scholarly journals The impact of genomic structural variation on the transcriptome, chromatin, and proteome in the human brain

2021 ◽  
Author(s):  
Ricardo A Vialle ◽  
Katia de Paiva Lopes ◽  
David A Bennett ◽  
John F Crary ◽  
Towfique Raj
Keyword(s):  
Human Brain ◽  
Structural Variation ◽  
Brain Regions ◽  
Cis Acting ◽  
Genomic Structural Variation ◽  
Protein Levels ◽  
Post Mortem Brain ◽  
Whole Genomes ◽  
The Impact ◽  
The Brain

Structural variants (SVs), defined as any genomic rearrangements of 50 or more bp, are an important source of genetic diversity and have been linked to many diseases. However, their contribution to molecular traits in the brain and impact on neurodegenerative diseases remains unknown. Here, we report 170,996 SVs which were constructed using 1,760 short-read whole genomes from aging and Alzheimer's disease subjects. We quantified the impact of cis-acting SVs on several molecular traits including histone modification, gene expression, mRNA splicing, and protein abundance in post-mortem brain tissues. More than 3,800 genes were associated with at least one molecular phenotype, and 712 (18%) with more than one phenotype, with a significant positive correlation in the direction of effect between RNA, histone peaks, and protein levels. SV associations with RNA and protein levels shared the same direction of effect in more than 87% of SV-gene pairs. We found reproducibility of SV-eQTLs across three groups of samples and multiple brain regions ranging from 81 to 98%, including the innate immune system related genes ERAP2 and GBP3. Additionally, associations of SVs with progressive supranuclear palsy, an amyloid-independent primary tauopathy, identified previously known and novel SVs at the 17q.21.31 MAPT locus and several other novel suggestive associations. Our study provides a comprehensive view of the mechanisms linking structural variation to gene regulation and provides a valuable resource for understanding the functional impact of SVs in the aged human brain.

scholarly journals Increasing and decreasing interregional brain coupling increases and decreases oscillatory activity in the human brain

2021 ◽  
Vol 118 (37) ◽  
pp. e2100652118
Author(s):  
Alejandra Sel ◽  
Lennart Verhagen ◽  
Katharina Angerer ◽  
Raluca David ◽  
Miriam C. Klein-Flügge ◽  
...  
Keyword(s):  
Human Brain ◽  
Alpha Rhythm ◽  
Primary Motor Cortex ◽  
Premotor Cortex ◽  
Motor Task ◽  
Brain Regions ◽  
Spike Timing ◽  
Oscillatory Activity ◽  
The Impact ◽  
The Brain

The origins of oscillatory activity in the brain are currently debated, but common to many hypotheses is the notion that they reflect interactions between brain areas. Here, we examine this possibility by manipulating the strength of coupling between two human brain regions, ventral premotor cortex (PMv) and primary motor cortex (M1), and examine the impact on oscillatory activity in the motor system measurable in the electroencephalogram. We either increased or decreased the strength of coupling while holding the impact on each component area in the pathway constant. This was achieved by stimulating PMv and M1 with paired pulses of transcranial magnetic stimulation using two different patterns, only one of which increases the influence exerted by PMv over M1. While the stimulation protocols differed in their temporal patterning, they were comprised of identical numbers of pulses to M1 and PMv. We measured the impact on activity in alpha, beta, and theta bands during a motor task in which participants either made a preprepared action (Go) or withheld it (No-Go). Augmenting cortical connectivity between PMv and M1, by evoking synchronous pre- and postsynaptic activity in the PMv–M1 pathway, enhanced oscillatory beta and theta rhythms in Go and No-Go trials, respectively. Little change was observed in the alpha rhythm. By contrast, diminishing the influence of PMv over M1 decreased oscillatory beta and theta rhythms in Go and No-Go trials, respectively. This suggests that corticocortical communication frequencies in the PMv–M1 pathway can be manipulated following Hebbian spike-timing–dependent plasticity.

scholarly journals Developmental cannabidiol exposure increases anxiety and modifies genome-wide brain DNA methylation in adult female mice

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Nicole M. Wanner ◽  
Mathia Colwell ◽  
Chelsea Drown ◽  
Christopher Faulk
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Coat Color ◽  
Brain Regions ◽  
Functional Enrichment ◽  
Positive Effects ◽  
Genome Wide ◽  
Nulliparous Female ◽  
The Impact ◽  
The Brain

