scholarly journals Changes in dynamic transitions between integrated and segregated states underlie visual hallucinations in Parkinson's disease

2021 ◽  
Author(s):  
Angeliki Zarkali ◽  
Andrea Luppi ◽  
Emmanuel A Stamatakis ◽  
Suzanne Reeves ◽  
Peter McColgan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Visual Processing ◽  
Temporal Dynamics ◽  
Expression Profiles ◽  
Receptor Gene ◽  
Structural Connectivity ◽  
Brain Regions ◽  
State Transitions ◽  
Visual Hallucinations ◽  
Density Profiles

Background: Visual hallucinations in Parkinsons disease (PD) are transient, suggesting a change in dynamic brain states. However, the causes underlying these dynamic brain changes are not known. Methods: Focusing on fundamental network properties of integration and segregation, we used rsfMRI to examine alterations in temporal dynamics in PD patients with hallucinations (n=16) compared to those without hallucinations (n=75) and a group of normal controls (n=32). We used network control theory to examine how structural connectivity guides transitions between functional states. We then studied the brain regions most involved in these state transitions, and examined corresponding neurotransmitter density profiles and receptor gene expression in health. Results: There were significantly altered temporal dynamics in PD with hallucinations, with an increased proportion of time spent in the Segregated state compared to non-hallucinators and controls; less between-state transitions; and increased dwell time in the Segregated state. The energy cost needed to transition from integrated-to-segregated state was lower in PD-hallucinators compared to non-hallucinators. This was primarily driven by subcortical and transmodal cortical brain regions, including the thalamus and default mode network regions. The regional energy needed to transition from integrated-to-segregated state was significantly correlated with regional neurotransmitter density and gene expression profiles for serotoninergic (including 5HT2A), GABAergic, noradrenergic and cholinergic but not dopaminergic density profiles. Conclusions: We describe the patterns of temporal functional dynamics in PD-hallucinations, and link these with neurotransmitter systems involved in early sensory and complex visual processing. Our findings provide mechanistic insights into visual hallucinations in PD and highlighting potential therapeutic targets.

scholarly journals Differences in network controllability and regional gene expression underlie hallucinations in Parkinson’s disease

Brain ◽  
2020 ◽  
Vol 143 (11) ◽  
pp. 3435-3448
Author(s):  
Angeliki Zarkali ◽  
Peter McColgan ◽  
Mina Ryten ◽  
Regina Reynolds ◽  
Louise-Ann Leyland ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Localization ◽  
Expression Patterns ◽  
Structural Connectivity ◽  
Brain Regions ◽  
Brain Network ◽  
Visual Hallucinations ◽  
Regional Gene

Abstract Visual hallucinations are common in Parkinson’s disease and are associated with poorer prognosis. Imaging studies show white matter loss and functional connectivity changes with Parkinson’s visual hallucinations, but the biological factors underlying selective vulnerability of affected parts of the brain network are unknown. Recent models for Parkinson’s disease hallucinations suggest they arise due to a shift in the relative effects of different networks. Understanding how structural connectivity affects the interplay between networks will provide important mechanistic insights. To address this, we investigated the structural connectivity changes that accompany visual hallucinations in Parkinson’s disease and the organizational and gene expression characteristics of the preferentially affected areas of the network. We performed diffusion-weighted imaging in 100 patients with Parkinson’s disease (81 without hallucinations, 19 with visual hallucinations) and 34 healthy age-matched controls. We used network-based statistics to identify changes in structural connectivity in Parkinson’s disease patients with hallucinations and performed an analysis of controllability, an emerging technique that allows quantification of the influence a brain region has across the rest of the network. Using these techniques, we identified a subnetwork of reduced connectivity in Parkinson’s disease hallucinations. We then used the Allen Institute for Brain Sciences human transcriptome atlas to identify regional gene expression patterns associated with affected areas of the network. Within this network, Parkinson’s disease patients with hallucinations showed reduced controllability (less influence over other brain regions), than Parkinson’s disease patients without hallucinations and controls. This subnetwork appears to be critical for overall brain integration, as even in controls, nodes with high controllability were more likely to be within the subnetwork. Gene expression analysis of gene modules related to the affected subnetwork revealed that down-weighted genes were most significantly enriched in genes related to mRNA and chromosome metabolic processes (with enrichment in oligodendrocytes) and upweighted genes to protein localization (with enrichment in neuronal cells). Our findings provide insights into how hallucinations are generated, with breakdown of a key structural subnetwork that exerts control across distributed brain regions. Expression of genes related to mRNA metabolism and membrane localization may be implicated, providing potential therapeutic targets.

