in pericytes substantially reduced capillary RBC flow by 42% (p = 0.03) during the stimulation period compared to the velocity before stimulation. Our data suggests that pericytes contract in vivo and regulate capillary blood flow in the aging mouse brain. By extension, this might have implications for neurological disorders of the aging human brain associated with neurovascular dysfunction and pericyte loss such as stroke and Alzheimer’s disease.

Influence of 7T GRE-MRI Signal Compartment Model Choice on Tissue Parameters.

Quantitative assessment of tissue microstructure is important in studying human brain diseases and disorders. Ultra-high field magnetic resonance imaging (MRI) data obtained using a multi-echo gradient echo sequence have been shown to contain information on myelin, axonal, and extracellular compartments in tissue. Quantitative assessment of water fraction, relaxation time (T2*), and frequency shift using multi-compartment models has been shown to be useful in studying white matter properties via specific tissue parameters. It remains unclear how tissue parameters vary with model selection based on 7T multiple echo time gradient-recalled echo (GRE) MRI data. We applied existing signal compartment models to the corpus callosum and investigated whether a three-compartment model can be reduced to two compartments and still resolve white matter parameters [i.e., myelin water fraction (MWF) and g-ratio]. We show that MWF should be computed using a three-compartment model in the corpus callosum, and the g-ratios obtained using three compartment models are consistent with previous reports. We provide results for other parameters, such as signal compartment frequency shifts.

First person – Yi Liu

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Yi Liu is first author on ‘Direct interaction between CEP85 and STIL mediates PLK4-driven directed cell migration’, published in JCS. Yi conducted the research described in this article while a PhD student in Dr Laurence Pelletier's lab at Lunenfeld-Tanenbaum Research Institute, University of Toronto, Canada. He is now a Postdoc in the lab of Dr Rudolf Jaenisch at Whitehead Institute for Biomedical Research, MIT, USA, where he uses stem cells to study complex human brain disorders.

Protein phosphatase PP2A regulates microtubule orientation and dendrite pruning in Drosophila.

Pruning that selectively eliminates inappropriate projections is crucial for sculpting neural circuits during development. During Drosophila metamorphosis, ddaC sensory neurons undergo dendrite-specific pruning in response to the steroid hormone ecdysone. However, the understanding of the molecular mechanisms underlying dendrite pruning remains incomplete. Here, we show that protein phosphatase 2A (PP2A) is required for dendrite pruning. The catalytic (Microtubule star/Mts), scaffolding (PP2A-29B), and two regulatory subunits (Widerborst/Wdb and Twins/Tws) play important roles in dendrite pruning. Functional analyses indicate that PP2A, via Wdb, facilitates the expression of Sox14 and Mical prior to dendrite pruning. Furthermore, PP2A, via Tws, governs the minus-end-out orientation of microtubules (MTs) in the dendrites. Moreover, the levels of Klp10A, a MT depolymerase, increase when PP2A is compromised. Attenuation of Klp10A fully rescues the MT orientation defects in mts or pp2a-29b RNAi ddaC neurons, suggesting that PP2A governs dendritic MT orientation by suppressing Klp10A levels and/or function. Taken together, this study sheds light on a novel function of PP2A in regulating dendrite pruning and dendritic MT polarity in sensory neurons.

Building a Human Brain for Research.

OPINION article Front. Mol. Neurosci., 18 February 2020Sec. Methods and Model Organisms Volume 13 - 2020 | https://doi.org/10.3389/fnmol.2020.00022

N-Acetylaspartate Is an Important Brain Osmolyte.

Most of the human diseases related to various proteopathies are confined to the brain, which leads to the development of various forms of neurological disorders. The human brain consists of several osmolytic compounds, such as N-Acetylaspartate (NAA), myo-inositol (mI), glutamate (Glu), glutamine (Gln), creatine (Cr), and choline-containing compounds (Cho). Among these osmolytes, the level of NAA drastically decreases under neurological conditions, and, hence, NAA is considered to be one of the most widely accepted neuronal biomarkers in several human brain disorders. To date, no data are available regarding the effect of NAA on protein stability, and, therefore, the possible effect of NAA under proteopathic conditions has not been fully uncovered. To gain an insight into the effect of NAA on protein stability, thermal denaturation and structural measurements were carried out using two model proteins at different pH values. The results indicate that NAA increases the protein stability with an enhancement of structure formation. We also observed that the stabilizing ability of NAA decreases in a pH-dependent manner. Our study indicates that NAA is an efficient protein stabilizer at a physiological pH.

