BRAIN Initiative: Organizing Resources for Brain Cell Type-Specific Access and Manipulation Across Species

Presenter:

Greg Farber, Ph.D.
Office of Technology Development and Coordination

Goal:

The BRAIN Initiative 2.0 report  suggested supporting a cell type-specific armamentarium to precisely access and manipulate brain cells and circuits. Building upon cell census projects, this effort would enhance study of brain function through scaled production of specific cell type targeting and manipulation reagents to investigate cell types and to access disease-relevant circuits. The goal of this concept is to evaluate molecular/genetic technologies and then create pilot production and distribution resources for cell type-specific access and manipulation reagents for several vertebrate species.

Rationale:

The Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative and other initiatives have defined detailed cell censuses and developed powerful, cell-resolved manipulation technologies. Scalable resources for accessing these manifold cell types are needed to study cause-and-effect relationships between complex circuits and behavior. Prior efforts to gain greater access to genetically defined circuit components, including the FlyLight resource and GENSAT project, were based on transgenic lines that required cumbersome germline modification. Viral vectors, such as adeno-associated virus, transduce neurons without transgenesis in many species including primates. But control of vector transduction through selective tropism and targeting of expression via gene regulatory elements, which the BRAIN Initiative has partially fostered, need further development for more comprehensive cell type access, including for ex vivo human tissue. These challenges were discussed at a recent National Academies meeting , NINDS workshop , and BRAIN Intitiative workshop . Access consequently remains limited in many circuits and less genetically tractable species including primates for advanced reagents to monitor and manipulate cell types (e.g., calcium/voltage/neurochemical indicators, opto-/chemogenetic effectors, gene editors). Moreover, gene editing in postmitotic neurons for potential translational efforts will require more efficient and targeted editor delivery.

This concept seeks research to evaluate viral, non-viral, transgenic, and gene regulatory element screening technologies and create reagent resources to access brain cell subtypes and monitor and manipulate circuits. Reagent production efforts will apply gene transfer, gene regulation, genome engineering, activity sensor/effector, and atlasing technologies for use in both genetically tractable and less tractable systems, including primates and human tissue, which are relevant for future translational efforts. Reagent validation studies will provide feedback to improve scaled resources, informed by deeper understanding of neural gene transfer and regulation mechanisms. Precise targeting could ultimately aid in human disorders, for example, by providing access for gene editors to specific cell types to repair mutations.