Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

Since 2014, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has aimed to accelerate the development and application of innovative neurotechnologies, enabling researchers to produce a new dynamic picture of the brain that reveals how individual cells and complex neural circuits interact in both time and space. It is expected that these advances will ultimately lead to new ways to treat and prevent brain disorders.

As one of several federal agencies involved in the BRAIN Initiative, NIH's contributions to the BRAIN initiative were initially guided by the "BRAIN 2025: A Scientific Vision," a strategic plan that detailed seven high-priority research areas. This plan was updated and enhanced in 2019 by: "The BRAIN Initiative 2.0: From Cells to Circuits, Toward Cures" and "The BRAIN Initiative and Neuroethics: Enabling and Enhancing Neuroscience Advances for Society." This and other BRAIN Initiative Funding Opportunity Announcements (FOAs) are based on this vision and issued with input from Advisory Councils of the 10 NIH Institutes and Centers supporting the BRAIN Initiative, as assisted by the NIH BRAIN Multi-Council Working Group.

The NIH BRAIN Initiative recognizes that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogeneous teams. There are many benefits that flow from a diverse scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved populations participate in, and benefit from research, and enhancing public trust.

To support the best science, the NIH BRAIN Initiative encourages inclusivity in research. Examples of structures that promote diverse perspectives include but are not limited to:

• Transdisciplinary research projects and collaborations among neuroscientists and researchers from fields such as computational biology, physics, engineering, mathematics, computer and data sciences, as well as bioethics.
• Engagement from different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, minority-serving, community-based).
• Individual applications and partnerships that enhance geographic and regional heterogeneity.
• Investigators and teams composed of researchers at different career stages.
• Participation of individuals from diverse backgrounds, including groups historically underrepresented in the biomedical, behavioral, and clinical research workforce (see NOT-OD-20-031), such as underrepresented racial and ethnic groups, those with disabilities, those from disadvantaged backgrounds, and women.
• Project-based opportunities to enhance the research environment to benefit early- and mid-career investigators.

The NIH also encourages businesses to participate in the BRAIN Initiative. It is possible for companies to submit applications directly to BRAIN Initiative program announcements or to collaborate with academic researchers in joint submissions. Small businesses should consider applying to one of the BRAIN Initiative small business FOAs.

The BRAIN Initiative requires a high level of coordination and sharing among investigators. It is expected that BRAIN Initiative awardees will cooperate and coordinate their activities after awards are made by participating in Program Director/Principal Investigator (PD/PI) meetings and in other activities such as the annual PD/PI meeting. The data sharing expectations for BRAIN Initiative awards can be found at NOT-MH-19-010.

This FOA is related to the transformative project, "A Cell Type-Specific Armamentarium for Understanding Brain Function and Dysfunction," described in the "The BRAIN Initiative 2.0: From Cells to Circuits, Toward Cures" report of the Advisory Committee to the NIH Director BRAIN Initiative Working Group 2.0.

Research Objectives

High-Impact, Molecular Payloads for Monitoring and Manipulating Brain Circuits Using Brain Cell Access Reagents

The BRAIN Initiative Armamentarium project is a large-scale effort with a goal to generate and implement methods to specifically access, manipulate, and monitor brain cell types across multiple species. With the emergence of more detailed brain cell censuses, there is now the possibility to monitor and manipulate "brain cell function and resolve questions of cause and effect between cell types, their functional outputs, and illnesses of the brain," according to the BRAIN Initiative 2.0 report. Developing robust technologies to access defined cell types is supported through various BRAIN Initiative Armamentarium FOAs, including RFA-MH-20-556 and RFA-MH-21-180.

This FOA is intended to support the accelerated engineering and optimization of high-impact, molecular technologies to monitor and/or manipulate brain cell activity in experimental animals (e.g., fluorescent protein indicators of neuronal state variables, molecular integrators of neural activity, optogenetic, chemogenetic, sonogenetic, magnetogenetic actuators, activity-dependent molecular switches). In particular, tools are sought that can be delivered selectively as payloads to cell types using new brain cell access reagents produced by investigators in the field who are focused on such vectors. In the future, combining scaled-up, cell type-selective reagents produced under other Armamentarium brain cell type-selective access FOAs (RFA-MH-20-556, RFA-MH-21-180) with optimized molecules for monitoring and/or manipulating neural activity developed under this payloads optimization FOA promises to open new frontiers in neuroscience. Reproducibility and reliability of molecular access, monitoring, and perturbation of circuit components will enable the study of neural coding, computation, storage, and retrieval at cellular resolution. The compatibility of such technologies with recording and modulation of targeted cell types in intact brains of animals will enable the dissection of neural circuits through correlation or causal manipulation of circuit component activity with behaviors. Ultimately, a dynamic picture of neural activity and functional circuits will provide insights into how to diagnose, treat, and prevent human brain disorders in the future.