scholarly journals Dynamical consequences of regional heterogeneity in the brain’s transcriptional landscape

2020 ◽  
Author(s):  
Gustavo Deco ◽  
Kevin Aquino ◽  
Aurina Arnatkevičiūtė ◽  
Stuart Oldham ◽  
Kristina Sabaroedin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Large Scale ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Global Gene Expression ◽  
Brain Regions ◽  
Biophysical Model ◽  
Neuronal Dynamics ◽  
Regional Heterogeneity ◽  
Magnetic Resonance Imaging Mri

AbstractBrain regions vary in their molecular and cellular composition, but how this heterogeneity shapes neuronal dynamics is unclear. Here, we investigate the dynamical consequences of regional heterogeneity using a biophysical model of whole-brain functional magnetic resonance imaging (MRI) dynamics in humans. We show that models in which transcriptional variations in excitatory and inhibitory receptor (E:I) gene expression constrain regional heterogeneity more accurately reproduce the spatiotemporal structure of empirical functional connectivity estimates than do models constrained by global gene expression profiles and MRI-derived estimates of myeloarchitecture. We further show that regional heterogeneity is essential for yielding both ignition-like dynamics, which are thought to support conscious processing, and a wide variance of regional activity timescales, which supports a broad dynamical range. We thus identify a key role for E:I heterogeneity in generating complex neuronal dynamics and demonstrate the viability of using transcriptional data to constrain models of large-scale brain function.

scholarly journals Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set

2008 ◽  
Vol 33 (2) ◽  
pp. 240-256 ◽  
Author(s):  
Winnie S. Liang ◽  
Travis Dunckley ◽  
Thomas G. Beach ◽  
Andrew Grover ◽  
Diego Mastroeni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Expression Profiles ◽  
Brain Regions ◽  
Elderly Persons ◽  
Data Set ◽  
Healthy Elderly ◽  
Neuronal Gene ◽  
Laser Capture

Alzheimer's Disease (AD) is the most widespread form of dementia during the later stages of life. If improved therapeutics are not developed, the prevalence of AD will drastically increase in the coming years as the world's population ages. By identifying differences in neuronal gene expression profiles between healthy elderly persons and individuals diagnosed with AD, we may be able to better understand the molecular mechanisms that drive AD pathogenesis, including the formation of amyloid plaques and neurofibrillary tangles. In this study, we expression profiled histopathologically normal cortical neurons collected with laser capture microdissection (LCM) from six anatomically and functionally discrete postmortem brain regions in 34 AD-afflicted individuals, using Affymetrix Human Genome U133 Plus 2.0 microarrays. These regions include the entorhinal cortex, hippocampus, middle temporal gyrus, posterior cingulate cortex, superior frontal gyrus, and primary visual cortex. This study is predicated on previous parallel research on the postmortem brains of the same six regions in 14 healthy elderly individuals, for which LCM neurons were similarly processed for expression analysis. We identified significant regional differential expression in AD brains compared with control brains including expression changes of genes previously implicated in AD pathogenesis, particularly with regard to tangle and plaque formation. Pinpointing the expression of factors that may play a role in AD pathogenesis provides a foundation for future identification of new targets for improved AD therapeutics. We provide this carefully phenotyped, laser capture microdissected intraindividual brain region expression data set to the community as a public resource.

scholarly journals Distinct properties in ventral pallidum projection neuron subtypes

2021 ◽  
Author(s):  
Nimrod Bernat ◽  
Rianne Campbell ◽  
Hyungwoo Nam ◽  
Mahashweta Basu ◽  
Tal Odesser ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Critical Role ◽  
Gene Expression Profiles ◽  
Cell Types ◽  
Projection Neuron ◽  
Brain Regions ◽  
Ventral Pallidum ◽  
Lateral Habenula

The ventral pallidum (VP), a major component of the basal ganglia, plays a critical role in motivational disorders. It sends projections to many different brain regions but it is not yet known whether and how these projections differ in their cellular properties, gene expression patterns, connectivity and role in reward seeking. In this study, we focus on four major outputs of the VP - to the lateral hypothalamus (LH), ventral tegmental area (VTA), mediodorsal thalamus (MDT), and lateral habenula (LHb) - and examine the differences between them in 1) baseline gene expression profiles using projection-specific RNA-sequencing; 2) physiological parameters using whole-cell patch clamp; and 3) their influence on cocaine reward using chemogenetic tools. We show that these four VP efferents differ in all three aspects and highlight specifically differences between the projections to the LH and the VTA. These two projections originate largely from separate populations of neurons, express distinct sets of genes related to neurobiological functions, and show opposite physiological and behavioral properties. Collectively, our data demonstrates for the first time that VP neurons exhibit distinct molecular and cellular profiles in a projection-specific manner, suggesting that they represent different cell types.

