scholarly journals MRI of Capn15 knockout mice and analysis of Capn15 distribution reveal possible roles in brain development and plasticity

2019 ◽  
Author(s):  
Congyao Zha ◽  
Carole A Farah ◽  
Vladimir Fonov ◽  
David A. Rudko ◽  
Wayne S Sossin
Keyword(s):  
Brain Development ◽  
Knockout Mice ◽  
Brain Plasticity ◽  
Small Animal ◽  
Cell Types ◽  
Cysteine Proteases ◽  
Brain Regions ◽  
Conditional Knockout ◽  
Specific Cell ◽  
The Brain

AbstractPurposeThe non-classical Small Optic Lobe (SOL) family of calpains are intracellular cysteine proteases that are expressed in the nervous system and appear to play an important role in neuronal development in both Drosophila, where loss of this calpain leads to the eponymous small optic lobes, and in mouse and human, where loss of this calpain (Capn15) leads to eye anomalies. However, the brain regions where this calpain is expressed and the areas most affected by the loss of this calpain have not been carefully examined.ProceduresWe utilize an insert strain where lacZ is expressed under the control of the Capn15 promoter, together with immunocytochemistry with markers of specific cell types to address where Capn 15 is expressed in the brain. We use small animal MRI comparing WT, Capn15 knockout and Capn15 conditional knockout mice to address the brain regions that are affected when Capn 15 is not present, either in early development of the adult.ResultsCapn15 is expressed in diverse brain regions, many of them involved in plasticity such as the hippocampus, lateral amygdala and Purkinje neurons. Capn15 knockout mice have smaller brains, and present specific deficits in the thalamus and hippocampal regions. There are no deficits revealed by MRI in brain regions when Capn15 is knocked out after development.ConclusionsAreas where Capn15 is expressed in the adult are not good markers for the specific regions where the loss of Capn15 specifically affects brain development. Thus, it is likely that this calpain plays distinct roles in brain development and brain plasticity.

scholarly journals The architecture of brain co-expression reveals the brain-wide basis of disease susceptibility

2020 ◽  
Author(s):  
CL Hartl ◽  
G Ramaswami ◽  
WG Pembroke ◽  
S Muller ◽  
G Pintacuda ◽  
...  
Keyword(s):  
Gene Networks ◽  
Regulatory Networks ◽  
Disease Risk ◽  
Cell Types ◽  
Brain Regions ◽  
Specific Cell ◽  
Risk Variants ◽  
Normal Individuals ◽  
Broad Array ◽  
The Brain

AbstractGene networks have proven their utility for elucidating transcriptome structure in the brain, yielding numerous biological insights. Most analyses have focused on expression relationships within a circumspect number of regions – how these relationships vary across a broad array of brain regions is largely unknown. By leveraging RNA-sequencing in 864 samples representing 12 brain regions in a cohort of 131 phenotypically normal individuals, we identify 12 brain-wide, 114 region-specific, and 50 cross-regional co-expression modules. We replicate the majority (81%) of modules in regional microarray datasets. Nearly 40% of expressed genes fall into brain-wide modules corresponding to major cell classes and conserved biological processes. Region-specific modules comprise 25% of expressed genes and correspond to region-specific cell types and processes, such as oxytocin signaling in the hypothalamus, or addiction pathways in the nucleus accumbens. We further leverage these modules to capture cell-type-specific lncRNA and gene isoforms, both of which contribute substantially to regional synaptic diversity. We identify enrichment of neuropsychiatric disease risk variants in brain wide and multi-regional modules, consistent with their broad impact on cell classes, and highlight specific roles in neuronal proliferation and activity-dependent processes. Finally, we examine the manner in which gene co-expression and gene regulatory networks reflect genetic risk, including the recently framed omnigenic model of disease architecture.

scholarly journals Location Matters: Navigating Regional Heterogeneity of the Neurovascular Unit

2021 ◽  
Vol 15 ◽  
Author(s):  
Louis-Philippe Bernier ◽  
Clément Brunner ◽  
Azzurra Cottarelli ◽  
Matilde Balbi
Keyword(s):  
Brain Function ◽  
Energy Demand ◽  
Neurovascular Unit ◽  
Cell Types ◽  
Brain Regions ◽  
Regional Heterogeneity ◽  
Regional Specialization ◽  
Multiple Cell ◽  
Cellular Components ◽  
The Brain

