Publications by authors named "Alexander Tolpygo"

8 Publications

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ZEBrA: Zebra finch Expression Brain Atlas-A resource for comparative molecular neuroanatomy and brain evolution studies.

J Comp Neurol 2020 08 19;528(12):2099-2131. Epub 2020 Feb 19.

Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon.

An in-depth understanding of the genetics and evolution of brain function and behavior requires a detailed mapping of gene expression in functional brain circuits across major vertebrate clades. Here we present the Zebra finch Expression Brain Atlas (ZEBrA; www.zebrafinchatlas.org, RRID: SCR_012988), a web-based resource that maps the expression of genes linked to a broad range of functions onto the brain of zebra finches. ZEBrA is a first of its kind gene expression brain atlas for a bird species and a first for any sauropsid. ZEBrA's >3,200 high-resolution digital images of in situ hybridized sections for ~650 genes (as of June 2019) are presented in alignment with an annotated histological atlas and can be browsed down to cellular resolution. An extensive relational database connects expression patterns to information about gene function, mouse expression patterns and phenotypes, and gene involvement in human diseases and communication disorders. By enabling brain-wide gene expression assessments in a bird, ZEBrA provides important substrates for comparative neuroanatomy and molecular brain evolution studies. ZEBrA also provides unique opportunities for linking genetic pathways to vocal learning and motor control circuits, as well as for novel insights into the molecular basis of sex steroids actions, brain dimorphisms, reproductive and social behaviors, sleep function, and adult neurogenesis, among many fundamental themes.
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http://dx.doi.org/10.1002/cne.24879DOI Listing
August 2020

Traumatic microbleeds suggest vascular injury and predict disability in traumatic brain injury.

Brain 2019 11;142(11):3550-3564

Center for Neuroscience and Regenerative Medicine, Bethesda, Maryland, USA.

Traumatic microbleeds are small foci of hypointensity seen on T2*-weighted MRI in patients following head trauma that have previously been considered a marker of axonal injury. The linear appearance and location of some traumatic microbleeds suggests a vascular origin. The aims of this study were to: (i) identify and characterize traumatic microbleeds in patients with acute traumatic brain injury; (ii) determine whether appearance of traumatic microbleeds predict clinical outcome; and (iii) describe the pathology underlying traumatic microbleeds in an index patient. Patients presenting to the emergency department following acute head trauma who received a head CT were enrolled within 48 h of injury and received a research MRI. Disability was defined using Glasgow Outcome Scale-Extended ≤6 at follow-up. All magnetic resonance images were interpreted prospectively and were used for subsequent analysis of traumatic microbleeds. Lesions on T2* MRI were stratified based on 'linear' streak-like or 'punctate' petechial-appearing traumatic microbleeds. The brain of an enrolled subject imaged acutely was procured following death for evaluation of traumatic microbleeds using MRI targeted pathology methods. Of the 439 patients enrolled over 78 months, 31% (134/439) had evidence of punctate and/or linear traumatic microbleeds on MRI. Severity of injury, mechanism of injury, and CT findings were associated with traumatic microbleeds on MRI. The presence of traumatic microbleeds was an independent predictor of disability (P < 0.05; odds ratio = 2.5). No differences were found between patients with punctate versus linear appearing microbleeds. Post-mortem imaging and histology revealed traumatic microbleed co-localization with iron-laden macrophages, predominately seen in perivascular space. Evidence of axonal injury was not observed in co-localized histopathological sections. Traumatic microbleeds were prevalent in the population studied and predictive of worse outcome. The source of traumatic microbleed signal on MRI appeared to be iron-laden macrophages in the perivascular space tracking a network of injured vessels. While axonal injury in association with traumatic microbleeds cannot be excluded, recognizing traumatic microbleeds as a form of traumatic vascular injury may aid in identifying patients who could benefit from new therapies targeting the injured vasculature and secondary injury to parenchyma.
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http://dx.doi.org/10.1093/brain/awz290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821371PMC
November 2019

An active texture-based digital atlas enables automated mapping of structures and markers across brains.

Nat Methods 2019 04 11;16(4):341-350. Epub 2019 Mar 11.

Department of Physics, University of California, San Diego, CA, USA.

Brain atlases enable the mapping of labeled cells and projections from different brains onto a standard coordinate system. We address two issues in the construction and use of atlases. First, expert neuroanatomists ascertain the fine-scale pattern of brain tissue, the 'texture' formed by cellular organization, to define cytoarchitectural borders. We automate the processes of localizing landmark structures and alignment of brains to a reference atlas using machine learning and training data derived from expert annotations. Second, we construct an atlas that is active; that is, augmented with each use. We show that the alignment of new brains to a reference atlas can continuously refine the coordinate system and associated variance. We apply this approach to the adult murine brainstem and achieve a precise alignment of projections in cytoarchitecturally ill-defined regions across brains from different animals.
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http://dx.doi.org/10.1038/s41592-019-0328-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736610PMC
April 2019

A high-throughput neurohistological pipeline for brain-wide mesoscale connectivity mapping of the common marmoset.

Elife 2019 02 5;8. Epub 2019 Feb 5.

Laboratory for Marmoset Neural Architecture, RIKEN Center for Brain Science, Wako, Japan.