Abstract Background Use of cannabidiol (CBD), the primary non-psychoactive compound found in cannabis, has recently risen dramatically, while relatively little is known about the underlying molecular mechanisms of its effects. Previous work indicates that direct CBD exposure strongly impacts the brain, with anxiolytic, antidepressant, antipsychotic, and other effects being observed in animal and human studies. The epigenome, particularly DNA methylation, is responsive to environmental input and can direct persistent patterns of gene regulation impacting phenotype. Epigenetic perturbation is particularly impactful during embryogenesis, when exogenous exposures can disrupt critical resetting of epigenetic marks and impart phenotypic effects lasting into adulthood. The impact of prenatal CBD exposure has not been evaluated; however, studies using the psychomimetic cannabinoid Δ9-tetrahydrocannabinol (THC) have identified detrimental effects on psychological outcomes in developmentally exposed adult offspring. We hypothesized that developmental CBD exposure would have similar negative effects on behavior mediated in part by the epigenome. Nulliparous female wild-type Agouti viable yellow (Avy) mice were exposed to 20 mg/kg CBD or vehicle daily from two weeks prior to mating through gestation and lactation. Coat color shifts, a readout of DNA methylation at the Agouti locus in this strain, were measured in F1 Avy/a offspring. Young adult F1 a/a offspring were then subjected to tests of working spatial memory and anxiety/compulsive behavior. Reduced-representation bisulfite sequencing was performed on both F0 and F1 cerebral cortex and F1 hippocampus to identify genome-wide changes in DNA methylation for direct and developmental exposure, respectively. Results F1 offspring exposed to CBD during development exhibited increased anxiety and improved memory behavior in a sex-specific manner. Further, while no significant coat color shift was observed in Avy/a offspring, thousands of differentially methylated loci (DMLs) were identified in both brain regions with functional enrichment for neurogenesis, substance use phenotypes, and other psychologically relevant terms. Conclusions These findings demonstrate for the first time that despite positive effects of direct exposure, developmental CBD is associated with mixed behavioral outcomes and perturbation of the brain epigenome.

scholarly journals Comparison of age‐dependent alterations in thioredoxin 2 and thioredoxin reductase 2 expressions in hippocampi between mice and rats

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Yeon Ho Yoo ◽  
Dae Won Kim ◽  
Bai Hui Chen ◽  
Hyejin Sim ◽  
Bora Kim ◽  
...  
Keyword(s):  
Thioredoxin Reductase ◽  
Pyramidal Cells ◽  
Brain Regions ◽  
Young Age ◽  
Cresyl Violet ◽  
Western Blots ◽  
Protein Levels ◽  
Cresyl Violet Staining ◽  
Age Dependent ◽  
The Brain

Abstract Background Aging is one of major causes triggering neurophysiological changes in many brain substructures, including the hippocampus, which has a major role in learning and memory. Thioredoxin (Trx) is a class of small redox proteins. Among the Trx family, Trx2 plays an important role in the regulation of mitochondrial membrane potential and is controlled by TrxR2. Hitherto, age-dependent alterations in Trx2 and TrxR2 in aged hippocampi have been poorly investigated. Therefore, the aim of this study was to examine changes in Trx2 and TrxR2 in mouse and rat hippocampi by age and to compare their differences between mice and rats. Results Trx2 and TrxR2 levels using Western blots in mice were the highest at young age and gradually reduced with time, showing that no significant differences in the levels were found between the two subfields. In rats, however, their expression levels were the lowest at young age and gradually increased with time. Nevertheless, there were no differences in cellular distribution and morphology in their hippocampi when it was observed by cresyl violet staining. In addition, both Trx2 and TrxR2 immunoreactivities in the CA1-3 fields were mainly shown in pyramidal cells (principal cells), showing that their immunoreactivities were altered like changes in their protein levels. Conclusions Our current findings suggest that Trx2 and TrxR2 expressions in the brain may be different according to brain regions, age and species. Therefore, further studies are needed to examine the reasons of the differences of Trx2 and TrxR2 expressions in the hippocampus between mice and rats.

