BRAIN Initiative: Engineering and optimization of molecular technologies for functional dissection of neural circuits (UM1 Clinical Trial Not Allowed)
Funding Agency:
- National Institutes of Health
Applications to this FOA are expected to create Molecular Payloads Centers that focus on iterative optimization of molecular technologies for monitoring and/or manipulating neural activity in defined brain cell types in experimental animals. Existing tools beyond the proof-of-concept stage are the focus of this FOA. Tools will be optimized to enable high-impact neuroscience research in the brains of experimental animals. The optimization will entail engineering and testing efforts at large scale with feedback among multidisciplinary investigator teams. The optimized technologies are expected to have transformative impact to reveal more about dynamic functions of cells and circuits that underlie behavior. The molecular tools are expected to enable studies exploiting cell type selectivity or specificity. The technologies are expected to be targetable to user-defined cell types, for example, through the use of brain cell type-selective access reagents from or similar to those developed by BRAIN Initiative Armamentarium cell access awards.
Each Molecular Payloads Center is expected to integrate: (1) large-scale molecular engineering, (2) in vivo validation of improvements seen in engineering assays in intact brains of experimental animals, (3) benchmarking throughout the technology development against existing best-in-class tools, and (4) adaptation of tools into easily produced and applied formats for neuroscience users. It is possible that the optimization efforts could result in optional demonstration experiments that establish groundbreaking capabilities of improved molecular tools in vivo.
Large-Scale Molecular Engineering
This FOA requires engineering of molecules to improve performance of existing tools to monitor and/or manipulate brain cell activity that regulates circuit function. Applicants must set design metrics to be targeted in the engineering plans. The experimental plans must include large-scale molecular engineering efforts with targeted performance metrics, where early-phase molecular technology optimization includes testing molecular variants at sufficient scale to achieve the targeted performance. Multiple types of platforms may be proposed to pursue various optimization goals. In addition to other in vitro engineering systems, it is anticipated that platforms that more closely resemble intact brains of animals (e.g., ex vivo cultured brain slices) will be used to test molecules at intermediate scales. In terms of the molecular engineering systems, preliminary data should be included to demonstrate that the systems are predictive of tool performance in vivo in the intact animal brain. Technology development needed for improving engineering systems, especially for enhancing the engineering scale or the tool feature types optimized, may be proposed in addition to the plans for use of existing systems.
In Vivo Validation in Intact Brains of Experimental Animals
For the optimized subset of reagents emerging from the tool engineering, reagents must be attempted to be validated in intact brains of experimental animals in vivo to quantitatively assess the performance improvements. The quantitative assessment assays intended for measuring improvements are expected to be supported by preliminary data. Feedback and refinement through iterative molecular engineering and in vivo validation cycles must be conducted among tool engineers and tool validators. Sufficient effort for in vivo validation experiments should be provided in the form of a dedicated "In Vivo Validation Scientist" position to devote a minimum of 9 calendar months in each year for design, performance, analysis, and interpretation of in vivo validation experiments.
Benchmarking Against Existing Best-In-Class Tools
In both the engineering process and the in vivo validation experiments in intact brains of experimental animals, applicants must assess whether tools have been substantially improved over the current technology, based on quantitative benchmarking experiments for the delineated design metrics. The quantitative metrics for the benchmarking experiments must be delineated so that they are relevant to neuroscience tool users for end-use cases (e.g., signal-to-noise ratio of a neural activity sensor in response to an action potential, rise kinetics of a neural activity sensor in response to subthreshold neuronal membrane voltage depolarization, photocurrents of an optogenetic effector in response to light stimulation in neurons). Purely biophysical quantitative metrics may be included in addition to the above design metrics directly relevant to neuroscience end-use cases.
Adaptation of Tools for Neuroscience Users
All of the in vivo validated, optimized molecular tools must be adapted and packaged for broad uptake and successful use by the neuroscience community. Optionally, plans for tool transition may be proposed and are encouraged for collaboration with current awardees of BRAIN Initiative Armamentarium FOAs, including RFA-MH-20-556 and RFA-MH-21-180 (see for awardees: https://reporter.nih.gov/).
Application budgets are not limited but need to reflect the actual needs of the proposed project.
June 28, 2023
Douglas S. Kim, Ph.D., National Institute of Mental Health (NIMH), Telephone: 301-827-6463, Email: douglas.kim@nih.gov