UM1NS132250

Brain Connects: A Center for High-Throughput Integrative Mouse Connectomics - Project Summary/Abstract

The proposed project will demonstrate the feasibility of generating a complete synapse-level brain map (connectome) by developing a serial-section electron microscopy pipeline that could scale to a whole mouse brain. This work will image 10 cubic millimeters, itself an unprecedentedly large dataset that may exceed tens of petabytes. Yet the mouse brain is 50 times larger.

Reaching this ambitious goal will require advances in whole-brain staining, imaging, image-processing, analysis, and dissemination tools. We will scale and test these tools by producing a connectome of the hippocampal formation, a critical brain region for memory and spatial navigation.

Specifically, we will define our volume of interest via microCT scanning of a whole brain. Then we will cut it into semithin serial sections and image them with multibeam scanning electron microscopy and ion beam milling. This technique images a thin layer of tissue and then removes it to reveal the next layer until each section is fully imaged, minimizing distortions caused by previous ultra-thin sectioning approaches.

The imaging data will be processed by an improved version of our state-of-the-art pipeline. After quality monitoring and image compression, our automated system will assemble the full volume from imaged slices and then label tissue elements: neurons, glia, blood vessels, myelin, cell bodies, and synapses. This reconstruction will then be proofread and registered to the Allen Institute Brain Atlas, allowing us to relate our data to other types of data.

Our analysis will identify cell types by region and layer, and reveal the detailed connectivity of hippocampal formation circuits. Using custom software, we will integrate these structural results on cell types with other approaches based on light microscopy and single-cell gene expression, allowing us to relate our results to the extensive literature on hippocampal formation structure and function.

To promote diverse perspectives, we will involve undergraduates from underrepresented backgrounds in the proofreading and scientific discovery phases of our work, offering them mentoring as well as research experience.

We will turn these data into a lasting resource for the scientific community and the public by scaling up free access via online sharing tools to allow any interested party to render, proofread, or otherwise analyze the cells and circuits in this volume. To illustrate how this resource can be combined with other discoveries, we will define cell types based on their morphology and connectivity, characterize the relationship between these assignments and transcriptomic-based classifications, and integrate this information with previous work.

Finally, we will define local and long-range microcircuit motifs in our data and use it to identify circuit principles and mechanisms of memory and spatial cognition, by testing and improving models of the hippocampal formation.

Throughout the project, we will monitor key performance parameters, such as imaging throughput of a single microscope, to evaluate the feasibility and cost of scaling up to a whole mouse brain connectome.

President And Fellows Of Harvard College

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.372 - 21st Century Cures Act - Brain Research through Advancing Innovative Neurotechnologies

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Cambridge, Massachusetts 021381903 United States

Single Zip Code

BRAIN Initiative Connectivity across Scales (BRAIN CONNECTS): Comprehensive Centers for Mouse Brain (UM1 Clinical Trial Not Allowed) (RFA-NS-22-048)

Amendment Since initial award the total obligations have increased 4223% from $497,158 to $21,489,807.