Home | Math
RESOURCE CORE: Registration And HistologyBrain functions arise from the coordinated activity of many brain regions which communicate by anatomically specific pathways. In this way local circuit processing by multiple far-flung areas, communicating with one another, lead in the aggregate to the processing of events and the generation of behavior. A full understanding that process requires levels of explanation at multiple levels: neural processing in any particular region, and how that region fits into brain-wide networks.In the study of working memory, animal models are valuable because they allow both function and anatomy to be probed with high resolution. Human studies provide the clinical relevance and identify key questions and phenomena, but only in nonhuman animals can activity and connectivity be probed routinely at a cellular level.This core facility will serve several essential functions in building a broad integrative framework for the program project. First, the facility will support the registration of observed areas in an anatomical framework that includes connectivity and functional significance. Second, the facility will support long-distance, transsynaptic tracing to identify paths of connectivity through which information is conveyed between distant brain regions that are involved in evidence accumulation. Third, the facility will organize this information in a relational database that links all experiments done by the collaborating laboratories, and in a format that can be coordinated with in the entire neuroscience research community. Taken together, these functions are essential in placing recorded and perturbed neural activity into a brainwide anatomical context. The Registration and Histology resource core will rely on a combination of classical and newer technologies, which will be organized according to the following three major goals:Goal 1: Register brains and automate cell recognition. Using methods for nonlinear stretching of images of brain sections, all recorded and perturbed brain regions in this U19 project will be placed in anatomical context. Automated cell recognition methods will be used to survey both directly imaged regions and indirectly connected regions, and classify neurons and other objects of interest. These methods will be applied to images gathered using light-sheet microscopy and two-photon tomography.Goal 2: Identify tracts and pathways using virus-based methods. We will build the capability to trace pathways using viruses whose tracing properties are directional and controlled. Using a viral core facility that is already in house, we will use viruses that are retrograde single-step (weakened rabies, retro-AAV) and multi-step (pseudorabies) as well as anterograde (herpes simplex virus strain H129). These viruses will drive the expression of labels that can be visualized and quantified.`Goal 3: Build anatomical datasets and integrate them with functional in vivo experiments. Light-sheet microscopic capabilities will be combined with clearing methods such as iDISCO and enhanced to allow rapid-throughput scanning of entire brains. Automated cell counting methods will be used to quantify the strength and location of pathways that are connected to the site of recording or perturbation.As technologies for registration and tracing advance over time, this core facility will keep up by acquiring the new technology. The capabilities of this Core require the services of two full-time personnel, one to perform labeling and imaging, and one to perform alignment, registration, and database construction and management.The ultimate service of this Core will be to reveal where the one brain region's activity is projected in distal sites, as well as which cell types and distal sites provide influence that impacts the region. This service will be used on a routine basis in experiments done by all the collaborators.Background and SignificanceOur initial approach to locating brain regions for recording and perturbation has been to use stereotaxic coordinates and functional optical imaging. This approach does not take full advantage of the tremendous effort that has been put into mapping the connectivity of brain regions. The combination of the Allen Brain Atlas and long-distance connectivity mapping has provided a recent expansion in the amount of detailed anatomical information available for registering our physiological data. We will use classical and modern methods of characterizing regions and pathways to place our obsevations in a brain-wide functional context. Consider the following example: Our observations of cerebellar requirements for evidence accumulation are based on lobule-specific perturbations and imaging. Yet