The neurovascular unit (NVU) of the brain is composed of multiple cell types that act synergistically to modify blood flow to locally match the energy demand of neural activity, as well as to maintain the integrity of the blood-brain barrier (BBB). It is becoming increasingly recognized that the functional specialization, as well as the cellular composition of the NVU varies spatially. This heterogeneity is encountered as variations in vascular and perivascular cells along the arteriole-capillary-venule axis, as well as through differences in NVU composition throughout anatomical regions of the brain. Given the wide variations in metabolic demands between brain regions, especially those of gray vs. white matter, the spatial heterogeneity of the NVU is critical to brain function. Here we review recent evidence demonstrating regional specialization of the NVU between brain regions, by focusing on the heterogeneity of its individual cellular components and briefly discussing novel approaches to investigate NVU diversity.

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 The HIV-1 Transgenic Rat: Relevance for HIV Noninfectious Comorbidity Research

2020 ◽  
Vol 8 (11) ◽  
pp. 1643
Author(s):  
Frank Denaro ◽  
Francesca Benedetti ◽  
Myla D. Worthington ◽  
Giovanni Scapagnini ◽  
Christopher C. Krauss ◽  
...  
Keyword(s):  
Neuronal Degeneration ◽  
Cell Types ◽  
Transgenic Rat ◽  
Specific Cell ◽  
Rat Tissues ◽  
Local Production ◽  
Specific Tissue ◽  
Effective Models ◽  
The Brain ◽  
Hiv 1

HIV noninfectious comorbidities (NICMs) are a current healthcare challenge. The situation is further complicated as there are very few effective models that can be used for NICM research. Previous research has supported the use of the HIV-1 transgenic rat (HIV-1TGR) as a model for the study of HIV/AIDS. However, additional studies are needed to confirm whether this model has features that would support NICM research. A demonstration of the utility of the HIV-1TGR model would be to show that the HIV-1TGR has cellular receptors able to bind HIV proteins, as this would be relevant for the study of cell-specific tissue pathology. In fact, an increased frequency of HIV receptors on a specific cell type may increase tissue vulnerability since binding to HIV proteins would eventually result in cell dysfunction and death. Evidence suggests that observations of selective cellular vulnerability in this model are consistent with some specific tissue vulnerabilities seen in NICMs. We identified CXCR4-expressing cells in the brain, while specific markers for neuronal degeneration demonstrated that the same neural types were dying. We also confirm the presence of gp120 and Tat by immunocytochemistry in the spleen, as previously reported. However, we observed very rare positive cells in the brain. This underscores the point that gp120, which has been reported as detected in the sera and CSF, is a likely source to which these CXCR4-positive cells are exposed. This alternative appears more probable than the local production of gp120. Further studies may indicate some level of local production, but that will not eliminate the role of receptor-mediated pathology. The binding of gp120 to the CXCR4 receptor on neurons and other neural cell types in the HIV-1TGR can thus explain the phenomena of selective cell death. Selective cellular vulnerability may be a contributing factor to the development of NICMs. Our data indicate that the HIV-1TGR can be an effective model for the studies of HIV NICMs because of the difference in the regional expression of CXCR4 in rat tissues, thus leading to specific organ pathology. This also suggests that the model can be used in the development of therapeutic options.

Three-Dimensional Time-Lapse Digital Movie Analysis of the Developing Fruit Fly Eye in Organ Culture

1997 ◽  
Vol 3 (S2) ◽  
pp. 1129-1130
Author(s):  
John Archie Pollock ◽  
Bejon T. Maneckshana ◽  
Teresa E. Leonardo
Keyword(s):  
Organ Culture ◽  
Compound Eye ◽  
Eye Development ◽  
Larval Instar ◽  
Three Dimensional ◽  
Fruit Fly ◽  
Time Lapse ◽  
Cell Types ◽  
Specific Cell ◽  
The Brain