Understanding the connectivity architecture of entire vertebrate brains is a fundamental but difficult task. Here we present an integrated neuro-histological pipeline as well as a grid-based tracer injection strategy for systematic mesoscale connectivity mapping in the common marmoset (). Individual brains are sectioned into ~1700 20 µm sections using the tape transfer technique, permitting high quality 3D reconstruction of a series of histochemical stains (Nissl, myelin) interleaved with tracer labeled sections. Systematic in-vivo MRI of the individual animals facilitates injection placement into reference-atlas defined anatomical compartments. Further, by combining the resulting 3D volumes, containing informative cytoarchitectonic markers, with in-vivo and ex-vivo MRI, and using an integrated computational pipeline, we are able to accurately map individual brains into a common reference atlas despite the significant individual variation. This approach will facilitate the systematic assembly of a mesoscale connectivity matrix together with unprecedented 3D reconstructions of brain-wide projection patterns in a primate brain.
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http://dx.doi.org/10.7554/eLife.40042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384052PMC
February 2019

Towards a comprehensive atlas of cortical connections in a primate brain: Mapping tracer injection studies of the common marmoset into a reference digital template.

J Comp Neurol 2016 08;524(11):2161-81

Neuroscience Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.

The marmoset is an emerging animal model for large-scale attempts to understand primate brain connectivity, but achieving this aim requires the development and validation of procedures for normalization and integration of results from many neuroanatomical experiments. Here we describe a computational pipeline for coregistration of retrograde tracing data on connections of cortical areas into a 3D marmoset brain template, generated from Nissl-stained sections. The procedure results in a series of spatial transformations that are applied to the coordinates of labeled neurons in the different cases, bringing them into common stereotaxic space. We applied this procedure to 17 injections, placed in the frontal lobe of nine marmosets as part of earlier studies. Visualizations of cortical patterns of connections revealed by these injections are supplied as Supplementary Materials. Comparison between the results of the automated and human-based processing of these cases reveals that the centers of injection sites can be reconstructed, on average, to within 0.6 mm of coordinates estimated by an experienced neuroanatomist. Moreover, cell counts obtained in different areas by the automated approach are highly correlated (r = 0.83) with those obtained by an expert, who examined in detail histological sections for each individual. The present procedure enables comparison and visualization of large datasets, which in turn opens the way for integration and analysis of results from many animals. Its versatility, including applicability to archival materials, may reduce the number of additional experiments required to produce the first detailed cortical connectome of a primate brain. J. Comp. Neurol. 524:2161-2181, 2016. © 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/cne.24023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892968PMC
August 2016

Frequency-selective control of cortical and subcortical networks by central thalamus.

Elife 2015 Dec 10;4:e09215. Epub 2015 Dec 10.

Department of Neurology and Neurological Sciences, Stanford University, Stanford, United States.

Central thalamus plays a critical role in forebrain arousal and organized behavior. However, network-level mechanisms that link its activity to brain state remain enigmatic. Here, we combined optogenetics, fMRI, electrophysiology, and video-EEG monitoring to characterize the central thalamus-driven global brain networks responsible for switching brain state. 40 and 100 Hz stimulations of central thalamus caused widespread activation of forebrain, including frontal cortex, sensorimotor cortex, and striatum, and transitioned the brain to a state of arousal in asleep rats. In contrast, 10 Hz stimulation evoked significantly less activation of forebrain, inhibition of sensory cortex, and behavioral arrest. To investigate possible mechanisms underlying the frequency-dependent cortical inhibition, we performed recordings in zona incerta, where 10, but not 40, Hz stimulation evoked spindle-like oscillations. Importantly, suppressing incertal activity during 10 Hz central thalamus stimulation reduced the evoked cortical inhibition. These findings identify key brain-wide dynamics underlying central thalamus arousal regulation.
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http://dx.doi.org/10.7554/eLife.09215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721962PMC
December 2015

High-Throughput Method of Whole-Brain Sectioning, Using the Tape-Transfer Technique.

PLoS One 2015 16;10(7):e0102363. Epub 2015 Jul 16.

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America.

Cryostat sectioning is a popular but labor-intensive method for preparing histological brain sections. We have developed a modification of the commercially available CryoJane tape collection method that significantly improves the ease of collection and the final quality of the tissue sections. The key modification involves an array of UVLEDs to achieve uniform polymerization of the glass slide and robust adhesion between the section and slide. This report presents system components and detailed procedural steps, and provides examples of end results; that is, 20 μm mouse brain sections that have been successfully processed for routine Nissl, myelin staining, DAB histochemistry, and fluorescence. The method is also suitable for larger brains, such as rat and monkey.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102363PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504703PMC
April 2016

A low-cost technique to cryo-protect and freeze rodent brains, precisely aligned to stereotaxic coordinates for whole-brain cryosectioning.

J Neurosci Methods 2013 Sep 29;218(2):206-13. Epub 2013 Mar 29.

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.

A major challenge in the histological sectioning of brain tissue is achieving accurate alignment in the standard coronal, horizontal, or sagittal planes. Correct alignment is desirable for ease of subsequent analysis and is a prerequisite for computational registration and algorithm-based quantification of experimental data. We have developed a simple and low-cost technique for whole-brain cryosectioning of rodent brains that reliably results in a precise alignment of stereotactic coordinates. The system utilises a 3-D printed model of a mouse brain to create a tailored cavity that is used to align and support the brain during freezing. The alignment of the frozen block is achieved in relation to the fixed edge of the mold. The system also allows for two brains to be frozen and sectioned simultaneously. System components, procedural steps, and examples of the end results are presented.
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http://dx.doi.org/10.1016/j.jneumeth.2013.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4265468PMC
September 2013