it is known that the cerebellar cortex is divided not just into lobules, but parasagittal slabs of circuitry known as microzones. These microzones, which were defined first according to their alternating antigenicity for the protein zebrin, are important units of function because they tend to be associated with specific parts of the inferior olive, a principal source of instructive signals; and deep nuclei, the output of the cerebellum. The deep nuclei project in turn to specific regions of midbrain and neocortex. For these reasons, cerebellum appears to be parcellated in a manner that maps to the parcellation of neocortex. And in crus I, where we have seen reward error-related signals, one of those microzones strongly and specifically influences prefrontal cortex. It would be invaluable to know whether reward signals in cerebellum reach the prefrontal cortex.Such orderly maps have emerged throughout the brain, and are starting to be mapped in detail. The discovery and characterization of these long-distance mappings has been hampered in the past by an inability to trace a neuron beyond its axonal or dendritic terminations. However, this difficulty has been overcome in recent years thanks to the advent of virus-based directional and transsynaptic tracers. Viruses have now entered common use that are specifically taken up by axon terminals and transported retrogradely within a single neuron (retro-adeno-associated-virus, or retro-AAV), across one synapse ("Callaway" rabies virus), or across multiple synapses (pseudorabies virus, PRV); or anterogradely across multiple synapses (herpes simplex virus variant H129, or HSV-H129). These viruses are currently in use at Princeton for the purpose of identifying targets and partners of forebrain, midbrain, and cerebellar regions of interest.114306517005Figure X, Registration procedure. Original stacks of cleared brain tissue (left) will be brought into register with an Allen Brain Atlas reference frame through a series of rigid, affine, and B-spline stretches. The resulting alignment (right) has a median registration error of less than 0.2 mm.00Figure X, Registration procedure. Original stacks of cleared brain tissue (left) will be brought into register with an Allen Brain Atlas reference frame through a series of rigid, affine, and B-spline stretches. The resulting alignment (right) has a median registration error of less than 0.2 mm.A second wave of mapping-enabling technology consists of microscopies that can scan large volumes of brain tissue without need for aligning sections to recover the volume of interest. One such technology is light-sheet microscopy, which can image fluorescence from tissue samples that rendered near-transparent by processes such as iDISCO. Another technology is fluorescence two-photon tomography, in which successive block faces are imaged after removal of one section at a time, thus eliminating the alignment problem and allowing automated volumetric recovery. In both cases, a roughly-aligned whole brain volume can be obtained in under a day, several orders of magnitude faster than sectioning-based techniques.The combination of viral tracing and high-throughput volume microscopy creates a considerable data analysis challenge. This analysis challenge can be met by methods for large-scale cell recognition, tracing, and data handling, all of which have been made possible by advances in desktop computing and machine vision [Sebastian, correct usage?]. We propose to create a Core Facility at Princeton that spans all three of these domains. Our facility will use viral tracing, volume microscopy, and automated data analysis to map connectivity in every brain region that we image or perturb. These powerful anatomical approaches will add enormous depth to the interpretation of our in vivo experiments.-27305521970Figure XX. Cell recognition and placement in aligned brain. Left, a current approach being tested in which training examples are used to train a convolutional neural net to classify putative neurons, which are then compared with human-annotated images. Right, placement of detected cells in an aligned whole brain.00Figure XX. Cell recognition and placement in aligned brain. Left, a current approach being tested in which training examples are used to train a convolutional neural net to classify putative neurons, which are then compared with human-annotated images. Right, placement of detected cells in an aligned whole brain.Specific GoalsGoal 1: Register brains and automate cell recognition. We are building a pipeline to register image stacks to a common reference frame. In all experiments, a key step is to register individual cleared brains to Allen Brain Institute coordinates. This step will be carried