scholarly journals Associations of Vitamin D and Vitamin K and Their Metabolites Across Four Regions of the Human Brain: The Memory and Aging Project (MAP) (FS05-02-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Xueyan Fu ◽  
Will Patterson ◽  
Gregory Dolnikowski ◽  
Bess Dawson-Hughes ◽  
Martha Morris ◽  
...  
Keyword(s):  
Vitamin D ◽  
Human Brain ◽  
Vitamin K ◽  
Vitamin D3 ◽  
Rank Order ◽  
Temporal Cortex ◽  
Correlation Coefficients ◽  
Brain Regions ◽  
Multiple Regions ◽  
The Brain

Abstract Objectives Very little is known about the forms of vitamin D and vitamin K in the human brain. The objective of this study is to evaluate concentrations of vitamin D and vitamin K forms in human brain and their correlations across four human brain regions. Methods Vitamin D [D3, 25(OH)D and 1,25(OH)2D] and vitamin K [phylloquinone and menaquinone-4 (MK4)] concentrations were measured by LC/MS/MS and HPLC, respectively, in four brain regions from post-mortem samples obtained from participants in the Rush Memory and Aging Project (n = 130, mean age 82 yrs, 81% female). The brain regions analyzed were the mid-frontal cortex (MF) and mid-temporal cortex (MT) [two regions important for memory in Alzheimer's Disease (AD)], the cerebellum (CR, a region not affected by AD), and the anterior watershed white matter (AWS, a region associated with vascular disease). The correlations among the vitamin forms across brain regions were calculated using Spearman rank order correlation coefficients. Significance was set at P < 0.001. Results The average concentrations of vitamin D3, 25(OH)D and MK4 were 604 pg/g, 535 pg/g, and 3.4 pmol/g, respectively. 25(OH)D and MK4 were detected in >95% of the brain samples. Nearly 92% of 1,25(OH)2D and 80% of phylloquinone samples had concentrations below the limit of assay detection (LOD) 1,25(OH)2D = 20 ng/g, phylloquinone = 0.1 pmol/g). Vitamin D3 and 25(OH)D concentrations were positively correlated across all four regions (all Spearman r ≥ 0.78, P < 0.0001). The 1,25(OH)2D was significantly correlated between the MF and CR regions only (Spearman r = 0.30, P < 0.001, all other P ≥ 0.002). MK4 and PK were positively correlated across the four regions studied (MK4 all Spearman r ≥ 0.78, phylloquinone r ≥ 0.49, all P < 0.001). Conclusions To the best of our knowledge, this study is the first evaluation of the concentrations of vitamin D and vitamin K forms in multiple regions of the human brain. Overall, the vitamin D and vitamin K forms were each positively correlated across the four brain regions studied. Future studies are needed to clarify the roles of these nutrients in AD and dementia. Funding Sources National Institute of Aging.

scholarly journals STAB: a spatio-temporal cell atlas of the human brain

2020 ◽  
Vol 49 (D1) ◽  
pp. D1029-D1037
Author(s):  
Liting Song ◽  
Shaojun Pan ◽  
Zichao Zhang ◽  
Longhao Jia ◽  
Wei-Hua Chen ◽  
...  
Keyword(s):  
Human Brain ◽  
Single Cell ◽  
Temporal Dynamics ◽  
Cell Types ◽  
Brain Regions ◽  
Molecular Characteristics ◽  
Great Effort ◽  
Brain Functions ◽  
Spatio Temporal ◽  
The Brain

Abstract The human brain is the most complex organ consisting of billions of neuronal and non-neuronal cells that are organized into distinct anatomical and functional regions. Elucidating the cellular and transcriptome architecture underlying the brain is crucial for understanding brain functions and brain disorders. Thanks to the single-cell RNA sequencing technologies, it is becoming possible to dissect the cellular compositions of the brain. Although great effort has been made to explore the transcriptome architecture of the human brain, a comprehensive database with dynamic cellular compositions and molecular characteristics of the human brain during the lifespan is still not available. Here, we present STAB (a Spatio-Temporal cell Atlas of the human Brain), a database consists of single-cell transcriptomes across multiple brain regions and developmental periods. Right now, STAB contains single-cell gene expression profiling of 42 cell subtypes across 20 brain regions and 11 developmental periods. With STAB, the landscape of cell types and their regional heterogeneity and temporal dynamics across the human brain can be clearly seen, which can help to understand both the development of the normal human brain and the etiology of neuropsychiatric disorders. STAB is available at http://stab.comp-sysbio.org.

scholarly journals Differential Expression of CD31 and Von Willebrand Factor on Endothelial Cells in Different Regions of the Human Brain: Potential Implications for Cerebral Malaria Pathogenesis

