Notice Number: NOT-MH-18-058

Key Dates
Release Date: October 24, 2018

Issued by
National Institute of Mental Health (NIMH)

Purpose

The purpose of this Notice is to outline NIMH guidelines and priorities for potential applicants in the field of stress biology research.

The word ‘stress’ has several usages in both the scientific literature and conversational English, and this may impede rigorous scientific discussion. Recognizing the need for some shorthand, NIMH uses the term ‘stress biology research’ to refer generally to basic neuroscience studies involving adverse experimental manipulations and the observed responses to those manipulations. In translational studies, ‘stress biology research’ refers generally to investigations of adverse environmental exposures and the responses to them, including subjective perceptions of the exposure. However, NIMH expects investigators to go beyond these general usages in applications, progress reports, and publications. It is expected that NIMH-supported investigators distinguish independent from dependent variables, characterize properties of the adverse manipulations and exposures, and fully describe the neurobiological, physiological and behavioral responses measured.

Given the critical need for rigor and reproducibility in scientific research ( https://grants.nih.gov/reproducibility/index.htm ), NIMH strongly encourages investigators to consider the heterogeneity and complexity of stress biology research when making experimental design choices. The properties of adverse experimental manipulations and environmental exposures can vary in type, timing, intensity, duration and context. Neurobiological, physiological and behavioral responses are both dynamic and multifaceted. Because paradigm-specific manipulations and exposures may lead to unique responses, NIMH expects investigators to justify carefully the fundamental properties of their experimental designs and to provide experimental detail sufficient for replication, harmonization, and meta-analyses in all applications, progress reports, and publications. Investigators should also carefully consider and articulate how their research design fits within the larger field of stress biology research.

NIMH encourages investigators to design and conduct studies that assess outcome measures at multiple levels of analysis. Measurements may be made from the genomic to the behavioral, and multiple methodologies may be used at any given level. NIMH strongly discourages the use of broad-based behavioral screening assays in animals that have been designed to recapitulate categorical human psychiatric disorders. In both humans and animals, any behavioral outcome measures should directly relate to the specific neural circuits, molecular signaling pathways, and physiological systems under study. For basic, circuit-level neuroscience studies, NIMH emphasizes measures that reflect circuits and processes shared between animals and humans. For basic and translational studies at the genomic level, NIMH’s priorities follow the recommendations of the NAMHC Genomics Workgroup Report ( https://www.nimh.nih.gov/about/advisory-boards-and-groups/namhc/reports/namhc-genomics-workgroup-research-recommendations-summary.shtml ). In all cases, NIMH promotes the use of methods for data harmonization.

NIMH aims to support basic and translational research that addresses the pivotal contexts, timepoints and mechanisms whereby adverse experimental manipulations and environmental exposures lead to neurobiological or physiological dysfunction, behavioral disruption, and/or psychopathology. Ultimately, NIMH seeks to translate research identifying mediators and moderators of such negative responses into actionable targets for intervention. To that end, NIMH encourages investigators in the field of stress biology to take on a set of critical topics:

• The adaptive to maladaptive spectrum (resilience to susceptibility). Because improvements in personalized psychiatric care depend upon our ability to predict responses and stratify clinical populations, NIMH seeks to deepen our mechanistic understanding of how and when adverse experiences lead to different responses and outcomes in select groups of individuals. Within a population of individuals exposed to an adverse experience, some will be resilient while others will demonstrate varying degrees of susceptibility to its negative effects. Investigators are encouraged to consider how best to define and measure the dimensional constructs of adaptation, resilience and susceptibility . Given that outcomes can vary in severity, responses should be measured parametrically whenever possible, to maximize the interpretability and translational relevance of the data.
• Consideration of complex systemic interactions . Adverse experiences have the potential to modulate the function of multiple physiological systems (e.g., central and peripheral nervous systems, immune system, gut microbiota) and how these systems influence each other. However, our understanding of the mechanisms underlying these complex interactions is limited. Within the framework of NIMH’s overall research priorities ( https://www.nimh.nih.gov/about/strategic-planning-reports/index.shtml ), NIMH encourages investigators to address mechanisms whereby multiple physiological systems may interact to produce neurobiological, behavioral, and/or psychopathological responses to adverse manipulations or exposures.
• Inclusion of both sexes and consideration of sex differences. A body of literature documents a sex bias in the incidence of some mental illnesses that are particularly sensitive to adverse experience. Despite this long-standing knowledge, there is a substantial gap in our understanding of the mechanisms that contribute to these sex differences. To address this gap, NIMH expects that investigators will include both males and females in proposed stress biology research projects, unless there is a compelling rationale not to do so (https://orwh.od.nih.gov/sex-gender/nih-policy-sex-biological-variable ). NIMH also encourages interested applicants to propose projects to investigate biological and environmental factors that underlie sex differences in response to adverse experience. Cases where similar adverse manipulations or exposures lead to sexually dimorphic outcomes provide unique opportunities and challenges: in these cases, NIMH expects investigators to include clear justification for specific experimental designs and full discussion of alternative interpretations.
• Speeding Translation . NIMH seeks to maximize the ability of basic neuroscience and clinical research to contribute to understanding and optimizing treatments for psychiatric disorders. To facilitate this translation, investigators are encouraged to align definitions, usages, and measurements of constructs such as risk, resilience, and susceptibility across animal and human studies wherever possible. NIMH also seeks research that identifies and explores neurobiological mechanisms conserved across species and encourages consideration of how lab-based manipulations may or may not link to real-world exposures.
• Biomarkers. The development of translatable biomarkers would facilitate the study of stress responses, resilience, and vulnerability across both human and animal studies. Such biomarkers would enable clinical scientists to make specific hypotheses about how likely it is that a given therapeutic or preventative measure would work in a specific person at risk due to adverse experiences.

Information on current NIMH research priorities may be found on our Strategic Research Priorities website ; this site is updated annually. Information specific to stress biology research may be found on the NIMH Stress Biology Research FAQ and a related NIMH Director’s Message .

Program Directors/Principal Investigators (PD/PIs) planning to submit applications concerning stress biology are strongly encouraged to inquire via email at [email protected]prior to submission of an application to obtain feedback on the fit of the proposed project with NIMH’s funding priorities in this research area.

Inquiries

Please direct all inquiries to:

[email protected]