scholarly journals Characterizing the temporal dynamics of gene expression in single cells with sci-fate

2019 ◽  
Author(s):  
Junyue Cao ◽  
Wei Zhou ◽  
Frank Steemers ◽  
Cole Trapnell ◽  
Jay Shendure
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Temporal Dynamics ◽  
Single Cells ◽  
Receptor Activation ◽  
State Transitions ◽  
Proof Of Concept ◽  
Transcriptional Dynamics ◽  
A New Technique ◽  
Normal Differentiation

AbstractGene expression programs are dynamic, e.g. the cell cycle, response to stimuli, normal differentiation and development, etc. However, nearly all techniques for profiling gene expression in single cells fail to directly capture the dynamics of transcriptional programs, which limits the scope of biology that can be effectively investigated. Towards addressing this, we developed sci-fate, a new technique that combines S4U labeling of newly synthesized mRNA with single cell combinatorial indexing (sci-), in order to concurrently profile the whole and newly synthesized transcriptome in each of many single cells. As a proof-of-concept, we applied sci-fate to a model system of cortisol response and characterized expression dynamics in over 6,000 single cells. From these data, we quantify the dynamics of the cell cycle and glucocorticoid receptor activation, while also exploring their intersection. We furthermore use these data to develop a framework for inferring the distribution of cell state transitions. We anticipate sci-fate will be broadly applicable to quantitatively characterize transcriptional dynamics in diverse systems.

scholarly journals Cilium Expression Score Predicts Glioma Survival

2021 ◽  
Vol 12 ◽  
Author(s):  
Srinivas Rajagopalan ◽  
Amartya Singh ◽  
Hossein Khiabanian
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Brain Regions ◽  
Poor Survival ◽  
Aggressive Tumors ◽  
Regulated Gene Expression ◽  
Upregulated Genes ◽  
Expression Score

The accurate classification, prognostication, and treatment of gliomas has been hindered by an existing cellular, genomic, and transcriptomic heterogeneity within individual tumors and their microenvironments. Traditional clustering is limited in its ability to distinguish heterogeneity in gliomas because the clusters are required to be exclusive and exhaustive. In contrast, biclustering can identify groups of co-regulated genes with respect to a subset of samples and vice versa. In this study, we analyzed 1,798 normal and tumor brain samples using an unsupervised biclustering approach. We identified co-regulated gene expression profiles that were linked to proximally located brain regions and detected upregulated genes in subsets of gliomas, associated with their histologic grade and clinical outcome. In particular, we present a cilium-associated signature that when upregulated in tumors is predictive of poor survival. We also introduce a risk score based on expression of 12 cilium-associated genes which is reproducibly informative of survival independent of other prognostic biomarkers. These results highlight the role of cilia in development and progression of gliomas and suggest potential therapeutic vulnerabilities for these highly aggressive tumors.

scholarly journals Synaptic polarity and sign-balance prediction using gene expression data in the Caenorhabditis elegans chemical synapse neuronal connectome network

2020 ◽  
Author(s):  
Bánk G. Fenyves ◽  
Gábor S. Szilágyi ◽  
Zsolt Vassy ◽  
Csaba Sőti ◽  
Péter Csermely
Keyword(s):  
Gene Expression ◽  
Caenorhabditis Elegans ◽  
Gene Expression Data ◽  
Temporal Dynamics ◽  
Receptor Gene ◽  
Inhibitory Synapses ◽  
Directed Network ◽  
Chemical Synapse ◽  
Expression Data ◽  
C Elegans

AbstractGraph theoretical analyses of nervous systems usually omit the aspect of connection polarity, due to data insufficiency. The chemical synapse network of Caenorhabditis elegans is a well-reconstructed directed network, but the signs of its connections are yet to be elucidated. Here, we present the gene expression-based sign prediction of the C. elegans connectome, incorporating presynaptic neurotransmitter and postsynaptic receptor gene expression data (3,638 connections and 20,589 synapses total). We made successful predictions for more than two-thirds of all chemical synapses and determined a ratio of excitatory-inhibitory (E:I) interneuronal ionotropic chemical connections close to 4:1 which was found similar to that observed in many real-world networks. Our open source tool (http://EleganSign.linkgroup.hu) is simple but efficient in predicting polarities by integrating neuronal connectome and gene expression data.Author SummaryThe fundamental way neurons communicate is by activating or inhibiting each other via synapses. The balance between the two is crucial for the optimal functioning of a nervous system. However, whole-brain synaptic polarity information is unavailable for any species and experimental validation is challenging. The roundworm Caenorhabditis elegans possesses a fully mapped connectome with a comprehensive gene expression profile of its 302 neurons. Based on the consideration that the polarity of a synapse must be determined by the neurotransmitter(s) expressed in the presynaptic neuron and the receptors expressed in the postsynaptic neuron, we conceptualized and created a tool that predicts synaptic polarities based on connectivity and gene expression information. We were able to show for the first time that the ratio of excitatory and inhibitory synapses in C. elegans is around 4 to 1 which is in line with the balance observed in many natural systems. Our method opens a way to include spatial and temporal dynamics of synaptic polarity that would add a new dimension of plasticity in the excitatory:inhibitory balance. Our tool is freely available to be used on any network accompanied by any expression atlas.