The "BRAIN 2025: A Scientific Vision" report enumerated several core principles, including that "[n]ew methods should be critically tested through iterative interaction between tool-makers and experimentalists. After validation, mechanisms must be developed to make new tools available to all." As such, this FOA will foster close interaction between technologists and neurobiologists in a research consortium. The Armamentarium consortium will promote rigorous technology design, benchmarking, validation, and distribution.

Compliance with the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals (Policy), including completion of the Vertebrate Animals Section according to the criteria described below, is an absolute requirement. All institutions are also required to comply, as applicable, with the Animal Welfare Act, and other Federal statutes and regulations relating to animals.

Research Scope

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/).

Optional Demonstration Experiments In Vivo

Optionally, beyond and separate from the in vivo validation plans, it could be beneficial for the unique capabilities of optimized tools to be demonstrated for neuroscience users. But demonstration efforts are not required. Such optional demonstration experiments should assess groundbreaking technological advances and showcase unique technological capabilities of an optimized tool that was previously infeasible for the neuroscience field. As noted above, because optional demonstration studies require molecules to be improved first, demonstration studies must not be budgeted in Year 1. In planning optional demonstration projects using an optimized tool from in vivo validation, the proposed milestones should describe quantitative performance metrics for such an optimized tool that would be used. Demonstration projects may be performed by investigators involved in the in vivo validation work and/or other collaborating neuroscientists.

Working Together in the Armamentarium Consortium

Supported Molecular Payloads Centers are expected to work closely together and benefit from membership in the Armamentarium consortium of researchers, including other Armamentarium awardees from this FOA, RFA-MH-20-556, and RFA-MH-21-180. Coordination among consortium members is expected to include sharing of protocols, technologies, reagents, and data to improve the optimization process of molecular tools, as well as cooperation in publication and reagent distribution to integrate the best technologies into neuroscience research. To promote coordination, applications are expected to plan direct costs for 5% to 20% excess engineering system capacity and 5% to 20% excess in vivo validation capacity to engineer and validate similar technologies from other awards in the consortium of awardees. Excess capacity is expected to be used across awards to hasten the optimization of tools at the engineering stages and to improve the validation measurements of tools tested in vivo. In planning to propose excess capacities, applicants should plan relatively more excess capacity for engineering systems and/or in vivo validation platforms that are highly innovative or unique in capability in the field.

This FOA seeks applications in areas including, but not limited to:

Molecular Technologies

• Optimization of neural sensor molecules that report activity states to users via fluorescence, bioluminescence, chemiluminescence, magnetic resonance, light polarization, acoustics, subcellular localization, encoding information into nucleic acids, or other modalities.
• Development of genetically encoded, chemical/genetic, or other sensors that enable neural activity monitoring from user-targeted, genetically defined brain cells.
• Optimization of molecular sensors of various neural activities related to membrane voltage, released neurotransmitters/neuromodulators, neurochemical receptor activation, neurochemical reuptake, synaptic vesicle release, intracellular calcium, second messengers.
• Improvement of molecules that reflect integration of neural activity in specified brain cells over user-defined periods.
• Optimization of molecular switches modulated by neural activity that regulate gene function.
• Improvements in cellular localization of molecular tools to augment the fidelity or efficacy of molecular function.
• Optimization of genetically encoded or chemogenetic neural activity effector molecules that change activity states in user-defined brain cells and periods via molecules sensitive to photons, chemical, acoustic, thermal, magnetic, or other exogenous inputs.
• Optimization of molecular effectors of various neural activities related to membrane voltage, released neurotransmitters/neuromodulators, neurochemical receptor activation, neurochemical reuptake, synaptic vesicle release, ion flux, second messengers.
• Improvement of molecules that stably change neural activity in a step function manner over user-defined periods.

