scholarly journals Physical positioning markedly enhances brain transduction after intrathecal AAV9 infusion

2018 ◽  
Vol 4 (11) ◽  
pp. eaau9859 ◽  
Author(s):  
Michael J. Castle ◽  
Yuhsiang Cheng ◽  
Aravind Asokan ◽  
Mark H. Tuszynski
Keyword(s):  
Gene Expression ◽  
Gene Delivery ◽  
Neurological Disorders ◽  
Fold Increase ◽  
Brain Regions ◽  
Intrathecal Administration ◽  
Simple Method ◽  
Virus Serotype ◽  
Cortical Regions ◽  
The Brain

Several neurological disorders may benefit from gene therapy. However, even when using the lead vector candidate for intrathecal administration, adeno-associated virus serotype 9 (AAV9), the strength and distribution of gene transfer to the brain are inconsistent. On the basis of preliminary observations that standard intrathecal AAV9 infusions predominantly drive reporter gene expression in brain regions where gravity might cause cerebrospinal fluid to settle, we tested the hypothesis that counteracting vector “settling” through animal positioning would enhance vector delivery to the brain. When rats are either inverted in the Trendelenburg position or continuously rotated after intrathecal AAV9 infusion, we find (i) a significant 15-fold increase in the number of transduced neurons, (ii) a marked increase in gene delivery to cortical regions, and (iii) superior animal-to-animal consistency of gene expression. Entorhinal, prefrontal, frontal, parietal, hippocampal, limbic, and basal forebrain neurons are extensively transduced: 95% of transduced cells are neurons, and greater than 70% are excitatory. These findings provide a novel and simple method for broad gene delivery to the cortex and are of substantial relevance to translational programs for neurological disorders, including Alzheimer’s disease and related dementias, stroke, and traumatic brain injury.

scholarly journals Sequence Alterations of Cortical Genes Linked to Individual Connectivity of the Human Brain

2018 ◽  
Vol 29 (9) ◽  
pp. 3828-3835 ◽  
Author(s):  
Qilong Xin ◽  
Laura Ortiz-Terán ◽  
Ibai Diez ◽  
David L Perez ◽  
Julia Ginsburg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Functional Connectivity ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Brain Regions ◽  
Genetic Sequence ◽  
Cortical Areas ◽  
Cortical Regions ◽  
High Degree ◽  
The Brain

Abstract Individual differences in humans are driven by unique brain structural and functional profiles, presumably mediated in part through differential cortical gene expression. However, the relationships between cortical gene expression profiles and individual differences in large-scale neural network organization remain poorly understood. In this study, we aimed to investigate whether the magnitude of sequence alterations in regional cortical genes mapped onto brain areas with high degree of functional connectivity variability across individuals. First, human genetic expression data from the Allen Brain Atlas was used to identify protein-coding genes associated with cortical areas, which delineated the regional genetic signature of specific cortical areas based on sequence alteration profiles. Thereafter, we identified brain regions that manifested high degrees of individual variability by using test-retest functional connectivity magnetic resonance imaging and graph-theory analyses in healthy subjects. We found that rates of genetic sequence alterations shared a distinct spatial topography with cortical regions exhibiting individualized (highly-variable) connectivity profiles. Interestingly, gene expression profiles of brain regions with highly individualized connectivity patterns and elevated number of sequence alterations are devoted to neuropeptide-signaling-pathways and chemical-synaptic-transmission. Our findings support that genetic sequence alterations may underlie important aspects of brain connectome individualities in humans. Significance Statement: The neurobiological underpinnings of our individuality as humans are still an unsolved question. Although the notion that genetic variation drives an individual’s brain organization has been previously postulated, specific links between neural connectivity and gene expression profiles have remained elusive. In this study, we identified the magnitude of population-based sequence alterations in discrete cortical regions and compared them to the brain topological distribution of functional connectivity variability across an independent human sample. We discovered that brain regions with high degree of connectional individuality are defined by increased rates of genetic sequence alterations; these findings specifically implicated genes involved in neuropeptide-signaling pathways and chemical-synaptic transmission. These observations support that genetic sequence alterations may underlie important aspects of the emergence of the brain individuality across humans.

scholarly journals Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer’s disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Angela M. Crist ◽  
Kelly M. Hinkle ◽  
Xue Wang ◽  
Christina M. Moloney ◽  
Billie J. Matchett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Digital Pathology ◽  
Selective Vulnerability ◽  
Brain Regions ◽  
Biochemical Analyses ◽  
The Brain ◽  
Relevant Gene ◽  
Tau Expression

AbstractSelective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer’s disease (AD), however the degree of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5, RYBP, SLC38A2, FEM1B, and PYDC1. Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression.

scholarly journals Transcriptomic analysis of frontotemporal lobar degeneration with TDP-43 pathology reveals cellular alterations across multiple brain regions