out by rigid and affine stretching, followed by B-spline nonuniform stretching. The result of these steps is a transformation that is accurate to within ~0.2 mm (Figure X). To obtain reference data for registration, a broadly available signal such as autofluorescence will be taken during the acquisition. This volume will be used to register the experimenter's sample with a common coordinate system, the Allen Brain's mouse reference atlas. Custom software incorporated into our analysis pipeline leverages alignment software built on top of the National Library of Medicine's Insight Segmentation and Registration Toolkit (ITK). This allows for unbiased determination of anatomical location within each brain.38106477000Figure XXX, Anterograde tracing of posterior cerebellum to thalamic nuclei. Left, injection of HSV-H129 into cerebellum (green, bottom) leads to successive expression in deep nuclei and thalamus. Right, darker rectangles indicate stronger levels of expression in specific clusters of thalamic nuclei (outlined in red). Of particular interest is dorsomedial thalamus, which projects to mPFC and other associational regions).00Figure XXX, Anterograde tracing of posterior cerebellum to thalamic nuclei. Left, injection of HSV-H129 into cerebellum (green, bottom) leads to successive expression in deep nuclei and thalamus. Right, darker rectangles indicate stronger levels of expression in specific clusters of thalamic nuclei (outlined in red). Of particular interest is dorsomedial thalamus, which projects to mPFC and other associational regions).We are also addressing the challenge of automated cell recognition. Large-scale cell detection from volumetric data carries challenges that are reminiscent of other datasets such as those arising from cellular calcium imaging. We are currently leveraging convolutional neural net (CNN; Figure XX) software from the Seung laboratory [REF ] for calcium imaging by treating the third "z" dimension in a manner analogous to time. This method may be refined using nonnegative matrix factorization methods (collaboration with Eftychios Pnevmatikakis and Andrea Giovannucci, Flatiron Institute/Simons Foundation) As an alternative, we are pursuing an iterative cell-recognition/border-erosion method in collaboration with Partha Mitra (Cold Spring Harbor Laboratory). In both cases our goal is to attain 95 percent sensitivity (i.e. true positive rate) and specificity (i.e. positives as a total of true plus false positives) relative to ground truth as defined by human annotators.Goal 2: Identify tracts and pathways using virus-based methods. We will establish a facility that allows the tracing of pathways from sites of imaging or perturbation. A necessary step in building this capacity is the recovery of virus-specific signal from cells of interest.In the case of light-sheet microscopy, brains will be cleared using the iDISCO method, After transcardial perfusion and fixation, animal tissue will be permeabilized through a series of methanol dehydration steps, bleaching, and exposure to nonpolar solvents. Brains will then then passed through a typical immunostaining protocol of blocking, primary staining, and secondary staining, all steps occurring for longer-than-usual time periods because of the longer diffusion time into specimens. Next, using an organic based solvent approach the brain will be delipidized leaving a cleared brain of mostly crosslinked proteins. This approach is superior to aqueous based solutions which we have found produce less consistent clearing, and preserve less well the morphology of the tissue.?We have successfully combined iDISCO clearing with pseudorabies virus (PRV) and anterogradely transported viruses (herpes simplex virus variant H129, or HSV-H129). In preliminary results, we have begun to create a map of posterior cerebellum to thalamus with nucleus-level resolution (Figure XXX). This map identifies thalamic nuclei that project to regions with high potential relevance to evidence accumulation (PPC, PFC, M1, M2, and VTA). These preliminary results demonstrate the power of transsynaptic tracing to contribute to an integrative model for evidence accumulation.