Engineering Approaches

• Protein engineering strategies involving extensive mutagenesis, shuffling, or phylogenetic analyses of proteins or protein domains.
• Molecular modeling approaches to rationally optimize function based on structure or dynamics, and include structure determination of molecules to be engineered, if appropriate.
• Artificial intelligence or machine learning approaches for molecular designs that improve the efficiency of optimization efforts.
• Improved molecular variant production approaches of sufficient scale and quality for engineering assays.
• Use of advanced, high-throughput, and/or massively parallel screening assays of sufficient scale in vitro for improving molecular functions that are highly predictive of molecular performance in vivo.
• Use of lower scale ex vivo cultured brain slice experiments to test leading molecular variants emerging from earlier higher throughput testing.
• Testing of lead molecular technologies against best-in-class benchmark tools

In Vivo Validation Approaches

• Validation of tool performance in vivo in intact brains of experimental animals to verify improved tool performance seen during tool engineering and assessment of metrics such as signal detectability, effects on neural activity, background, kinetics, stability, scope of cells monitored, cytotoxicity, biocompatibility, ability to multiplex, ease of use, or other parameters.
• Validation of a given tool's performance using different modalities of sensing (e.g., microscopic imaging, fiber photometry) or perturbing (e.g., wide-field optogenetic stimulation, 2-photon optogenetic stimulation) neural cell activity.
• Use of standardized assays in vivo in intact brains of experimental animals to compare novel tool performance against prior best-in-class technology where experimental reproducibility and reliability of the testbed are high.

Technology Transition Efforts

• Adaptation of best-validated tools to be formatted or packaged for broad uptake, successful expression in neural cells, and use by the neuroscience community.
• Deposition of validated tools in reagent repositories.

Optional In Vivo Demonstration Approaches

• Demonstration experiments where experimental animal behavior is correlated with neural activity sensor signals detected in populations of brain cells in novel or unique ways.
• Demonstration experiments where experimental animal behavior or complex brain network activity is manipulated with neural activity effectors activated in targeted populations of brain cells in novel or unique ways.

Plan for Enhancing Diverse Perspectives (PEDP)

This FOA requires a Plan for Enhancing Diverse Perspectives as part of the application (see further below). Applicants are strongly encouraged to read the FOA instructions carefully and view the available PEDP guidance material.

Applications must include a Plan for Enhancing Diverse Perspectives submitted as Other Project Information as an attachment (see Section IV). The PEDP will be assessed as part of the scientific and technical peer review evaluation, as well as considered among programmatic matters with respect to funding decisions.

Proposed Milestones and Timeline

Applications must include Proposed Milestones and Timeline submitted as Other Project Information as an attachment (see Section IV). The Proposed Milestones and Timeline should explain critical indicators of progress for Molecular Payloads Centers for optimization of existing molecular technologies to monitor and/or manipulate brain cell activity. The Proposed Milestones and Timeline will be evaluated as part of the review process, but final versions will be agreed upon at the time of award. If justified by scientific and/or technological needs, future year milestones may be revised, upon request, based on data and information obtained in the current year.

Non-responsive Areas of Research

Applications will be considered non-responsive and will not be reviewed if they propose:

• Proof-of-concept of molecular tools instead of optimization of existing molecular technologies.
• Projects that fail to test optimized molecular tools in vivo in the intact brain of an experimental animal.
• Studies focused on disease mechanisms.
• Projects whose main goal is to address a biological mechanism or hypothesis rather than to optimize novel molecular tools.
• Projects primarily focused on hardware for monitoring or manipulating neural activity, as opposed to molecular tools.

For projects developing new technologies that have not yet achieved proof-of-concept for recording and manipulation of neural activity in the intact brains of experimental animals, potential applicants should consider responding to other BRAIN Initiative FOAs (RFA-MH-21-175, RFA-EY-21-001, RFA-NS-21-026, or reissued versions).

For projects focused on developing or improving hardware, as opposed to molecular tools, for monitoring and/or manipulating neural activity in brain cell types, potential applicants should consider responding to other BRAIN Initiative FOAs (RFA-MH-21-175, RFA-EY-21-001, RFA-NS-21-026, RFA-NS-21-027, or reissued versions).

Applicants are strongly encouraged to consult the NIMH Scientific/Research Contact listed below to discuss the alignment of their proposed work with the goals of this FOA and BRAIN Initiative program goals.

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Government

• Eligible Agencies of the Federal Government - Including the NIH Intramural Program
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Applications Involving the NIH Intramural Research Program

The requests by NIH intramural scientists will be limited to the incremental costs required for participation. As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

If selected, appropriate funding will be provided by the NIH Intramural Program. NIH intramural scientists will participate in this program as PDs/PIs in accord with the Terms and Conditions provided in this FOA. Intellectual property will be managed according to established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above.