2021 ◽  
Author(s):  
Rahat Hasan ◽  
Jack Humphrey ◽  
Conceicao Bettencourt ◽  
Tammaryn Lashley ◽  
Pietro Fratta ◽  
...  
Keyword(s):  
Gene Expression ◽  
Frontotemporal Lobar Degeneration ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Temporal Cortex ◽  
Neuronal Loss ◽  
Underlying Disease ◽  
Brain Regions ◽  
Neuronal Markers ◽  
The Brain

Frontotemporal lobar degeneration (FTLD) is a group of heterogeneous neurodegenerative disorders affecting the frontal and temporal lobes of the brain. Nuclear loss and cytoplasmic aggregation of the RNA-binding protein TDP-43 represents the major FTLD pathology, known as FTLD-TDP. To date, there is no effective treatment for FTLD-TDP due to an incomplete understanding of the molecular mechanisms underlying disease development. Here we compared post-mortem tissue RNA-seq transcriptomes from the frontal cortex, temporal cortex and cerebellum between 28 controls and 30 FTLD-TDP patients to profile changes in cell-type composition, gene expression and transcript usage. We observed downregulation of neuronal markers in all three regions of the brain, accompanied by upregulation of microglia, astrocytes, and oligodendrocytes, as well as endothelial cells and pericytes, suggesting shifts in both immune activation and within the vasculature. We validate our estimates of neuronal loss using neuropathological atrophy scores and show that neuronal loss in the cortex can be mainly attributed to excitatory neurons, and that increases in microglial and endothelial cell expression are highly correlated with neuronal loss. All our analyses identified a strong involvement of the cerebellum in the neurodegenerative process of FTLD-TDP. Altogether, our data provides a detailed landscape of gene expression alterations to help unravel relevant disease mechanisms in FTLD.

Brain Penetration of Intrathecal Iomeprol in Dogs

1996 ◽  
Vol 37 (3P2) ◽  
pp. 578-581 ◽  
Author(s):  
A. La Noce ◽  
P. Lorenzon ◽  
F. Pugliese ◽  
G. Pellecchi ◽  
I. Orlandini ◽  
...  
Keyword(s):  
Contrast Media ◽  
Contrast Agent ◽  
Nervous Tissue ◽  
Brain Structures ◽  
Brain Regions ◽  
Intrathecal Administration ◽  
Brain Penetration ◽  
Tissue Density ◽  
The Brain

Purpose: Iomeprol, a new nonionic iodinated compound for intravascular use, is being evaluated as a myelographic contrast agent because of its low neurotoxicity. This study aimed to assess the degree of brain penetration of iomeprol after intrathecal administration. Material and Methods: Brain penetration in dogs was investigated by CT and compared with that of iopamidol, iohexol, and ioversol, currently used as myelographic contrast media (CM). Nervous tissue density was determined in different brain structures by recording Hounsfield values. Results: The experiments revealed that CM diffused from the cisternae into the parenchyma, reaching a maximum at 5–24 h after injection. The density of the examined brain regions was still higher than the preinjection levels 24 h later. No differences in brain penetration were observed among the CM investigated. Conclusion: The study has shown that iomeprol penetrates into the brain to the same extent as the most widely used myelographic CM.

scholarly journals Functional neuroanatomy of intuitive physical inference

2016 ◽  
Vol 113 (34) ◽  
pp. E5072-E5081 ◽  
Author(s):  
Jason Fischer ◽  
John G. Mikhael ◽  
Joshua B. Tenenbaum ◽  
Nancy Kanwisher
Keyword(s):  
Action Planning ◽  
Brain Regions ◽  
Physical Structure ◽  
Functional Neuroanatomy ◽  
Physical Content ◽  
Structure And Dynamics ◽  
Close Relationship ◽  
Cortical Regions ◽  
Intuitive Grasp ◽  
The Brain

To engage with the world—to understand the scene in front of us, plan actions, and predict what will happen next—we must have an intuitive grasp of the world’s physical structure and dynamics. How do the objects in front of us rest on and support each other, how much force would be required to move them, and how will they behave when they fall, roll, or collide? Despite the centrality of physical inferences in daily life, little is known about the brain mechanisms recruited to interpret the physical structure of a scene and predict how physical events will unfold. Here, in a series of fMRI experiments, we identified a set of cortical regions that are selectively engaged when people watch and predict the unfolding of physical events—a “physics engine” in the brain. These brain regions are selective to physical inferences relative to nonphysical but otherwise highly similar scenes and tasks. However, these regions are not exclusively engaged in physical inferences per se or, indeed, even in scene understanding; they overlap with the domain-general “multiple demand” system, especially the parts of that system involved in action planning and tool use, pointing to a close relationship between the cognitive and neural mechanisms involved in parsing the physical content of a scene and preparing an appropriate action.

scholarly journals Rhes protein transits from neuron to neuron and facilitates mutant huntingtin spreading in the brain.

