Despite the many advances in the neuroscience of the aging brain in recent years, the underlying mechanisms of selective CNS vulnerability to aging effects, of cellular and molecular mechanisms of brain repair, or of involvement of glial cells in brain aging remain unclear. Cataloging brain cell types and their connectivity is a prerequisite to understanding how they are organized into circuits and how they change in brain disorders; uncovering age-related changes will open a new dimension in research on the aging brain. The classification of cell types can be facilitated by systematic collection and integrated analysis of three data elements at a cellular level: (1) molecular signature (e.g., transcriptome, epigenome, proteome, metabolome), (2) anatomy (e.g., location, size, orientation, morphology, and connectivity), and (3) function (e.g., electrophysiology, functional connectivity).
The systematic identification, characterization, and positional mapping of various cell types in the adult mouse brain have been recently undertaken by the “Brain Research through Advancing Innovative Neurotechnologies Initiative”, also known as the BRAIN Initiative, which aims at revolutionizing our understanding of the mammalian brain (https://www.braininitiative.nih.gov/). By accelerating the development and application of innovative technologies, researchers will be able to produce a new, dynamic picture of the brain that, for the first time, will show how individual cells and complex neural circuits interact in both time and space. It is expected that the application of these new tools and technologies will ultimately lead to new ways to treat and prevent brain disorders. The BRAIN Initiative is a public-private collaborative effort in which the National Institute on Aging actively participates. This FOA will build upon extensive efforts of the BRAIN Initiative; specifically, it will build on previously and currently funded research under such RFAs as: (1) the Cell Census Consortium (BICCC) to pilot cell classification strategies for a comprehensive brain cell census (RFA-MH-14-215), (2) the Cell Census Network (BICCN) – Comprehensive Center on the Mouse Brain Cell Atlas (RFA-MH-17-230), and (3) the Cell Census Network (BICCN) – Specialized Collaboratory on the Mouse Brain Cell Atlas (RFA-MH-17-225).
The BRAIN Initiative efforts involve identifying the gene expression patterns and signatures that define specific cell types, an accurate census of each cell type’s representation, and spatial characterization that includes anatomical features of these cell types within their resident tissue. Although research supported by the BRAIN Initiative will reveal fundamental organizational principles of the mammalian nervous system, and provide invaluable resources for neuroscientists in aging research, its focus is not on aging research.
Current single-cell technologies promise a new era in the call for a brain cell census as high dimensional molecular information is available at an unparalleled scale and resolution. This unprecedented progress opens new research areas to explore in the aging central nervous system that include cell-type classification based on molecular identity, connectivity, and morphology; a taxonomy of cell types based on molecular identity and connectivity; and estimates of the number/percentage of defined cell types in specific region(s) and/or circuit(s), and their changes with aging.
Specifically, the FOA invites applications to:
- Define single-cell transcriptome data to unveil brain cell classes and types, as well as tissue composition and ratio data for various cell types (e.g., neurons, glial cells, vascular cells, immune cells, progenitor cells) in the aging brain;
- Define single-cell epigenome data (e.g., chromatin accessibility, DNA methylation) in the aging brain; and
- Provide anatomical cell data, including spatial location and morphology (e.g., cell size, shape, neurite arborization, connectivity) in selected brain regions of young and old mice.
Atlases and common coordinate systems play a fundamental role in gathering, analyzing, communicating, and standardizing data. This FOA embraces the existing efforts of the research community (e.g., the BRAIN Initiative) to collaboratively build up brain atlases with broadly accessible common brain coordinate systems to integrate and disseminate brain cell census data. Thus, this FOA supports the use of common mouse species, common brain samples, and common brain coordinate systems to minimize source variability and maximize resource sharing. Accordingly, this FOA requires that imaging–based cell census data will be registered to common coordinate systems, which include in-situ hybridization, immunohistochemistry, cell morphology, neuronal connectivity mapping, and functional cell imaging.
This FOA requires the use of C57BL/6J mice and must include animals of at least two ages, i.e., two months (specifically, post-natal day 56 (P56)) of age, and 18 months of age. The applicants are also strongly encouraged to perform the cell census using middle-aged animals, e.g., nine months of age. The cell census must be performed on both males and females.
The PD/PIs, key personnel, and collaborators currently supported under BRAIN Initiative-related funding announcements (1) the Cell Census Consortium (BICCC) to pilot cell classification strategies for a comprehensive brain cell census (RFA-MH-14-215), (2) the Cell Census Network (BICCN) – Comprehensive Center on the Mouse Brain Cell Atlas (RFA-MH-17-230), and (3) the Cell Census Network (BICCN) – Specialized Collaboratory on the Mouse Brain Cell Atlas (RFA-MH-17-225) are strongly encouraged to apply.
The FOA encourages collaboration with, and applications from, investigators who are currently funded by the BRAIN Initiative to maximize resource sharing while minimizing variability by standardizing sequencing, cell clustering and mapping methods. The ultimate utility of cell census data for the broad research community may reside in an effective integration of different cell census data elements including molecular content and cell anatomy. Each element of data may be limited in its own value; however, when combined with all data collected by individual projects funded by this FOA and the BRAIN Initiative, the aggregate data should inform an integrative description closer to nature. Rapid data exchange and integration are critical for defining cell types and unveiling the organizational rules behind cellular makeup and neural circuits.
Applications proposing approaches at early stages of technology development, studies of cultured cells or isolated cells maintained under culture conditions, and other studies outside of the research scope of this FOA will be considered non-responsive and will not be reviewed.
Deadline: February 8, 2019 (letters of intent); March 8, 2019 (full proposals)
Filed Under: Funding Opportunities