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Strategic Objective 1

Strategic Objective 1 focuses on the basic science required for understanding mental illnesses. This objective serves as a foundation for a research continuum leading to better interventions and services.

Strategic Objective 1: Define the Mechanisms of Complex Behaviors

The basic science of mental illnesses has seen extraordinary progress over the past 6 years. The genomics revolution, fueled by rapid sequencing, has revealed complex genetic variation associated with mental illnesses. Epigenomics has demonstrated the molecular mechanisms by which environmental factors like stress and social experience influence behavior. In neuroscience, new tools such as optogenetics and DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) have enabled precise mapping and manipulation of brain circuits in nonhuman animals. New techniques have improved the resolution of structural and functional imaging in humans, and sensor technologies are transforming the study of behavior. Together, these new tools, techniques, and technologies can help us understand the still mysterious links between genes, experience, brain, and behavior.

The human brain is thought to have close to 86 billion neurons, each making on average about 10,000 connections. Approximately 100,000 miles of axons serve as information highways between neurons.14 Although this complexity is formidable, new reference atlases that have emerged from the Human Connectome Project and the BrainSpan Project provide unprecedented resources for mapping genes and pathways in the human brain. In the next 5 years, we expect a new generation of tools and technologies to be developed via the BRAIN Initiative. These tools will help create a detailed map of the circuits involved in complex behavior, including those associated with mental illnesses.

The questions we are asking include: What are the neural bases of perception, cognition, motivation, and social behavior? How do these aspects of mental function—which represent how we perceive, interpret, react to, and interact with the world—become altered in mental illnesses? The answers will come from discovery-based and hypothesis-testing studies examining the biological mechanisms underlying the regulation and dysregulation of mental processes. How these mechanisms emerge across development and among diverse populations; how they differ based on sex, gender, age, race, and ethnicity; how they change with experience (e.g., trauma or poverty); and, how they are influenced by environmental factors (e.g., cultural, economic, geographical, social, technological) are all critical questions for research. A more refined understanding of the molecules, genes, cells, and neural circuits underlying complex behaviors will be the starting point for the interventions of tomorrow.

Over the past 6 years, large, replicated genomic studies have revealed many common and rare variants associated with the most heritable conditions (e.g., schizophrenia, bipolar disorder, autism). We have gone from few clues to many. However, we still cannot explain the root cause(s) of mental illnesses. The task now is to sort through the complex patterns of genomic variation to define and elucidate how these variations confer risk. This strategy should not only identify critical pathways and circuits but potential new therapeutic targets. Nongenetic factors (e.g., environment, experience, the microbiome, to name just a few) have also been shown to increase the risk of mental illnesses. How does the interplay of genetic and environmental factors influence the development of mental illnesses? By understanding genomic, epigenomic, and other non-genomic factors and their interplay, we can begin to explain how our brain generates adaptive and maladaptive behaviors—predicting, interpreting, and responding to a complex world.

While genomic research has taught us that individual variation is a source of risk and resilience for illnesses, the study of brain circuits is still focused more on group averages than on individual differences. To address the range of individual variation in brain circuits, the Human Connectome Project is providing a reference atlas of neuronal connectivity—or a connectome—of 1,200 healthy brains. Moving forward from this baseline atlas, we will need to explore the details of individual differences in circuitry across diverse populations. We know little about the range of variation in connectomes across development, and even less about the potentially altered connectomes underlying mental illnesses from birth to the onset of illness. Imagine the questions we could answer, and the possibilities for new interventions, if we could define connectomes for mental illnesses that span development. When do structural and functional differences begin to manifest? How do differences in circuitry relate to differences in function? When is it best to intervene to correct deficits, and how do we intervene? To understand changes in neural structure and function related to mental illnesses, we must apply and build upon the research tools and technologies that we have in hand to begin to elucidate connectomes for mental illnesses, extending current group studies for use in individuals.

To improve our understanding of the structure and function of the brain in both health and illness and lay the foundation for future interventions, NIMH will employ the following strategies:

To unravel the mechanisms that lead to mental illnesses and target novel treatments to those mechanisms, more comprehensive descriptions of the molecules, cells, and circuits associated with typical and atypical behavior are necessary. What classes of neurons and glia are involved in a given aspect of mental function? Which brain regions contribute to a single thought or action, and how are these regions interconnected? These questions will be answered by defining the cellular components of circuits, including their molecular properties and anatomical connections. New tools and techniques that span biological scales—from single-cell analysis, to macro-electrode arrays, to systems-level brain imaging—are needed to address these questions. We still have little understanding of the neural basis for changes in structure or activity observed in human brain imaging. Most structural changes have not been validated with postmortem anatomy, and most functional changes have not been validated with in vivo physiology. Progress on this strategy will reveal how the brain is organized across the molecular, cellular, and systems levels, and will provide a foundation for understanding mental illnesses. To implement this strategy, NIMH will support research to:

  • Determine the molecular, cellular, and systems components underlying brain connectivity and dynamic patterns of brain activity using model systems, stem cells, and human studies.
  • Identify the mechanisms responsible for establishing and maintaining circuits.
  • Identify and validate novel assays to quantify changes in the activity of molecules, cells, and circuits.
  • Elucidate the basic biology linking changes in molecular-, cellular-, and circuit-based targets to alterations in complex behaviors.

Understanding the risk of developing a mental illness requires examination of genomic, epigenomic, and other factors such as the environment and experience across diverse populations. It is crucial to describe how these factors jointly influence the risk of developing mental illnesses; this knowledge provides a foundation for early prediction and preventive interventions. Novel study designs, genotyping technologies, and innovative statistical and bioinformatic methods will augment the analysis and interpretation of observed gene-environment interplay and will speed the transition of this knowledge to practice. Progress in these areas will broaden our understanding of the precise factors at the root of mental illnesses. To implement this strategy, NIMH will support research to:

  • Define genomic variations associated with mental illnesses and determine the biological consequences of these variations.
  • Define the molecular mechanisms that determine how experience has enduring effects on gene expression, brain function, and behavior.
  • Delineate environmental and biological factors altering genomic risk for mental illnesses.
  • Develop analytical tools for multi-scale data integration.

Most of what we currently know about the human brain connectome comes from studying healthy individuals. To understand changes in neural structure and function related to mental illnesses, we must apply the research tools and technologies we have in hand to characterize the connectomes for mental illnesses. It is becoming increasingly possible to map both local and distant connections in the brain, enabling an understanding of the relationships between neuronal structure and function at the systems level. To have comprehensive connectomes for mental illnesses, we must extend existing structural and functional mapping to the cellular level. The BRAIN Initiative will bring us improved technologies—technologies that are faster, less expensive, and scalable for anatomic reconstruction of neural circuits at all biological scales—and innovative tools, for example, molecular markers for synapses, tracers for identifying circuit inputs and outputs, and novel microscopy techniques for reconstruction of brain circuits. Until then, the application of existing tools and technologies will continue the transformation of how we visualize structural and functional differences in the brain connectomes for mental illnesses. To implement this strategy, NIMH will support research to:

  • Identify cells and brain networks that contribute to various aspects of mental function and dysfunction, such as cognition, emotion, and social behavior.
  • Determine how changes in the physiological properties of molecules, cells, and circuits contribute to mental illnesses.
  • Develop biomarkers of impaired neural function in humans at the level of molecules, cells, and circuits.
  • Develop innovative technologies, as well as new pharmacological and genetic tools, to interrogate and modulate the signaling pathways and circuits altered by mental illnesses.