GOAL 1: Identify the biological, environmental, behavioral, and social causes and consequences of drug use and addiction across the lifespan
The human brain is incredibly complex, with hundreds of billions of neurons and glial cells interacting to enable us to think, feel, perceive, learn, and act in extraordinarily nuanced ways. Recent advances in neuroimaging, opto- and chemogenetics, genetics, epigenetics, and other research technologies are revolutionizing our understanding of the brain and brain disorders, spanning molecules, cells, circuits, systems, and individual and social behaviors.
This goal includes a focus on basic science, which involves investigating fundamental brain functions relevant to drug use (including nicotine) and addiction, such as reward, motivation, decision-making, impulse control, emotional regulation, and stress reactivity, among others. Fully understanding a circuit requires identifying and characterizing the component cells, defining their synaptic connections, observing the dynamic patterns of activity as the circuit functions in the living brain, and perturbing these patterns to test their significance. It also requires an understanding of the algorithms that govern information processing within a circuit and between interacting circuits. Basic studies of neuronal, glial, and neural circuit functions and how they are perturbed by drugs is also fundamental for identifying new therapeutic targets, feeding the translational pipeline toward development of new prevention and treatment strategies.
Miniature Microscope "Sees" Inside a Rodent’s Brain
The holy grail of neuroscience is the ability to trace complex behaviors to the activity of specific neurons within discrete neuronal ensembles. Now, a technological advance that allows researchers to "see" individual neurons and record their activity while rodents perform a specific behavior is bringing us significantly closer to achieving this goal.
To image neuronal activity deep inside the brain of freely moving animals, NIDA researchers developed a miniaturized microscope that can be mounted on the skull of mice and rats. The prototype consists of a 3D-printed microscope body equipped with miniature optics and a cell-phone-camera-like photographic image detector, called a CMOS chip. The CMOS chip, image-acquisition electronics, and software were developed in collaboration with Dr. Eugenio Culurciello’s lab at Weldon School of Biomedical Engineering, Purdue University.
This amazing optical device is just 20 mm tall and weighs 2.7 grams—about the weight and diameter of a penny. With it, researchers will now be able to focus on a 900 µm (9/10ths of a millimeter) field of view and record the activity of hundreds of thousands of neurons simultaneously. This microscope can be used to visualize brain activity in genetically modified mice that express a protein called GCaMP6, which fluoresces as a function of intracellular calcium levels, making neuronal activity visible to the sensor. In early studies, this miniature microscope was capable of detecting GCaMP6 fluorescence changes deep in the brain, in an area called the dorsal striatum, which plays a role in reward and addiction.
This technology heralds a new era in our ability to study the exquisitely choreographed neuronal activity that underlies both simple and complex behaviors.
This goal will also focus on understanding the role of behavioral, social, and environmental factors in substance use and addiction. Research is needed to better understand how these factors interact to influence vulnerability for initiation of drug use, escalation to substance use disorders (SUDs), and transitions between the stages of SUDs. It is also important to understand how drug use and SUDs impact an individual’s environment, behavior, and social interactions. In addition, understanding how these factors interact with one another and with genetic and neurobiological mediators of drug use and SUDs is important for developing novel prevention and treatment intervention strategies. NIDA will continue to support behavioral and cognitive research and develop new animal models that better capture the complexities of behavioral, cognitive, environmental, and social aspects of addiction.
President Obama’s BRAIN Initiative is accelerating technology development in neuroimaging and brain circuit manipulation, driving a qualitative shift in the questions we can answer through research. Much of the research conducted under this initiative in the past few years has focused on a few isolated brain regions, but these new tools and maps are beginning to provide us with the opportunity to study the complex interactions that exist among neurons and functional brain circuits; how these are influenced by genetics, environment, drugs, and addiction; and how they respond to treatments. This fundamental knowledge will allow researchers to start to address critical public health questions such as:
- how, when, and for how long to intervene (for both prevention and treatment)
- how to maximize prevention of SUDs
- how to enhance treatment response and recovery
- how to mitigate harms
Advances in genetic and epigenetic approaches are contributing to our understanding of the causes of drug use and SUDs. SUDs are complex developmental disorders with high heritability that are also strongly influenced by environment—particularly during childhood and early adolescence.40 New scientific and computational methodologies are needed to elucidate the complex interplay of genetic and environmental factors across developmental trajectories of SUDs and comorbid conditions.
Gene discovery efforts provide the foundation for identification of drug targets, tailoring treatments by genotype (pharmacogenetics) and ultimately defining how environmental factors interact with genetic factors to contribute to SUD risk. By comparing SUD gene discovery data sets with other genome-wide association studies (GWAS), it is possible to identify gene variants that are comorbid with other disorders. Human genetic data will be used to inform preclinical genetic studies and vice versa, so that animal genetic studies can advance our understanding of human addiction.
Recent advances in genome editing using techniques such as CRISPR/Cas96, as well as sequencing technology, single-cell sampling, and computational tools41–43, provide the necessary tools to study reward phenotypes through precise manipulation of gene expression within specific neuronal populations. Studies using cell culture models of human neurons from people suffering from SUDs are allowing researchers to understand the effects of drugs on human neurons in vitro, which can be used to validate animal models or more efficiently screen the potential safety and efficacy of new medications. In addition, the arsenal of tools to directly modify the activation of brain cells (e.g., optogenetics, Designer Receptors Exclusively Activated by Designer Drugs [DREADDs]) is allowing causal investigation of circuits and behaviors in animals and the effects of drug use.44,45
To improve our understanding of the range of factors that mediate drug use behaviors and risk for addiction and build the foundation for future interventions, NIDA will support the following objectives:
- Objective 1.1: Characterize the genetic, neurobiological, environmental, social, and developmental factors that mediate risk and resilience for drug use and addiction
- Objective 1.2: Identify the factors that influence drug use trajectories
- Objective 1.3: Establish the effects of drug use, addiction, and recovery on genes, molecules, cells, brain circuits, behavior, and health across the lifespan
- Objective 1.4: Identify the bidirectional effects of drug use and common comorbidities