2020 ◽  
Vol 10 (1) ◽  
pp. 31 ◽  
Author(s):  
Smart Ikechukwu Mbagwu ◽  
Luis Filgueira
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Human Brain ◽  
Expression Pattern ◽  
Von Willebrand Factor ◽  
Brain Regions ◽  
And Function ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
The Brain

Cerebral microvascular endothelial cells (CMVECs) line the vascular system of the brain and are the chief cells in the formation and function of the blood brain barrier (BBB). These cells are heterogeneous along the cerebral vasculature and any dysfunctional state in these cells can result in a local loss of function of the BBB in any region of the brain. There is currently no report on the distribution and variation of the CMVECs in different brain regions in humans. This study investigated microcirculation in the adult human brain by the characterization of the expression pattern of brain endothelial cell markers in different brain regions. Five different brain regions consisting of the visual cortex, the hippocampus, the precentral gyrus, the postcentral gyrus, and the rhinal cortex obtained from three normal adult human brain specimens were studied and analyzed for the expression of the endothelial cell markers: cluster of differentiation 31 (CD31) and von-Willebrand-Factor (vWF) through immunohistochemistry. We observed differences in the expression pattern of CD31 and vWF between the gray matter and the white matter in the brain regions. Furthermore, there were also regional variations in the pattern of expression of the endothelial cell biomarkers. Thus, this suggests differences in the nature of vascularization in various regions of the human brain. These observations also suggest the existence of variation in structure and function of different brain regions, which could reflect in the pathophysiological outcomes in a diseased state.

Modeling the dose distribution in a human brain structure using CT images on the surface of Mars

2020 ◽  
Author(s):  
Salman Khaksarighiri ◽  
Jingnan Guo ◽  
Robert Wimmer-Schweingruber ◽  
Lennart Rostl
Keyword(s):  
Radiation Dose ◽  
Human Brain ◽  
Brain Structure ◽  
Dose Distribution ◽  
Cosmic Radiation ◽  
Cosmic Ray ◽  
Ct Images ◽  
Human Brains ◽  
The Impact ◽  
The Brain

&lt;p&gt;One of the most important steps in the near-future space age will be a manned mission to Mars. Unfortunately, such a mission will cause astronauts to be exposed to unavoidable cosmic radiation in deep space and on the surface of Mars. Thus a better understanding of the radiation environment for a Mars mission and the consequent biological impacts on humans, in particular the human brains, is critical. To investigate the impact of cosmic radiation on human brains and the potential influence on the brain functions, we model and study the cosmic particle-induced radiation dose in a realistic head structure. Specifically speaking, 134 slices of computed tomography (CT) images of an actual human head have been used as a 3D phantom in Geant4 (GEometry ANd Tracking) which is a Monte Carlo tool simulating energetic particles impinging into different parts of the brain and deliver radiation dose therein. As a first step, we compare the influence of different brain structures (e.g., with or without bones, with or without soft tissues) to the resulting dose therein to demonstrate the necessity of using a realistic brain structure for our investigation. Afterwards, we calculate energy-dependent functions of dose distribution for the most important (most abundant and most biologically-relevant) particle types encountered in space and on Mars such as protons, Helium ions and neutrons. These functions are then used to fold with Galactic Cosmic Ray (GCR) spectra on the surface of Mars for obtaining the dose rate distribution at different lobes of the human brain. Different GCR spectra during various solar cycle conditions have also been studied and compared.&lt;/p&gt;

scholarly journals “Neurocovid”: An Analysis of the Impact of Covid-19 on the Older Adults. Evolving Psychological and Neuropsychological Understanding

2021 ◽  
Author(s):  
Sara Palermo
Keyword(s):  
Older Adults ◽  
Nervous System ◽  
Adverse Effects ◽  
Human Brain ◽  
The Elderly ◽  
Cognitive Frailty ◽  
Daily Routines ◽  
The Impact ◽  
The Brain