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their full SAM and Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see 2.3.9.4 Similar, Essentially Identical, or Identical Applications)

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Email: nimhpeerreview@mail.nih.gov

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

For this specific FOA, the Research Strategy is limited to 12 pages, exclusive of the Specific Aims page.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

Plan for Enhancing Diverse Perspectives (PEDP)

In an "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity. The PEDP should provide a holistic and integrated view of how enhancing diverse perspectives is viewed and supported throughout the application and can incorporate elements with relevance to any review criteria (significance, investigator(s), innovation, approach, and environment) as appropriate. Where possible, applicant(s) should align their description with these required elements within the research strategy section. The PEDP will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured. The PEDP may be no more than 1-page in length and should include a timeline and milestones for relevant components that will be considered as part of the review. Examples of items that advance inclusivity in research and may be part of the PEDP can include, but are not limited to:

• Discussion of engagement with different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, minority-serving, community-based).
• Description of any planned partnerships that may enhance geographic and regional diversity.
• Plan to enhance recruiting of women and individuals from groups historically underrepresented in the biomedical, behavioral, and clinical research workforce.
• Proposed monitoring activities to identify and measure PEDP progress benchmarks.
• Plan to utilize the project infrastructure (i.e., research and structure) to support career-enhancing research opportunities for diverse junior, early- and mid-career researchers.
• Description of any training and/or mentoring opportunities available to encourage participation of students, postdoctoral researchers and co-investigators from diverse backgrounds.
• Plan to develop transdisciplinary collaboration(s) that require unique expertise and/or solicit diverse perspectives to address research question(s).
• Publication plan that enumerates planned manuscripts and proposed lead authorship.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as research participants including those from under-represented backgrounds.

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), please see https://braininitiative.nih.gov/about/plan-enhancing-diverse-perspectives-pedp.

Proposed Milestones and Timeline

In an Other Attachment, provide proposed milestones and timeline explaining critical indicators of progress for the Molecular Payloads Center for optimization of existing molecular technologies to monitor and/or manipulate brain cell activity. This attachment should be entitled "Proposed Milestones and Timeline.pdf . Applications missing the Proposed Milestones and Timeline will be considered incomplete and will not be reviewed. The attachment should have maximum length of 2 pages and include proposed annual milestones that:

• Are tailored to the unique scope of each Molecular Payloads Center and are written concretely enough to evaluate what exactly will be achieved (e.g., signal parameters of monitoring tools, effector parameters of manipulation tools, scale of tool variants tested, sensitivity of optimization platforms, tool validation steps, numbers of tools optimized, packaging of optimized tools for users, etc.) during the course of the research.
• Indicate any alternative strategies should efforts fail to perform as expected.
• In planning for any optional demonstration projects, describe quantitative performance metrics to be attained for any optimized and in vivo validated tool planned to be used in demonstration projects.

In addition to and along-side the proposed milestones, a proposed timeline that describes when key milestones are likely to be met. Final versions of the milestones and timeline will be agreed upon at the time of award.

All instructions in the SF424 (R&R) Application Guide must be followed.

R&R Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

Molecular engineering experiments:

• Budget for molecular engineering experiments for molecular tools proposed in this application.
• Engineering excess capacity funds: Applicants should also set aside direct costs for 5% to 20% excess engineering system capacity funds to engineer similar technologies from other awards in the consortium to hasten tool optimization through sharing of capacity. The set-aside amount should be presented in the Other Direct Costs category under the heading, "Molecular Engineering Excess Capacity Funds." The use of the set-aside funds will be restricted at time of award and released upon request of the awardee, advice of the Consortium Steering Group, and authorization by NIMH.

In vivo validation experiments:

• For design, performance, analysis, and interpretation of in vivo validation experiments, budgets should include support for a dedicated "In Vivo Validation Scientist" position to devote a minimum of 9 calendar months each year to in vivo validation experimental activities. This position should be designated as an "In Vivo Validation Scientist" in the application.
• Budget for in vivo validation experiments for molecular tools proposed in this application.
• In vivo validation excess capacity funds: Applicants should also set aside direct costs for 5% to 20% excess in vivo validation capacity funds to validate similar technologies to improve validation measurements from other awards in the consortium through sharing of capacity. The set-aside amount should be presented in the Other Direct Costs category under the heading, "In Vivo Validation Excess Capacity Funds." The use of the set-aside funds will be restricted at time of award and released upon request of the awardee, advice of the Consortium Steering Group and authorization by NIMH.