Short and long TNF-alpha exposure recapitulates canonical astrogliosis events in human-induced pluripotent stem cells-derived astrocytes.

Astrogliosis comprises a variety of changes in astrocytes that occur in a context-specific manner, triggered by temporally diverse signaling events that vary with the nature and severity of brain insults. However, most mechanisms underlying astrogliosis were described using animals, which fail to reproduce some aspects of human astroglial signaling. Here, we report an in vitro model to study astrogliosis using human-induced pluripotent stem cells (iPSC)-derived astrocytes which replicate temporally intertwined aspects of reactive astrocytes in vivo. We analyzed the time course of astrogliosis by measuring nuclear translocation of NF-kB, production of cytokines, changes in morphology and function of iPSC-derived astrocytes exposed to TNF-α. We observed NF-kB p65 subunit nuclear translocation and increased gene expression of IL-1β, IL-6, and TNF-α in the first hours following TNF-α stimulation. After 24 hr, conditioned media from iPSC-derived astrocytes exposed to TNF-α exhibited increased secretion of inflammation-related cytokines. After 5 days, TNF-α-stimulated cells presented a typical phenotype of astrogliosis such as increased immunolabeling of Vimentin and GFAP and nuclei with elongated shape and shrinkage. Moreover, ~50% decrease in aspartate uptake was observed during the time course of astrogliosis with no evident cell damage, suggesting astroglial dysfunction. Together, our results indicate that human iPSC-derived astrocytes reproduce canonical events associated with astrogliosis in a time dependent fashion. The approach described here may contribute to a better understanding of mechanisms governing human astrogliosis with potential applicability as a platform to uncover novel biomarkers and drug targets to prevent or mitigate astrogliosis associated with human brain disorders.

Persistent Cyfip1 Expression Is Required to Maintain the Adult Subventricular Zone Neurogenic Niche.

Neural stem cells (NSCs) persist throughout life in the subventricular zone (SVZ) neurogenic niche of the lateral ventricles as Type B1 cells in adult mice. Maintaining this population of NSCs depends on the balance between quiescence and self-renewing or self-depleting cell divisions. Interactions between B1 cells and the surrounding niche are important in regulating this balance, but the mechanisms governing these processes have not been fully elucidated. The cytoplasmic FMRP-interacting protein (Cyfip1) regulates apical-basal polarity in the embryonic brain. Loss of Cyfip1 during embryonic development in mice disrupts the embryonic niche and affects cortical neurogenesis. However, a direct role for Cyfip1 in the regulation of adult NSCs has not been established. Here, we demonstrate that Cyfip1 expression is preferentially localized to B1 cells in the adult mouse SVZ. Loss of Cyfip1 in the embryonic mouse brain results in altered adult SVZ architecture and expansion of the adult B1 cell population at the ventricular surface. Furthermore, acute deletion of Cyfip1 in adult NSCs results in a rapid change in adherens junction proteins as well as increased proliferation and number of B1 cells at the ventricular surface. Together, these data indicate that Cyfip1 plays a critical role in the formation and maintenance of the adult SVZ niche; furthermore, deletion of Cyfip1 unleashes the capacity of adult B1 cells for symmetric renewal to increase the adult NSC pool.SIGNIFICANCE STATEMENT Neural stem cells (NSCs) persist in the subventricular zone of the lateral ventricles in adult mammals, and the size of this population is determined by the balance between quiescence and self-depleting or renewing cell division. The mechanisms regulating these processes are not fully understood. This study establishes that the cytoplasmic FMRP interacting protein 1 (Cyfip1) regulates NSC fate decisions in the adult subventricular zone and adult NSCs that are quiescent or typically undergo self-depleting divisions retain the ability to self-renew. These results contribute to our understanding of how adult NSCs are regulated throughout life and has potential implications for human brain disorders.