-457204069080Figure XXXX, Alignment of two-photon imaged regions with cleared light-sheet volumetric reconstructions.00Figure XXXX, Alignment of two-photon imaged regions with cleared light-sheet volumetric reconstructions.Goal 3: Build anatomical datasets and integrate them with functional in vivo experiments. To place calcium imaging experiments into full anatomical context, imaged regions will be registered with cleared brains. The pattern of fluorescent cells and artificially-placed fiduciary marks will be used to align two-photon image stacks with cleared brain tissue (Figure XXXX). This alignment will be a routine part of every imaging experiment. In some experiments, at the end of in vivo imaging, tracing virus will be injected at the imaging site to obtain detailed projection patterns at distal sites. Brains will be imaged in up to four spectral channels using a light-sheet microscope (LaVision BioTec). This imaging approach optimizes speed, allowing for high throughput acquisition, and allows whole-brain imaging at a resolution of 1.63 ?m/pixel in X-Y directions and 5 ?m/pixel in the Z direction, without the need for physical sectioning. A tile scan at 4x is over 150,000 images. In experiments requiring increased resolution, volumes will be acquired using fluorescence two-photon tomography. Custom python code will be used acquisition, stitching and image blending into a single volume. The data will then be compressed for long-term storage.Resource StrategyThe Registration and Histology core facility will have two full-time staff and be housed in the Bezos Center for Systems Neuroscience. The staff members will have the following duties:1) Technician for staining, clearing, and imaging. This wet-bench technician will process brains for clearing and light-sheet microscopy, or serial two-photon tomography (STP). He/she will also perform imaging.2) Data analyst. This data analyst will align images, register brains with the Allen Brain Atlas, perform initial data analysis, and establish and maintain the anatomical component of the project database. He/she will manage data storage and provide advice to postdocs and students on data storage and management. These functions will be coordinated with the data core [insert NAME OF THAT CORE HERE].Example ProjectsThis core facility will provide a uniform source of high-quality reconstruction for all members of the U19 collaboration. This will result in cost-effectiveness and increased efficiency for anatomical and histological work.Example project 1: tracing of in vivo imaging experimental animals. Any time an in vivo imaging experiment is done, tracer will be injected as a routine final step in the live animal. Projections to and from an imaged site will be characterized in anterograde (HSV-H129) or retrograde (retro-AAV, PRV) directions. The PFC, ACC, and parietal cortex are polysynaptic target regions of ventral tegmental and cerebellum and thus will be injected with the retrograde viral tracer PRV.Example project 2: Long-distance polysynaptic mapping between neocortex and cerebellum. Most existing anatomical knowledge of long-distance projections focuses on the direct terminations of axons. Virus-based methods will allow the identification of targets which are joined by disynaptic or longer paths of connectivity. Prominent examples include neocortex, striatum, and cerebellum, which are joined in an orderly manner that has been difficult to trace because of the presence of intermediate sites such as the ventral tegmental area and the deep cerebellar nuclei. We will start with two major brain divisions where we expect spatial resolution to be good, the neocortex and cerebellum. We will test the hypothesis that cerebellar lobules VI and VII, and crus I and II, are polysynaptically connected with specific nonmotor forebrain targets through thalamic and VTA intermediates. Cerebellar perinatal damage leads to a decrease in contralateral PFC volume relative to the ipsilateral PFC by the age of 2 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2xkdWM8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2xkdWM8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (32, 46). Furthermore, a neuroimaging meta-analysis identified lobules VI, VII and Crus I to be associated with language, working memory, spatial tasks, executive function and emotional functioning in humans ADDIN EN.CITE <EndNote><Cite><Author>Stoodley</Author><Year>2009</Year><RecNum>391</RecNum><DisplayText>(38)</DisplayText><record><rec-number>391</rec-number><foreign-keys><key app="EN" db-id="d2sxfs9znr5fz7epz9tx9xw4xfxsrad0wxrv" timestamp="1406729307">391</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Stoodley, Catherine J.</author><author>Schmahmann, Jeremy D.