scholarly journals Decoding images in the mind’s eye: The temporal dynamics of visual imagery

2019 ◽  
Author(s):  
Sophia M. Shatek ◽  
Tijl Grootswagers ◽  
Amanda K. Robinson ◽  
Thomas A. Carlson
Keyword(s):  
Mental Imagery ◽  
Visual Processing ◽  
Temporal Dynamics ◽  
Brain Activity ◽  
Brain Regions ◽  
Time Resolved ◽  
Santa Claus ◽  
Physical Stimuli ◽  
Multivariate Pattern ◽  
The Mind

AbstractMental imagery is the ability to generate images in the mind in the absence of sensory input. Both perceptual visual processing and internally generated imagery engage large, overlapping networks of brain regions. However, it is unclear whether they are characterized by similar temporal dynamics. Recent magnetoencephalography work has shown that object category information was decodable from brain activity during mental imagery, but the timing was delayed relative to perception. The current study builds on these findings, using electroencephalography to investigate the dynamics of mental imagery. Sixteen participants viewed two images of the Sydney Harbour Bridge and two images of Santa Claus. On each trial, they viewed a sequence of the four images and were asked to imagine one of them, which was cued retroactively by its temporal location in the sequence. Time-resolved multivariate pattern analysis was used to decode the viewed and imagined stimuli. Our results indicate that the dynamics of imagery processes are more variable across, and within, participants compared to perception of physical stimuli. Although category and exemplar information was decodable for viewed stimuli, there were no informative patterns of activity during mental imagery. The current findings suggest stimulus complexity, task design and individual differences may influence the ability to successfully decode imagined images. We discuss the implications of these results for our understanding of the neural processes underlying mental imagery.

scholarly journals Scopolamine-induced Delirium Promotes Neuroinflammation and Neuropsychiatric Disorder in Mice

2020 ◽  
Author(s):  
So Yeong Cheon ◽  
Bon-Nyeo Koo ◽  
So Yeon Kim ◽  
Eun Hee Kam ◽  
Junhyun Nam ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Cytokines ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Brain Regions ◽  
Mice Model ◽  
Tnf Α ◽  
Compare Gene Expression ◽  
Pro Inflammatory Cytokines

Abstract BackgroundPostoperative delirium is a common neuropsychiatric syndrome resulting in a high postsurgical mortality rate and decline in postdischarge function. Extensive research has been performed on both human and animal delirium models due to their clinical significance, focusing on systemic inflammation and consequent neuroinflammation playing a key in the pathogenesis of postoperative cognitive dysfunctions. Since animal models are widely utilized for pathophysiological study of neuropsychiatric disorders, this study aimed at examining the validity of the scopolamine-induced delirium mice model with respect to the neuroinflammatory hypothesis of delirium. MethodsMale C57BL/6 mice were treated with intraperitoneal scopolamine (2 mg/kg). Neurobehavioural tests were performed to evaluate the changes in cognitive functions, including learning and memory, and the level of anxiety after surgery or scopolamine treatment. The levels of pro-inflammatory cytokines (IL-1ꞵ, IL-18, and TNF-α) and inflammasome components (NLRP3, ASC, and caspase-1) in different brain regions were measured. Gene expression profiles were also examined using whole-genome RNA sequencing analyses to compare gene expression patterns of different mice models.Results Scopolamine treatment showed significant increase in the level of anxiety and impairments in memory and cognitive function associated with increased level of pro-inflammatory cytokines and NLRP3 inflammasome components. Genetic analysis confirmed the different expression patterns of the genes involved in immune response and inflammation and those related with the development of the nervous system in both surgery and scopolamine-induced mice models. Conclusions The scopolamine-induced delirium mice model successfully showed that analogous neuropsychiatric changes coincide with the neuroinflammatory hypothesis for pathogenesis of delirium.

Sign in / Sign up

Export Citation Format

Share Document