Size discrimination in adult zebrafish (Danio rerio): Normative data and individual variation

In humans, aging and neurodegenerative diseases have been found to be associated with impairment in both mathematical abilities and estimation of continuous quantities such as size, weight or distance. Zebrafish (Danio rerio) is rapidly becoming a model for human aging and brain disorders but we currently lack any instrument for rapid assessment of quantity estimation abilities in this species. Here we developed a simple method based on spontaneous preference of zebrafish for using the larger available hole to pass an obstacle. We collected a large amount of data from small groups of zebrafish moving between compartments of their tank and we used these normative data to compare the performance of individually tested fish. Zebrafish significantly discriminated size ratios from 0.60 to 0.91 with their performance decreasing while increasing the size ratio between the smaller and the larger hole presented. On average, individually tested fish showed the same performance, but a large inter-individual variability was observed. Test-retest analyses revealed a good reliability of this test, with 0.60 and 0.75 ratios being the most informative. Experience did not affect individual performance, suggesting the suitability of this test to measure the longitudinal changes and the effects of pharmacological treatments on cognitive abilities.

From basic brain research to treating human brain disorders

The human brain is the most complex entity we know. Disorders of the human brain are embedded in this complexity. Potential advances in treating these disorders result from the growing understanding of this complex organization. The brains of monkeys have some important similarities to the human brain in structure and organization, and monkeys have therefore been extensively studied to help us to understand human brain disorders. With this in mind, the National Academy of Sciences (NAS) convened a colloquium, “Using Monkey Models to Understand and Develop Treatments for Human Brain Disorders,” in Irvine, California on January 7th and 8th, 2019. The colloquium articles in this issue of PNAS offer a glimpse into the relationship of scientific discovery to the treatment of brain disorders. We begin by considering how this kind of scientific discovery works. The better we know how a machine works, the more likely we are able to fix it when it breaks. When our automobile needs repair, we take it to someone we think understands how it works and therefore is likely to be able to fix it. We do the same thing when we have a brain disorder; we go to the doctor we think understands the brain system underlying the specific disorder and hope that she can provide a treatment. It is the understanding of the brain system that comes first; without that understanding the treatment is likely to be a hit or miss guess or an expensive failure. The understanding is not all or none, it is continually developing, often over many years. Anyone who has close experience with a brain disease knows that current medicine is mostly groping in the dark with these disorders. It is the job of basic science to turn on some lights. Consider an example of the contribution to clinical … [↵][1]1To whom correspondence may be addressed. Email: bob{at}lsr.nei.nih.gov. [1]: #xref-corresp-1-1

Low-cost embedded system for optical imaging of intrinsic signals

This paper describes the proof-of-concept evaluation of a low-cost imaging system for obtaining functional connectivity maps of in vivo murine models. This non-contact system is based on the Raspberry Pi 3 and its V2 camera and offers a method for obtaining resting-state images of brain activity without the use of extrinsic contrast agents. The system was fully characterized in terms of dark signal, linearity, sensor noise resolution and spatial frequency response. One mouse was observed in vivo and functional connectivity maps were obtained by combining resting-state analysis and optical intrinsic signals imaging. Intra-mouse variations in functional connectivity remain consistent across multiple imaging sessions. In principle, inexpensive optical imaging of intrinsic signals allows the study of the mechanisms underlying human brain disorders in well-controlled murine models.

MR Brain Image Segmentation Using k-Means Clustering and Expectation Maximization

Magnetic Resonance Images (MRI) for brain play an important role to identify the disease, dysfunction or disorder of human brain. These images are the primary source to study, analyse and diagnose the anatomy of the brain. This paper presents a new combinatorial technique titled, “MR Brain Image Segmentation using k-Means Clustering and Expectation Maximization (MRB-KMEM)” that performs skull stripping, impulse noise removal, segmentation of brain tissues and classification of brain images. The skull is removed using the technique of morphology-bound brain segmentation and Progressive Switching Median Filter (PSMF) is used to suppress brain image distortion. Further, brain tissues segmentation into white matter and grey matter is performed by KM-EM. The research outcomes can be used to study the features of a brain, its defects and to detect Alzheimer’s disease.

A Case of Subcortical Band Heterotopia Presented with Epilepsy and Speech Regression

Subcortical Heterotopia is a rare developmental disorder of human brain due to mutation in the DCX or LIS1gene.It is predominantly a disease of female. It usually present with refractory seizure and varying degree of mental retardation. Here a case of 22 years lady who presented with refractory seizure is reported. Her MRI revealed Double cortex and her EEG revealed Frontal intermittent rhythmic delta activity (FIRDA).
 Bangladesh Journal of Neuroscience 2019; Vol. 35 (2): 115-118