The compound eye of the fruit fly, Drosophila melanogaster, is composed of a highly ordered array of facets (FIG. 1), each containing a precise set of neurons and supporting cells. The eye arises during the third larval instar from an undifferentiated epithelium, the eye imaginai disc, which is connected to the brain via the optic stalk (FIG. 2). During eye development, movement of the morphogenetic furrow, progressive recruitment of specific cell types and the growth of photoreceptor axons into the brain are each dynamic processes that are routinely studied indirectly in fixed tissues. While stereotyped development and the ‘crystalline’ like structure of the eye facilitates this analysis, certain experiments are hindered by the inability to observe developmental processes as they occur. To overcome this limitation, we have combined organ culture with advanced microscopy tools to enable the observation of eye development in living tissue.

scholarly journals The Presence of Human Herpesvirus 6 in the Brain in Health and Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1520
Author(s):  
Gabriel Santpere ◽  
Marco Telford ◽  
Pol Andrés-Benito ◽  
Arcadi Navarro ◽  
Isidre Ferrer
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Current Knowledge ◽  
Human Herpesvirus ◽  
Brain Regions ◽  
Specific Cell ◽  
Human Herpesvirus 6 ◽  
Detection Techniques ◽  
Herpesvirus 6 ◽  
The Brain

The human herpesvirus 6 (HHV‐6) ‐A and ‐B are two dsDNA beta‐herpesviruses infectingalmost the entire worldwide population. These viruses have been implicated in multipleneurological conditions in individuals of various ages and immunological status, includingencephalitis, epilepsy, and febrile seizures. HHV‐6s have also been suggested as playing a role inthe etiology of neurodegenerative diseases such as multiple sclerosis and Alzheimer’s disease. Theapparent robustness of these suggested associations is contingent on the accuracy of HHV‐6detection in the nervous system. The effort of more than three decades of researching HHV‐6 in thebrain has yielded numerous observations, albeit using variable technical approaches in terms oftissue preservation, detection techniques, sample sizes, brain regions, and comorbidities. In thisreview, we aimed to summarize current knowledge about the entry routes and direct presence ofHHV‐6 in the brain parenchyma at the level of DNA, RNA, proteins, and specific cell types, inhealthy subjects and in those with neurological conditions. We also discuss recent findings relatedto the presence of HHV‐6 in the brains of patients with Alzheimer’s disease in light of availableevidence.

scholarly journals Regulation and Modulation of pH in the Brain

2003 ◽  
Vol 83 (4) ◽  
pp. 1183-1221 ◽  
Author(s):  
MITCHELL CHESLER
Keyword(s):  
Intracellular Ph ◽  
Neural Activity ◽  
Extracellular Fluid ◽  
Cell Types ◽  
Brain Regions ◽  
Metabolic Products ◽  
Homeostatic Function ◽  
Acid Extrusion ◽  
Activity Dependent ◽  
The Brain

Chesler, Mitchell. Regulation and Modulation of pH in the Brain. Physiol Rev 83: 1183-1221, 2003; 10.1152/physrev.00010.2003.—The regulation of pH is a vital homeostatic function shared by all tissues. Mechanisms that govern H+ in the intracellular and extracellular fluid are especially important in the brain, because electrical activity can elicit rapid pH changes in both compartments. These acid-base transients may in turn influence neural activity by affecting a variety of ion channels. The mechanisms responsible for the regulation of intracellular pH in brain are similar to those of other tissues and are comprised principally of forms of Na+/H+ exchange, Na+-driven Cl-/HCO3- exchange, Na+-HCO3- cotransport, and passive Cl-/HCO3- exchange. Differences in the expression or efficacy of these mechanisms have been noted among the functionally and morphologically diverse neurons and glial cells that have been studied. Molecular identification of transporter isoforms has revealed heterogeneity among brain regions and cell types. Neural activity gives rise to an assortment of extracellular and intracellular pH shifts that originate from a variety of mechanisms. Intracellular pH shifts in neurons and glia have been linked to Ca2+ transport, activation of acid extrusion systems, and the accumulation of metabolic products. Extracellular pH shifts can occur within milliseconds of neural activity, arise from an assortment of mechanisms, and are governed by the activity of extracellular carbonic anhydrase. The functional significance of these compartmental, activity-dependent pH shifts is discussed.

scholarly journals Unique Glycan Signatures Regulate Adeno-Associated Virus Tropism in the Developing Brain