Demonstration project experiments:

• Do not include costs for optional demonstration project experiments, which are distinct from the required in vivo validation experiments, in the first year.

Consortium Annual In-Person Meeting Costs:

• Applications may include allowable costs for participating in the consortium annual in-person meetings.

PEDP implementation costs:

• Applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy Statement section 7: https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm).

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims

Describe the scientific, molecular technology optimization, in vivo validation, tool adaptation for distribution, and optional technology demonstration goals of the proposed research program, and state in order of planned accomplishment the aims of the Center to optimize molecular technologies for monitoring and/or manipulating brain cell activity in vivo in experimental animals.

Research Strategy:

This FOA is intended to create Molecular Payloads Centers for optimization of existing molecular technologies to monitor and/or manipulate brain cell activity. In addition to the information requested in the Application Guide, address the items in the identified sections listed below. The applicant is not limited to these sections, as applicable.

Overall Center Organization

• Provide an overview of the Molecular Payloads Center organization for optimization of existing molecular technologies to monitor and/or manipulate brain cell activity.
• Describe overview for collaborative strategies of the Molecular Payloads Center to ensure efficient cooperation, for sharing of protocols, technologies, reagents, and data with other consortium awards and coordination on publication of research results, dissemination of reagents, and dissemination of data with other consortium awards.

Current State-of-the-Art Statement

• In a section titled, "Current State-of-the-Art Statement," define the current state of technology, including benchmarks against which proposed technology and improvements will be measured.

Significance

• Provide information on how far the proposed monitoring and/or manipulation technology is beyond the proof-of-concept stage.
• For each Specific Aim individually or for all Specific Aims collectively, explain the significance of:
  • The tools to be optimized for cellular/circuit neuroscience and their potential transformative impact.
  • The chosen design metrics and goals for optimization for neuroscience studies in vivo in the brains of experimental animals.
  • The scaled engineering system(s) planned to be used for molecular engineering in terms of the ability of the system(s) to achieve planned optimizations.
  • The in vivo validation system(s) for testing improvements in terms of the ability of the system(s) to compare tools in paradigms relevant for experimental animal neuroscience.
  • Any optional in vivo tool demonstration studies to highlight unique use-cases of the technology.

Innovation

• For each Specific Aim individually or for all Specific Aims collectively, describe the innovation of:
  • The tools to be optimized for circuit neuroscience.
  • The scaled engineering system(s) planned to be used for molecular engineering.
  • The in vivo validation system(s) for testing improvements.
  • Any optional in vivo tool demonstration studies.

Engineering of Brain Cell Type-Targetable Tools for Activity Monitoring or Manipulation

• Describe plans for large-scale engineering of improved molecules to monitor and/or manipulate brain cell activity for functional dissection of circuits, where early-phase molecular tool optimization includes testing of molecules at sufficient scale.
• Describe the design metrics to be targeted in the engineering plans stated in terms relevant to neuroscience tool users for end-use cases.
• Describe any technology development needed for improving engineering systems that may be proposed.
• Describe the predictivity of the engineering systems for in vivo performance.
• Describe any intermediate scale platforms that more closely resemble the intact brains of animals (e.g., ex vivo cultured brain slices) planned to be used to test molecules.
• Describe plans for the engineering process to assess whether tools have been substantially improved over the current technology, based on quantitative benchmarking experiments for the delineated design metrics.
• Describe plans for providing 5% to 20% excess (in terms of direct costs) engineering system capacity to engineer similar technologies from other awards in the consortium to hasten tool optimization through sharing of capacity.

Validation of Tools In Vivo

• Describe plans to validate in intact brains of experimental animals in vivo the performance improvements for the optimized subset of reagents emerging from the tool engineering.
• Describe plans for the validation processes to assess whether tools have been substantially improved over the current technology, based on quantitative benchmarking experiments for the delineated design metrics in intact brains of experimental animals.
• Describe plans for iterative molecular engineering and in vivo validation cycles where feedback and refinement are conducted between tool engineers and tool validators.
• Include sufficient effort for in vivo validation experiments in the form of a dedicated "In Vivo Validation Scientist" position to devote a minimum of 9 calendar months each year in each year for design, performance, analysis, and interpretation of in vivo validation experiments as laboratory staff. Designate such personnel as "In Vivo Validation Scientist" in the application.
• Describe plans for providing 5% to 20% excess (in terms of direct costs) in vivo validation system capacity to validate similar technologies to improve validation measurements from other awards in the consortium through sharing of capacity.

