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Priorities for Strategy 1.1

Updated: January 2019

Describe the molecules, cells, and neural circuits associated with complex behaviors

NIMH encourages research on basic neuroscience processes that underlie cognitive, affective, or social functions. Discovery-based and hypothesis-testing studies examining mechanisms of regulation or dysregulation of these processes are of particular interest. Investigators are encouraged to integrate their research across levels of analysis, to utilize neurodevelopmental approaches, and to select appropriate biological systems for further study.

Research Priorities

  1. Determine the molecular, cellular, and systems components underlying brain connectivity and dynamic patterns of brain activity using model systems, stem cells, and human studies.

    Priority areas include:

    1. Determining the dynamic interactions of neurons, astrocytes, oligodendrocytes, microglia, and other cell types (including cells of the immune system) and how they contribute to information processing.
    2. Exploring the genomic, molecular, and physiologic bases of cell-to-cell variation and determining the functional consequences of this variation.
    3. Identifying the molecular mechanisms that control synaptic plasticity and circuit function; such mechanisms may involve the immune system and/or the microbiome.
    4. Determining the developmental processes and trajectories that lead to the establishment of functional brain networks and/or determining the modifier or risk factors (e.g., genomic, environmental) affecting the development of network function.
    5. Evaluating the utility of modifying network function for therapeutic benefit.
    6. Developing novel computational tools and techniques for the analysis and interpretation of neural activity including single unit, local field potentials, and other electrophysiological temporal dynamic patterns.
    7. Developing, optimizing, utilizing, and integrating neuroanatomical approaches to map neural circuits at micro-, meso-, and macro-scales.

  2. Identify the mechanisms responsible for establishing and maintaining circuits.

    Priority areas include:

    1. Investigating molecular and cellular processes involved in regulating the development of diverse neuronal and glial cell types and/or their integration into circuits relevant to cognitive, affective, and social functioning.
    2. Establishing a systems-level understanding of the development and regulation of neural circuits associated with cognitive, affective, and social behaviors.
    3. Investigating the signaling networks and plasticity mechanisms that mediate adaptive changes in circuits and how alterations may lead to maladaptive behaviors.
    4. Elucidating how central and peripheral physiological system signals across neural, immune, and microbiota impact the development and function of circuits underlying cognitive, affective, and social behaviors
    5. Identifying and experimentally validating computational algorithms that the brain uses for affective, cognitive, and social processing; in particular, the neural activity patterns, such as oscillatory signals that may be providing the scaffolding for optimal neural processing.
    6. Determining the neurophysiological rules that govern how and when the brain switches among states (e.g., switching from memory encoding to recall).
    7. Developing and validating experimentally grounded theories for how the brain computes affective, cognitive, and social functions across all spatiotemporal scales and levels of neurobiological abstraction.
    8. Understanding the structural and functional maturation of specific brain circuits that contribute to both normal and maladaptive cognitive, affective, and social behaviors.

  3. Identify and validate novel assays to quantify changes in the activity of molecules, cells, and circuits.

    Priority areas include:

    1. Developing assays that can be used to interrogate key regulators of cellular communication using in situ and circuit-based models for screening, target discovery, and development of novel probes of cell function.
    2. Improving human cell-based assays using induced pluripotent stem cells (iPSCs) or other cellular models for studying the molecular bases of mental illnesses, with an emphasis on optimizing robustness and reproducibility, and fidelity to in vivo human cell phenotypes, maturation, three-dimensional organization, and/or circuit function.
    3. Developing novel age-appropriate imaging tools with higher spatial and temporal resolution for visualization and analyses of brain structure and function, with particular emphasis on advancing real-time measurement approaches.
    4. Developing non-invasive tools for interrogating and manipulating brain circuit function for therapeutic purposes.
    5. Validating novel and objective measures of circuit function and synaptic plasticity in humans and experimental systems as research tools and for assessing therapeutic targets.
    6. Overcoming the significant barriers and limitations of standard behavioral batteries used in preclinical animal studies by developing and testing novel, objective, circuit-based behavioral and physiological measures linked to functional domains disrupted in mental illnesses.
    7. Advancing novel assays and tools to develop biomarkers of disease and for therapeutic discovery.
    8. Advancing objective, quantitative tools and measures to track, manipulate, and analyze behavior at high temporal resolution in a range of species and settings, and across multiple modalities and systems. 
    9. Experimentally validating novel imaging tools and methods that are sensitive to the processes and mechanisms of brain maturation, including those that can capture dynamic growth and change, and their implications for mental health.

  4. Elucidate the basic biology linking changes in molecular-, cellular-, and circuit-based targets to alterations in complex behaviors.

    Priority areas include:

    1. Utilizing appropriate experimental systems for studying mental health-relevant phenotypes to understand conserved and/or convergent neurobiological mechanisms (i.e., molecular, cellular, circuits, and behaviors) in humans.
    2. Investigating the role of coordinated neural activity in typical cognitive, affective, and social processes, and aberrant processes in mental illnesses.
    3. Developing novel computational modeling approaches to understand how changes in molecular and cellular processes relate to changes in circuit function and behavior.
    4. Advancing mechanistic approaches to understand fundamental processes relevant to emotional and cognitive disorders. Animal studies that incorporate novel behavioral assays that are linked to specific mechanisms at multiple levels of analysis (e.g., molecular, cellular, circuit, and/or systems) will be prioritized over studies relying on traditional behavioral tests (e.g., tail suspension, forced swim, amphetamine-induced hyperactivity).