2021 ◽  
Author(s):  
Uri Nimrod Ramirez Jarquin ◽  
Manish Sharma ◽  
Neelam Shahani ◽  
Yunqing Li ◽  
Siddaraju Boregowda ◽  
...  
Keyword(s):  
Protein Transport ◽  
Brain Slices ◽  
Brain Regions ◽  
Medium Spiny Neurons ◽  
Striatal Neurons ◽  
Spiny Neurons ◽  
Tunneling Nanotube ◽  
Intact Brain ◽  
Cortical Regions ◽  
The Brain

Rhes (RASD2) is a thyroid hormone-induced gene that regulates striatal motor activity and promotes neurodegeneration in Huntington disease (HD) and tauopathy. Previously, we showed that Rhes moves between cultured striatal neurons and transports the HD protein, polyglutamine-expanded huntingtin (mHTT) via tunneling nanotube (TNT)-like membranous protrusions. However, similar intercellular Rhes transport has not yet been demonstrated in the intact brain. Here, we report that Rhes induces TNT-like protrusions in the striatal medium spiny neurons (MSNs) and transported between dopamine-1 receptor (D1R)-MSNs and D2R-MSNs of intact striatum and organotypic brain slices. Notably, mHTT is robustly transported within the striatum and from the striatum to the cortical areas in the brain, and Rhes deletion diminishes such transport. Moreover, we also found transport of Rhes to the cortical regions following restricted expression in the MSNs of the striatum. Thus, Rhes is a first striatum-enriched protein demonstrated to move and transport mHTT between neurons and brain regions, providing new insights on interneuronal protein transport in the brain.

scholarly journals Royal Jelly Acid, 10-Hydroxy-Trans-2-Decenoic Acid,for Psychiatric and Neurological Disorders: How helpful could it be?!

2019 ◽  
pp. 1-4 ◽  
Author(s):  
Mohammed Ali Amira ◽  
Omar Hendawy Amin
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Molecular Mechanism ◽  
Neurological Disorders ◽  
Royal Jelly ◽  
Decenoic Acid ◽  
Lipid Component ◽  
Main Fatty Acid ◽  
Anti Inflammatory ◽  
The Brain

10-hydroxy-trans-2-decenoic acid (10H2DA), also known as royal jelly acid, is the main lipid component of RJ. It possesses anti-tumor, neurogenic, anti-inflammatory, antioxidant, bactericidal, nematocidal, and estrogen-like properties. A limited number of studies demonstrate the potentials of its main fatty acid, 10-H2DA, for alleviating anxiety and depressive-like behaviors as well as for enhancing neuronal functioning. However, the exact mechanism through which 10-H2DA produces its effect is not well-understood. This mini review gives examples of how 10H2DA might positively contribute to the treatment of psychiatric and neurological disorders. In addition, it surveys the available knowledge about the molecular mechanism through which it regulates transcriptional processes and gene expression in the brain.

scholarly journals Ultrasound-Mediated Blood-Brain Barrier Opening Improves Whole Brain Gene Delivery in Mice

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1245
Author(s):  
Marie-Solenne Felix ◽  
Emilie Borloz ◽  
Khaled Metwally ◽  
Ambre Dauba ◽  
Benoit Larrat ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Fold Increase ◽  
Brain Barrier ◽  
Whole Brain ◽  
External Threats ◽  
Blood Brain ◽  
The Brain

Gene therapy represents a powerful therapeutic tool to treat diseased tissues and provide a durable and effective correction. The central nervous system (CNS) is the target of many gene therapy protocols, but its high complexity makes it one of the most difficult organs to reach, in part due to the blood-brain barrier that protects it from external threats. Focused ultrasound (FUS) coupled with microbubbles appears as a technological breakthrough to deliver therapeutic agents into the CNS. While most studies focus on a specific targeted area of the brain, the present work proposes to permeabilize the entire brain for gene therapy in several pathologies. Our results show that, after i.v. administration and FUS sonication in a raster scan manner, a self-complementary AAV9-CMV-GFP vector strongly and safely infected the whole brain of mice. An increase in vector DNA (19.8 times), GFP mRNA (16.4 times), and GFP protein levels (17.4 times) was measured in whole brain extracts of FUS-treated GFP injected mice compared to non-FUS GFP injected mice. In addition to this increase in GFP levels, on average, a 7.3-fold increase of infected cells in the cortex, hippocampus, and striatum was observed. No side effects were detected in the brain of treated mice. The combining of FUS and AAV-based gene delivery represents a significant improvement in the treatment of neurological genetic diseases.

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