Transitioning Validated Tools to the Neuroscience Community

• Describe details on how all the in vivo validated, optimized molecular tools will be adapted and packaged for broad uptake and successful use by the neuroscience community.
• Optionally include collaborative plans for tool transition 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/).

Optional Tool Demonstration Experiments In Vivo

• As an additional option but not a requirement, describe plans to demonstrate the unique capabilities of optimized tools to the neuroscience field following successful validation.
• In the optional demonstration experiments, propose:
  • Use of the tool to answer a high-impact question concerning neural circuit function that was previously infeasible or difficult to perform with prior technologies.
  • Use of a tool that has attained quantitative performance metrics described as a milestone.
  • Experiments with personnel involved in the in vivo validation work and/or other collaborating neuroscientists.
• Do not include optional in vivo tool demonstration studies in the first year.

Letters of Support: Include letters of support/agreement for any collaborative/cooperative arrangements, subcontracts, or consultants.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

The following modifications also apply:

A central goal of this FOA is to generate transformative tools that will be widely used throughout the research community. Applications that propose to generate such tools are expected to include a detailed plan for sharing these resources and expected to include the following key elements:

• Project management of resource sharing;
• Description of what specific resources will be shared (e.g., model organisms, reagents, completed tools or repurposed components);
• Schedule/timeline for availability of resources to other users;
• Persons who will have access to the resources (written as broadly as possible to the extent consistent with applicable laws, regulations, rules, and policies);
• Plan for post award disposition of resources.
• Investigators are strongly encouraged to obtain a research resource ID from the Resource Identification Initiative (http://scicrunch.com/resources/info/add) and to use Resource IDs in their publications if available. (http://scicrunch.com/resources).

Data Sharing Plan: All applications, regardless of the amount of direct costs requested for any one year, must address a Data Sharing Plan as part of the Resource Sharing Plan. The data sharing expectations for BRAIN Initiative awards can be found at NOT-MH-19-010.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential fieldof the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applications must include annual milestones. Applications that fail to include annual milestones will be considered incomplete and will be withdrawn. Applications must include a PEDP submitted as Other Project Information as an attachment. Applications that fail to include a PEDP will be considered incomplete and will be withdrawn before review.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Section V. Application Review Information

1. Criteria

Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) as part of the Resource Sharing Plan will not be evaluated at time of review.

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

Because this FOA specifically seeks applications to optimize existing molecular tools for monitoring and/or manipulating brain cell activity, the NIH expects that some applications may propose mature and well-established approaches that may not be innovative per se.

Overall Impact

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the proposed Center address the needs of the research community that it will serve? Is the scope of activities proposed for the Center appropriate to meet those needs? Will successful completion of the aims bring unique advantages or capabilities to the research community?

Specific to this FOA:

• How accurately and completely has the state of the art been described, especially with regard to benchmarks to which the proposed tools will be compared?
• How transformative are the targeted improvements over the current technology for use in vivo in experimental animals?
• How likely are the large-scale engineering systems to produce substantially improved molecular payloads for neuroscientists?
• How relevant are the in vivo validation systems for testing improvements to experimental animal neuroscientists?
• If proposed, how important are any optional, in vivo tool demonstration studies to the field?
• How applicable will the improved tools be for use with brain cell type-targetable delivery and expression?
• To what extent do the efforts described in the Plan for Enhancing Diverse Perspectives further the significance of the project?

Investigator(s)

Are the PD(s)/PI(s) and other personnel well suited to their roles in the Center? Do they have appropriate experience and training, and have they demonstrated experience and an ongoing record of accomplishments in managing molecular neuroscience technology research? Do the investigators demonstrate significant experience with coordinating collaborative basic research? If the Center is multi-PD/PI, do the investigators have complementary and integrated expertise and skills; are their organizational structures appropriate for the Center? Does the applicant have experience overseeing selection and management of subawards, if needed?

Specific to this FOA:

• How appropriate is the effort for in vivo validation experiments for designing, performing, analyzing, and interpreting in vivo validation experiments, which should be planned in the form of a dedicated "In Vivo Validation Scientist" position who should devote a minimum of 9 calendar months in each year?
• If proposed, how appropriate are any optional collaborators for tool distribution?
• To what extent will the efforts described in the Plan for Enhancing Diverse Perspectives strengthen and enhance the expertise required for the project?

