Notice of NIMH’s Considerations Regarding the Use of Animal Neurobehavioral Approaches in Basic and Pre-clinical Studies

Notice Number: NOT-MH-19-053

Key Dates
Release Date: September 30, 2019

Related Announcements
None

Issued by
National Institute of Mental Health (NIMH)

Purpose

The purpose of this Notice is to outline NIMH guidelines and priorities for potential applicants considering animal neurobehavioral approaches in research relevant to mental illnesses.

Basic and pre-clinical research in animals is critical for understanding fundamental neurobiological mechanisms that drive complex behaviors and to facilitate NIMH efforts to transform the understanding and treatment of mental illnesses. When determining funding priorities for basic and pre-clinical neuroscience research, the NIMH weighs how well projects address the following :

  1. What is the question being asked?
  2. Is it an important question?
  3. Does the experimental system (i.e., model) proposed enable that question to be answered?

Potential applicants are reminded that the use of precise language in describing hypotheses, experimental designs, and the significance of results is critical for addressing these questions. In outlining the premise for studies, the relevance of a non-human model system to human clinical outcomes is limited by the species chosen, the specifics of the experimental manipulation, and the degree to which outcome measures reflect conserved neurobiological mechanisms. Rigorous behavioral neuroscience studies will provide the rationale for the selection of the experimental manipulations and detail the specific behavioral and neurobiological outcome measures that are best suited to address the questions and hypotheses. Study results should make an impact in their field of basic research without reliance on unsubstantiated links to clinical psychopathology. NIMH recommends the use of models “for” addressing neurobiological questions rather than models “of” specific mental illnesses. Similarly, NIMH strongly discourages description of animal behaviors in terms of emotions and thought processes that are accessible only in humans by self-report (e.g., terms such as depressed, anxious, lonely) or through clinical diagnoses.

NIMH strongly encourages investigators to consider the following points when designing non-human neurobehavioral studies of processes potentially related to mental illnesses:

A. Behavioral Tasks

Experimental design and interpretation of behavioral results are expected to address NIH guidelines for addressing research rigor (https://grants.nih.gov/policy/reproducibility/guidance.htm). Appropriately designed behavioral studies will consider the complexity of behavioral readouts, the multiple interacting processes (e.g., working memory, reward and motivation, attention, emotion processing, sensory and motor effects) that contribute to measures, and will identify and control for non-specific mediators to enable unbiased interpretation of results. Species, strain, sex, age and history of the animal are critical considerations in experimental designs. Randomization, blind assessment of outcomes, and adequately powered experiments are expected.

In rigorous studies, behavioral measures are selected to address scientific questions in the context of the brain processes examined and not for presumed congruence to human symptoms of mental illnesses. Claims of direct clinical relevance of behavioral measures in animals require demonstration that the specific measures reflect evolutionarily conserved brain processes in independent studies. Investigators are specifically encouraged to develop and test specific task-based behavioral assays as proxies for neural circuits whose activity is linked to underlying domains of function relevant to NIMH (e.g., RDoC). The inclusion of two or more behavioral assays to examine the same functional construct along with appropriate control measures enhance confidence regarding behavioral specificity of results. Moreover, investigators are encouraged to develop and/or use fine-grained, real-time measurements of behavior that allow assessment of relationships with brain activity. Recent advances in behavioral neuroscience, brain activity measurement methods, statistical tools, and machine learning offer platforms for quantitative and objective analysis of behavior. These methods allow computational formalisms to parameterize, describe, and predict behavior, as well as determination of how discrete behavioral motifs are encoded by the various neurobiological measures and are organized in real time.

B. Neurobiology of Risk Genes

NIMH prioritizes experimental research of disease-associated genetic variants according to the recommendations of the National Advisory Mental Health Council (NAMHC) Genomics Workgroup. Applicants are strongly encouraged to read the full reportsummary and specific guidance when drafting research proposals and to critically evaluate the rigor and strength of evidence implicating genetic or molecular changes associated with disease. Generally, for any given genetically complex trait, such as a psychiatric diagnosis, there are multiple contributing gene variants with each variant contributing to multiple traits. Since this complex relationship between genotype and phenotype in humans is not well understood, caution should be taken when extrapolating such a relationship between genes and behavior to other species.