2015 ◽  
Vol 89 (7) ◽  
pp. 3976-3987 ◽  
Author(s):  
Giridhar Murlidharan ◽  
Travis Corriher ◽  
H. Troy Ghashghaei ◽  
Aravind Asokan
Keyword(s):  
Polysialic Acid ◽  
Cell Types ◽  
Developing Brain ◽  
Specific Cell ◽  
Developmentally Regulated ◽  
Transport Pathways ◽  
Adeno Associated Virus ◽  
Viral Transport ◽  
The Central Nervous System ◽  
The Brain

ABSTRACTAdeno-associated viruses (AAV) are thought to spread through the central nervous system (CNS) by exploiting cerebrospinal fluid (CSF) flux and hijacking axonal transport pathways. The role of host receptors that mediate these processes is not well understood. In the current study, we utilized AAV serotype 4 (AAV4) as a model to evaluate whether ubiquitously expressed 2,3-linked sialic acid and the developmentally regulated marker 2,8-linked polysialic acid (PSA) regulate viral transport and tropism in the neonatal brain. Modulation of the levels of SA and PSA in cell culture studies using specific neuraminidases revealed possibly opposing roles of the two glycans in AAV4 transduction. Interestingly, upon intracranial injection into lateral ventricles of the neonatal mouse brain, a low-affinity AAV4 mutant (AAV4.18) displayed a striking shift in cellular tropism from 2,3-linked SA+ependymal lining to 2,8-linked PSA+migrating progenitors in the rostral migratory stream and olfactory bulb. In addition, this gain-of-function phenotype correlated with robust CNS spread of AAV4.18 through paravascular transport pathways. Consistent with these observations, altering glycan dynamics within the brain by coadministering SA- and PSA-specific neuraminidases resulted in striking changes to the cellular tropisms and transduction efficiencies of both parental and mutant vectors. We postulate that glycan signatures associated with host development can be exploited to redirect novel AAV vectors to specific cell types in the brain.IMPORTANCEViruses invade the CNS through various mechanisms. In the current study, we utilized AAV as a model to study the dynamics of virus-carbohydrate interactions in the developing brain and their impact on viral tropism. Our findings suggest that carbohydrate content can be exploited to regulate viral transport and tropism in the brain.

scholarly journals Thermodynamic Measures of Human Brain Development from Fetal Stage to Adulthood

2019 ◽  
Author(s):  
Edward A. Rietman ◽  
Sophie Taylor ◽  
Hava T. Siegelmann ◽  
Marco Cavaglia ◽  
Jack A. Tuszynski
Keyword(s):  
Free Energy ◽  
Brain Development ◽  
Gibbs Free Energy ◽  
Protein Interaction ◽  
Brain Regions ◽  
Protein Interaction Networks ◽  
Interaction Networks ◽  
Protein Protein Interaction ◽  
Protein Protein Interaction Networks ◽  
The Brain

AbstractThis paper analyzes the data obtained from tissue samples of the human brains containing protein expression values. The data have been processed for their thermodynamic measure in terms of the Gibbs free energy of the corresponding protein-protein interaction networks. We have investigated the functional dependence of the Gibbs free energies on age and found consistent trends for most of the 16 main brain areas. The peak of the Gibbs energy values is found at birth with a trend toward plateauing at the age of maturity. We have also compared the data for males and females and uncovered functional differences for some of the brain regions.Significance StatementIn this paper we briefly outline the theoretical basis for a novel analysis of brain development in terms of a thermodynamic measure (Gibbs free energy) for the corresponding protein-protein interaction networks. We analyzed the overall developmental patterns for Gibbs free energy as a function of age across all brain regions. Of particular note was the significant upward trend in the fetal stages, which is generally followed by a sharp dip at birth and a plateau at maturity. We then compared the trends for female and male samples. A crossover pattern was observed for most of the brain regions, where the Gibbs free energy of the male samples were lower than the female samples at prenatal and neonatal ages, but higher at ages 8-40.

scholarly journals Chemical targeting of voltage sensitive dyes to specific cell types in the brain

2020 ◽  
Author(s):  
Tomas Fiala ◽  
Jihang Wang ◽  
Matthew Dunn ◽  
Se Joon Choi ◽  
Peter Sebej ◽  
...  
Keyword(s):  
Cell Types ◽  
Specific Cell ◽  
Voltage Sensitive Dyes ◽  
The Brain
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