</author></authors></contributors><auth-address>Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. cstoodley@</auth-address><titles><title>Functional topography in the human cerebellum: A meta-analysis of neuroimaging studies</title><secondary-title>NeuroImage</secondary-title><alt-title>NeuroImage</alt-title></titles><periodical><full-title>Neuroimage</full-title></periodical><alt-periodical><full-title>Neuroimage</full-title></alt-periodical><pages>489-501</pages><volume>44</volume><number>2</number><keywords><keyword>Cerebellum</keyword><keyword>Cognition</keyword><keyword>Motor</keyword><keyword>Emotion</keyword><keyword>Topography</keyword><keyword>Functional imaging</keyword></keywords><dates><year>2009</year><pub-dates><date>1/15/</date></pub-dates></dates><isbn>1053-8119</isbn><accession-num>18835452</accession-num><urls><related-urls><url>;(38). Finally, several studies have indicated that lobules VI, VII and crus I and II are associated with nonmotor function PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3VyY2hlc25lPC9BdXRob3I+PFllYXI+MjAwMTwvWWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3VyY2hlc25lPC9BdXRob3I+PFllYXI+MjAwMTwvWWVh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ADDIN EN.CITE.DATA (39-45). Anterograde tracing from these lobules and crura will be done using HSV-H129.Significance. This core facility's services will be of extremely high significance. To date, nearly all studies of systems neuroscience function have encompassed imaging of one or a few small regions of tissue, on a local basis. This facility will add the capability to identify the precise region imaged in functional terms, both locally and in relation to the brainwide set of regions that are to be studied in this U19 proposal. Neocortex, striatum, cerebellum, and other subcortical areas are joined by precisely mapped relationships, and this Core will provide detailed information on the connectivity between the parts of these brain divisions which support evidence accumulation.Innovation. This core will be highly innovative. It will use advanced tissue-clearing technologies on a brainwide basis, a scale that requires automated cell identification and counting. In addition to these methods, it will be necessary to trace connectivity with directional and pathway-specific manner. The technologies to be used (iDISCO, cell recognition, viral tracing) are innovative both individually and in combination.In addition to the high innovation of this project, our approach to data archival will place the information from this collaboration in a context that is useful to neuroscientists worldwide. Our data will be tagged as to location, as well as to connectivity to distant brain regions. The functional connectivity BLAH BLAH BLAHApproach. These technologies rely on close communication with leaders in the field. We have light-sheet microscopy in-house. We are also in touch with innovators who either invented or polished methods to high reliability, such as iDISCO's Nicolas Renier (formerly with Marc Tessier-Lavigne, now at XXXX Paris); automated cell recognition and data analysis (Partha Mitra, Cold Spring Harbor, and S. Seung, co-PI on this U19); virus construction (Lynn Enquist at Princeton, and various collaborators at other institutions).BudgetStaff. (two salaries totaling $120,000 DC per year, plus benefits rate)Equipment. The Princeton Neuroscience Institute already has a LaVision Biotec light-sheet microscope. This microscope will be supplemented with an objective to allow wider field-of-view image acquisition. In addition, we will acquire a custom-built serial two-photon tomographic microscope based on a recent design at the Howard Hughes Medical Institute (Janelia Farm). Other equipment to be obtained includes nutators, incubators, and refrigerators, and a standard histology benchtop suite for sample processing and handling. (total $80,000 – if we really get the microscope, add $300,000 for that)Supplies. Reagents are needed for approximately 10 users, at ~100 brains per year. The primary expense is antibodies, whose cost varies greatly depending on the particular study and cell type(s) to be recovered. Additional costs include clearing reagents and other chemicals, as well as portable data storage.($30,000 DC per year)Computational Resources. For dedicated use in data analysis, the Registration and Histology Core will require two computers equipped with graphic acceleration and computational capabilities for [GIVE SPECIFICATIONS HERE]. Estimated storage requirements are 1 PB based on an acquisition rate of 2 TB/brain for the period of the grant. Beyond that time, per-brain costs may decrease as storage becomes less expensive. Storage costs will be coordinated with the data core [insert NAME OF THAT CORE HERE].(not sure…$20,000?)Literature Cited (pardon numbering – will fix once we are near the end on this one) ADDIN EN.REFLIST 32.Limperopoulos C, Chilingaryan G, Sullivan N, Guizard N, Robertson RL, Du Plessis AJ. Injury to the premature cerebellum: outcome is related to remote cortical development. Cerebral Cortex. 2012:bhs354.38.Stoodley CJ, Schmahmann JD. Functional topography in the human cerebellum: A meta-analysis of neuroimaging studies. NeuroImage. 