Importantly, although psychiatric disorders are diagnosed based on changes in human behavior, current behavioral measures in animals, individually or in combination, cannot establish or refute that a gene variant is causally involved in disease etiology. As such, applicants should carefully craft their research question when pursuing human genetic findings and choose the most appropriate experimental approach, giving due consideration to the nature of the risk variant or gene, the breadth of human traits associated with it, its conservation across species, and its temporal, spatial, and cellular expression pattern. In many cases, particularly for common variants, it may not be possible to disentangle how a single risk variant causally contributes to a psychiatric phenotype using animal paradigms. Instead, investigators are encouraged to pursue approaches that address the basic function of implicated genes based on their known and unknown biology without presumptions of how human behavioral phenotypes manifest in animals. Lastly, because genes and their variants converge and diverge across traits and intervening processes, it is difficult to delineate and make strong inferences about the causal chain of events leading from genotype to phenotype. This background biological complexity underscores the need to choose appropriate sets of matched control genes when attempting to identify commonalities among a set of disease-associated genes.

C. Understanding Effects of Interventions

The scientific value of animal model systems in addressing clinical questions related to both novel and approved treatments is significantly limited by challenges in modeling therapeutic treatment exposure including species differences in drug pharmacokinetics and target mediated actions, and the lack of clinically informative efficacy measures in animals. As already outlined in this notice, only measures that reflect activity of circuits that are conserved across animals and humans are appropriate for cross-species generalizations.

Evaluation of the impact of novel therapeutic targets and candidates in animal model systems should be focused on the specific circuits. Further research is needed to identify, develop, and evaluate behavioral assays as robust and reliable read-outs of brain processes of clinical interest. Where behavioral measures are included, NIMH recommends that applicants carefully select tasks to test the hypothesized neurobiological target.

In most cases, questions regarding the risks and benefits of approved treatments for mental illnesses are best examined in clinical populations with underlying psychopathology. Potential applicants using paradigms of drug exposure as a tool to perturb specific brain signaling pathways in developing and adult animals are encouraged to include complementary, non-pharmacological approaches. Finally, discovery and testing of novel therapeutic strategies in animals is generally prioritized over studies of mechanisms of beneficial or adverse effects of approved therapeutics.

DSex as a Biological Variable (SABV)

NIH expects that sex as a biological variable will be factored into research designs, analyses, and reporting in rigorous research. If no known sex differences have been established, it is reasonable to use mixed groups of males and females without powering specifically to test for sex differences. The existence of a sex predominance in the incidence of a mental illness is not an adequate rationale to omit equivalent consideration of both sexes in research designs for NIMH except for sex-specific conditions (e.g., post-partum functions, X-linked conditions). In small N studies, both sexes should be included to build an inclusive database. Sex differences in baseline measures or where similar experimental manipulations lead to sexually dimorphic outcomes in animal studies represent unique opportunities and create specific challenges for experimental design.

E. Neuroimmune Functions: Models of Maternal Immune Activation (MIA) as an Example

Studies of effects of immune system challenges on central nervous system development and function provide an illustrative example of how the approach outlined in this notice can be applied to a research topic. Extensive epidemiological and genetic association studies implicate inflammatory processes during pregnancy as risk factors for human neurodevelopmental disorders. The model of maternal immune activation (MIA) using viral and bacterial mimics was first described as an animal model ‘of’ schizophrenia and more recently as a model ‘of’ autism spectrum disorders. Using more precise and objective language, maternal immune activation is referred to as a model ‘for’ examining the effects of inflammation on specific cells and circuits relevant to multiple neurodevelopmental conditions. There are many different neuroimmunological questions of potential clinical interest. For example, projects could examine the mechanisms whereby MIA in response to viral or bacterial challenge or other environmental challenges impacts fetal brain development, circuit formation, and long-term neurobehavioral processes.

As in all research, the model, research design, and subject characteristics (age, sex, strain, species) are expected to be carefully chosen to best address the research question. Species differences in brain, behavior, neurodevelopment, neuroimmune signaling, and physiology are all important design considerations for hypothesis-driven approaches to link data derived from model systems to clinical conditions.

Additional information on NIMH priorities for animal studies

Program Directors/Principal Investigators (PD/PIs) planning to submit applications concerning stress biology are strongly encouraged to inquire via email at NIMHanimalstudies@mail.nih.gov 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: NIMHanimalstudies@mail.nih.gov