When SARS-CoV-2 began to spread, older adults experienced disproportionately greater adverse effects from the pandemic, including exacerbation of pre-existing physical and cognitive frailty conditions. More severe complications, higher mortality, and concerns about disruptions to their daily routines and access to care. Knowledge about the impact of COVID-19 on the brain is rapidly accumulating and this is reflected in the increasing use of the term “neurocovid”. Co-involvement of the central and peripheral nervous system had already been observed in SARS patients, but COVID-19 seems to invade it with greater affinity than other coronaviruses. This chapter provides an overview of the expanding understanding of the multiple ways in which COVID-19 affects the human brain, discuss the likelihood of long-term sequelae of neurocovid, and their implications for cognitive functions and behaviors in the elderly.

scholarly journals Neurorehabilitation in Multiple Sclerosis – Resilience in Practice

2017 ◽  
Vol 12 (01) ◽  
pp. 31 ◽  
Author(s):  
Jürg Kesselring ◽  
Keyword(s):  
Multiple Sclerosis ◽  
Best Practice ◽  
Healthcare Providers ◽  
Brain Regions ◽  
Standards Of Care ◽  
Key Factors ◽  
Disease Modifying Drugs ◽  
Randomised Controlled ◽  
The Impact ◽  
The Brain

In recent years, enormous strides have been made in increasing the range and efficacy of disease-modifying drugs available for the treatment of multiple sclerosis (MS) in its early and remitting stages, and more continue to emerge. Another equally important concept of successful treatment of MS is neurorehabilitation, which must be pursued alongside these medications. Key factors that contribute to the impact of neurorehabilitation include resilience and neuroplasticity. In the former, components such as nutrition, self-belief and physical activity provide a stronger response to the disease and improved responses to treatment. Neuroplasticity is the capacity of the brain to establish new neuronal networks after lesion damage has occurred and distant brain regions assume control of lost functions. In MS, it is vital that each patient is treated by a coordinated multidisciplinary team. This enables all aspects of the disease including problems with mobility, gait, bladder/bowel disturbances, fatigue and depression to be effectively treated. It is also important that the treating team adopts current best practice and provides internationally agreed standards of care. A further vital aspect of MS management is patient engagement, in which individuals are fully involved and are encouraged to strive and put effort into meeting treatment goals. In this approach, healthcare providers become motivators and patients need less intervention and consume fewer resources. Numerous interventions that promote neurorehabilitation are available, though evidence to support their use is limited by a lack of data from large randomised controlled trials. Combining interventions that promote neurorehabilitation with newer, more effective treatments creates a promising potential to substantially improve the outlook for patients at all stages of MS.

scholarly journals Same Brain, Different Look?—The Impact of Scanner, Sequence and Preprocessing on Diffusion Imaging Outcome Parameters

2021 ◽  
Vol 10 (21) ◽  
pp. 4987
Author(s):  
Ronja Thieleking ◽  
Rui Zhang ◽  
Maria Paerisch ◽  
Kerstin Wirkner ◽  
Alfred Anwander ◽  
...  
Keyword(s):  
Data Acquisition ◽  
Diffusion Imaging ◽  
Mean Diffusivity ◽  
Brain Regions ◽  
Clinical Diagnostics ◽  
Neuroimaging Data ◽  
Age Range ◽  
The Impact ◽  
The Brain ◽  
Healthy Participants

In clinical diagnostics and longitudinal studies, the reproducibility of MRI assessments is of high importance in order to detect pathological changes, but developments in MRI hard- and software often outrun extended periods of data acquisition and analysis. This could potentially introduce artefactual changes or mask pathological alterations. However, if and how changes of MRI hardware, scanning protocols or preprocessing software affect complex neuroimaging outcomes from, e.g., diffusion weighted imaging (DWI) remains largely understudied. We therefore compared DWI outcomes and artefact severity of 121 healthy participants (age range 19–54 years) who underwent two matched DWI protocols (Siemens product and Center for Magnetic Resonance Research sequence) at two sites (Siemens 3T Magnetom Verio and Skyrafit). After different preprocessing steps, fractional anisotropy (FA) and mean diffusivity (MD) maps, obtained by tensor fitting, were processed with tract-based spatial statistics (TBSS). Inter-scanner and inter-sequence variability of skeletonised FA values reached up to 5% and differed largely in magnitude and direction across the brain. Skeletonised MD values differed up to 14% between scanners. We here demonstrate that DTI outcome measures strongly depend on imaging site and software, and that these biases vary between brain regions. These regionally inhomogeneous biases may exceed and considerably confound physiological effects such as ageing, highlighting the need to harmonise data acquisition and analysis. Future studies thus need to implement novel strategies to augment neuroimaging data reliability and replicability.

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