2009;44(2):489-501. doi: . PubMed PMID: 18835452.39.Courchesne E, Karns CM, Davis HR, Ziccardi R, Carper RA, Tigue ZD, Chisum HJ, Moses P, Pierce K, Lord C, Lincoln AJ, Pizzo S, Schreibman L, Haas RH, Akshoomoff NA, Courchesne RY. Unusual brain growth patterns in early life in patients with autistic disorder: An MRI study. Neurology. 2001;57(2):245-54. doi: 10.1212/wnl.57.2.245. PubMed PMID: 11468308.40.Bailey A, Phillips W, Rutter M. Autism: Towards an Integration of Clinical, Genetic, Neuropsychological, and Neurobiological Perspectives. Journal of Child Psychology and Psychiatry. 1996;37(1):89-126. doi: 10.1111/j.1469-7610.1996.tb01381.x. PubMed PMID: 8655659.41.Courchesne E. New evidence of cerebellar and brainstem hypoplasia in autistic infants, children and adolescents: the MR imaging study by Hashimoto and colleagues. Journal of autism and developmental disorders. 1995;25(1):19-22. PubMed PMID: 7608031.42.Diamond A. Close Interrelation of Motor Development and Cognitive Development and of the Cerebellum and Prefrontal Cortex. Child Development. 2000;71(1):44-56. doi: 10.1111/1467-8624.00117. PubMed PMID: 10836557.43.Courchesne E, Townsend J, Akshoomoff NA, Saitoh O, Yeung-Courchesne R, Lincoln AJ, James HE, Haas RH, Schreibman L, Lau L. Impairment in shifting attention in autistic and cerebellar patients. Behavioral Neuroscience. 1994;108(5):848-65. doi: 10.1037/0735-7044.108.5.848. PubMed PMID: 1995-10213-001. PsycARTICLES Identifier: bne-108-5-848. PMID: 7826509. First Author & Affiliation: Courchesne, Eric.44.Carper RA, Courchesne E. Inverse correlation between frontal lobe and cerebellum sizes in children with autism. Brain : a journal of neurology. 2000;123(4):836-44. doi: Doi 10.1093/Brain/123.4.836. PubMed PMID: WOS:000086251400018.45.Courchesne E, Saitoh O, Yeung-Courchesne R, Press GA, Lincoln AJ, Haas RH, Schreibman L. Abnormality of cerebellar vermian lobules VI and VII in patients with infantile autism: identification of hypoplastic and hyperplastic subgroups with MR imaging. American Journal of Roentgenology. 1994;162(1):123-30. doi: 10.2214/ajr.162.1.8273650. PubMed PMID: 8273650.46.Bolduc M-E, Du Plessis AJ, Sullivan N, Guizard N, Zhang X, Robertson RL, Limperopoulos C. Regional cerebellar volumes predict functional outcome in children with cerebellar malformations. The Cerebellum. 2012;11(2):531-42. doi: 10.1007/s12311-011-0312-z. PubMed PMID: 21901523.6 pages. as a reference manager we’ll be using the Google Docs add-on Paperpile.Instructions from RFA:Specific Aims: Provide a concise description of the goals of the Resource Core. Explain how the Resource Core will contribute to individual Research Projects.Resource Strategy: A Resource Core can be a laboratory, a facility, a service, or other shared resource that supports at least two Research Project components. Descriptions for each Resource Core should include a brief overview and a description of the services and resources to be provided to other components. This section should address how the Resource Core will contribute to the overall goals of the program as well as which research projects will be supported by the Resource Core and the manner in which that support will be rendered. The description of each Resource Core should clearly indicate the facilities, resources, services, and professional skills that the facility will provide. Issues to be addressed can include: quality control, special expertise, cost effectiveness, and increased efficiency.Significance: Describe overall goals and the impact of the science proposed in relation to the state of the field. This section should also explain the contribution of the core to the overall goals of the program and how the component will interact with and benefit from other components. Innovation: Describe the unique and innovative contributions that will be made by this component. Explain how these contributions will be made possible by team synergy beyond the otherwise independent research projects. Approach: Describe and offer evidence for the feasibility of the proposed experiments, the advantages of any new methodologies, the potential pitfalls and alternative approaches for the project and how these might impact overall progress. ................
................
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.
Related searches
- math formula for home mortgages
- home speech home wh questions
- home parties for home decor
- home speech home word list
- math cheater solve my math problems free
- home loan vs home equity loan
- home decor home party companies
- home math activities for preschoolers
- home based home decor businesses
- home inspection checklist printable home inspection checklist new
- home interiors in home parties
- at home math activities for preschoolers