Innovation

Does the application propose novel reagents for the research community the Center will serve? Are the concepts, strategies, or reagents novel to one type of research program or applicable in a broad sense? Is a refinement, improvement, or new application of reagents proposed?

Specific to this FOA:

• How novel are the molecular engineering approaches?
• How new are the large-scale engineering systems planned to be used for molecular engineering?
• How inventive are the plans for in vivo validation of molecular technologies?
• If proposed, how groundbreaking are any optional demonstration experiments planned for optimized tools?
• To what extent will the efforts described in the Plan for Enhancing Diverse Perspectives meaningfully contribute to innovation?

Approach

Are the overall strategy, operational plan, and organizational structure well-reasoned and appropriate to accomplish the goals of the research community the Center will serve? Will the investigators promote strategies to ensure a robust and unbiased scientific approach across the Center, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the Center is in the early stages of operation, does the proposed strategy adequately establish feasibility and manage the risks associated with the activities of the program? Are an appropriate plan for work-flow and a well-established timeline proposed? Have the investigators presented adequate plans to ensure consideration of relevant biological variables, such as sex, for studies of vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Specific to this FOA:

• How appropriate are the plans for:
  • large-scale molecular engineering,
  • benchmarking against existing best-in-class tools,
  • in vivo validation of improvements seen in engineering assays in intact brains of experimental animals, and
  • adaptation of tools into easily produced and applied formats for neuroscience users?
• If proposed, how sound are any optional plans for:
  • demonstration experiments that establish groundbreaking capabilities of improved molecular tools in vivo?
• How well conceived are any technology development plans that may be proposed for improving engineering systems?
• How adequate are the plans in terms of the number of molecules to be engineered within the Molecular Payloads Center to achieve optimized molecular payloads for monitoring and/or manipulating neural cell activity?
• To what degree do the large-scale testing systems for new tools likely predict tool performance in vivo in the intact animal brain?
• How suitable are the planned cycles of iterative molecular engineering and in vivo validation, where feedback and refinement are conducted between tool engineers and tool users?
• How appropriate are the plans to provide 5% to 20% excess engineering system capacity to engineer similar technologies from other awards in the consortium of awardees to hasten tool optimization through sharing of capacity?
• How appropriate are the plans to provide 5% to 20% excess in vivo validation system capacity to validate similar technologies from other awards in the consortium of awardees to improve validation measurements through capacity sharing?
• Are the timeline and milestones associated with the Plan for Enhancing Diverse Perspectives well-developed and feasible?

Environment

Will the institutional environment in which the Center will operate contribute to the probability of success in facilitating the research community it serves? Are the institutional support, equipment and other physical resources available to the investigators adequate for the Center proposed? Will the Center benefit from unique features of the institutional environment, infrastructure, or personnel? Are resources available within the scientific environment to support electronic information handling?

Specific to this FOA:

• To what extent will features of the environment described in the Plan for Enhancing Diverse Perspectives (e.g., collaborative arrangements, geographic diversity, institutional support) contribute to the success of the project?

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

Not Applicable

Revisions

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Milestones

Are the Proposed Milestones and Timeline described in sufficient detail and are they appropriate for the project? Is the timeline reasonable? Are the milestones feasible, well developed, and quantifiable with regard to the specific aims? How appropriate are milestones and quantitative metrics for optimized and in vivo validated molecular tools planned for any optional demonstration projects?

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

Specific to this FOA:

A major goal of this FOA is to generate reagents that will be widely used throughout the neuroscience community for brain cell type-selective monitoring and/or manipulation in experimental animals. In light of this goal, how well does the application include an adequate and detailed plan for sharing these resources as appropriate and consistent with achieving the goals of the program?

To what extent does the plan provide a strong rationale for each of the following key elements as appropriate and consistent with achieving the goals of the program:

• Project management of resource sharing;
• Description of what specific resources will be shared;
• Schedule/timeline for availability of resources to other users;
• Persons who will have access to the resources; and
• Plan for post award disposition of resources?

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIMH, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities including the PEDP. .

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federalwide Research Terms and Conditions
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex (including gender identity, sexual orientation, and pregnancy). This includes ensuring programs are accessible to persons with limited English proficiency and persons with disabilities. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.
• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including reasonable accommodations and making services accessible to them, see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.
• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.
• For guidance on administering programs in compliance with applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 and 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75 and 2 CFR 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibilities as described below:

• Optimize molecular tools for monitoring and/or manipulating neural activity in defined brain cell types for the neuroscience field.
• Determine and coordinate the research approaches and procedures, conduct experiments, and analyze and interpret research data generated under this award.
• Meet or exceed the timeline stated in their application.
• Agree to participate as a voting member in a Consortium Steering Group composed of other awardees from this FOA and RFA-MH-20-556, RFA-MH-21-180, NIH staff, and an external expert group.
• Share protocols, technologies, reagents, and data with consortium members.
• Propose use of 5% to 20% excess capacity for engineering and in vivo validation based on achieved progress and opportunities in collaboration with consortium members.
• Not disclose confidential information obtained from other consortium members.
• Ensure that results are published in a timely manner.
• Coordinate with other consortium members the publication of research results, dissemination of reagents, and dissemination of data.
• Submit protocols, reagents, and data for use, quality assessment, and/or validation in any manner specified by the Steering Group or the NIH Project Scientist.
• Submit annual milestone reports to the NIH with completeness that include experimental design with rigor, including assumptions for the design of the experiments, the results of the investigations, interpretations of the results, and for concluding whether milestones have been met or not.
• Provide updates at least annually on implementation of the PEDP.
• Accept and implement common guidelines and procedures approved by the Steering Group.
• Attend Steering Group meetings. It is likely that there will be one in-person meeting per year and that other meetings will be held by telephone or using internet-assisted meeting software.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• A Program Officer will be assigned to this award. The Program Officer will be responsible for normal scientific and programmatic stewardship and guidance.
• Prior to award, the Program Officer will negotiate final milestones with the PD/PIs that will be incorporated in the Notice of Award.
• A group of NIH program staff from the ICs that make up the NIH BRAIN Initiative will form a Project Team for this award.
• The Project Team will include the Program Officer for these BRAIN Initiative awards.
• The Project Team will review annual progress reports and other documents from the awardees and will advise the Program Officer about their view of the progress being made by the awardee as well as about progress being made by others in the field.
• One or more extramural NIH program staff member will be assigned as Project Scientist for this award. The same person may serve as a Project Scientist for multiple BRAIN Initiative awards.
• The Project Scientist(s) will interact scientifically with the PDs/PIs of the cooperative agreement and other named key personnel as a partner in the research activities.
• The Program Officer and the Project Scientist(s) will be members of the Steering Group.

Areas of Joint Responsibility include:

• The purpose of the Steering Group is to transfer information and technologies among the awardees of this FOA, RFA-MH-20-556, and RFA-MH-21-180 and between the awardees and the BRAIN Initiative more broadly in order to achieve the goals outlined in the BRAIN 2025 and BRAIN 2.0 reports.
• The Steering Group will be comprised of the PDs/PIs of the awards of this FOA, RFA-MH-20-556, RFA-MH-21-180, the Project Scientist(s), the Program Officer, and a group of external experts.
• The PDs/PIs and Program Officer will invite a group of external experts to attend Steering Group meetings. The external expert group will be composed of three to five scientists who are not awardees of this FOA or RFA-MH-20-556 or RFA-MH-21-180, represent the broad research community, and have relevant expertise. The group may be enlarged permanently or on an ad hoc basis as needed.
• A chair of the Steering Group, who is an awardee of this FOA or RFA-MH-20-556 or RFA-MH-21-180, will be designated by the Steering Group on a rotating basis as needed.
• It is expected that most of the decisions on the activities of the Steering Group will be reached by consensus. If a vote is needed, each award will have one vote and the Project Scientist(s) collectively will have one vote.
• The Project Scientist may assist in research planning, may present experimental findings from an award from published sources or from relevant award projects, may participate in the design of experiments agreed to by the group, may participate in the analysis of results, may help ensure that duplication is avoided, and will interact scientifically with the Steering Group.
• The Program Officer and the external expert group members will attend Steering Group meetings as non-voting participants.
• In all cases, the role of NIH staff will be to assist and facilitate, but not to direct activities.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. These three members include: a designee of the Steering Group chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 1.

Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

3. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH FOAs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Douglas S. Kim, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-827-6463
Email: douglas.kim@nih.gov

Nick Gaiano, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-827-3420
Email: nick.gaiano@nih.gov

Heather Weiss
National Institute of Mental Health (NIMH)
Telephone: 301-443-4415
Email: weissh@mail.nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.