BRAIN at 10: A View from the National Institute on Drug Abuse

By Nora Volkow, MD, Director, and Rita Valentino, PhD, Director, Division of Neuroscience and Behavior, NIDA

This blog was originally posted on the The BRAIN Blog.

The BRAIN Initiative is marking a milestone—10 years of?advancing neuroscience and neurotechnology research by funding innovative projects. As part of a rotating series of blog posts, the directors of the BRAIN Initiative-partnering Institutes and Centers share their voice and perspectives on the impact BRAIN has made on their respective missions—and vice versa.

This year marks the 50th anniversary of the National Institute on Drug Abuse (NIDA). The research NIDA has funded and conducted over five decades has greatly advanced the biomedical understanding of addiction as a treatable condition involving brain systems governing reward, emotion, stress, and self-control. NIDA research has helped pave the way for effective prevention, treatment, and harm reduction approaches, and opened up new pathways to recovery.

NIDA has been a key player in the BRAIN Initiative, as our Institute continues to apply these new tools and emerging knowledge to inform research about the science of drug use and addiction. As the United States continues to face a devastating overdose epidemic fueled in recent years by an influx of illicit fentanyl, NIDA’s scientific efforts are ever more important. Central to those efforts is our significant investment in basic neuroscience research. Since its launch a decade ago, the BRAIN?Initiative has greatly aided and accelerated that research. Tools developed through the BRAIN Initiative are catalyzing scientists’ ability to precisely monitor and manipulate brain activity at multiple scales, giving us an ever more fine-grained understanding of the brain mechanisms underpinning drugs’ effects and suggesting potential avenues for mitigating, preventing, or reversing those effects to heal the brain.??

Why do you think it’s important for NIDA to participate in the NIH BRAIN Initiative?

The BRAIN initiative has transformed neuroscience research at many levels. It has created a culture of team science that has led to development and dissemination of new tools that have been used to characterize gene expression with cellular resolution across multiple species, tools that allow visualizing and manipulating neural circuits, as well as new approaches to data science and computational modeling. Our staff who work on BRAIN Initiative program teams get a unique exposure to these approaches and technologies that will critically shape our Institute’s research in future years.

Advances made possible through the BRAIN Initiative will transform translational research by improving the validity and innovation of the models we use to probe mechanisms underlying substance use and use disorders—enriching our research community’s capacity to innovate. NIDA participation in the BRAIN Initiative provides opportunities to accelerate the application of these advances among the researchers who focus on these questions.?And it enables NIDA to promote areas of focus where our Institute has been at the forefront, including investigation of non-neuronal cells (glia) and developmental studies that dovetail with the Adolescent Brain Cognitive Development (ABCD) study.

How has NIDA participated in the NIH BRAIN Initiative?

Several of NIDA’s scientific staff are members of BRAIN Initiative program teams, and our Institute leads or co-leads some key BRAIN projects.?NIDA co-leads the team that is?managing?the Data Science and Informatics project, which is creating the informatics infrastructure needed for storing, sharing, and interpreting the vast quantities of data gathered by the BRAIN Initiative. NIDA also co-leads the?Tools and Technologies for Brain Cells and Circuits research program, which is creating brain cell atlases of the neuronal and glial cells? in the brain. This fundamental knowledge will be used to build viral vectors to monitor and manipulate brain function at the cellular level.

We are also a major supporter of the Brain Behavior Quantification and Synchronization Program (BBQS). This uniquely transdisciplinary program, which was just launched in 2022, is supporting the development and validation of novel tools and methods for quantifying complex behaviors and simultaneously recording brain activity. This program promises to transform behavioral and cognitive neuroscience by supporting research that will generate high-resolution tools for analyzing behavior and new computational and theoretical approaches for understanding behavior as a complex system. NIDA leads the BBQS emphasis area on organismal behavior.

Although it was just launched two years ago, the BRAIN BBQS concept has influenced multiple NIDA initiatives, including Translating Socioenvironmental Influences on Neurocognitive Development and Addiction Risk (TranSINDA), Mechanistic Studies on Social Behavior in Substance Use Disorder (in both humans and animal models), and the NIDA Animal Genomics Consortium. These initiatives support research that identifies cause-and-effect relationships between socioenvironmental factors and brain function that guide behavior.

Toward advancing the emergence of common marmosets as a promising animal model in neuroscience, NIDA has also played a leadership role in BRAIN’s transgenic marmoset initiative. This set of projects is aimed at developing novel tools and techniques for marmoset genome editing and male germline editing to facilitate research on genetic underpinnings of brain health and disease, as well as assisted reproduction techniques to increase the efficiency of these procedures.

What major BRAIN-funded scientific advancements or conversations has NIDA been a part of?

As?one of the Institutes co-leading the?BRAIN Initiative’s Tools and Technologies for Brain Cells and Circuits research program,?NIDA has been closely involved in?shaping and?supporting the inventory and molecular mapping of?cell classes across the whole mouse brain, and there are ongoing plans to?accomplish the?same in human and nonhuman primate brains.?

A component of this program is the Cell Census Network, and among the brain regions of central interest in this project are the basal ganglia. The basal ganglia comprise the reward pathway and other circuits that play a major role in substance use disorders. Scientific staff at NIDA and several NIDA-funded grantees are participating in the effort to create a systematic map of this region to enhance our knowledge of its cellular and molecular architecture. This research could potentially lead to tools that could selectively target the basal ganglia’s cellular constituents, which would be a game changer for NIDA science.?

Through BRAIN Initiative programs like BBQS mentioned above, NIDA has been co-leading discussions about advancing cause and effect relationships in human neuroscience research. We now have large neurocognitive datasets that can be mined and analyzed using large-scale network approaches, such as those generated by the Human Connectome Project and the ongoing ABCD study. These databases have enabled novel insights about fundamental brain function and neurocognitive dysfunction. For instance, ABCD is deepening our understanding of how environmental exposures affect neurocognition including revealing factors like economic disadvantage and social discrimination that can be targeted in prevention efforts. But while these datasets are excellent for identifying associations between network structure/function and behavior, they generally cannot help us establish causal relationships, leaving a gap in our ability to translate findings to clinical application.

Data derived from new methods and approaches like systematic circuit perturbation in combination with neural recordings in a behavioral context hold potential to fill this gap and significantly advance our understanding of these important cause and effect relationships in human neuroscience.

How has the BRAIN Initiative advanced or shaped NIDA’s mission?

Many tools developed through the BRAIN Initiative are helping NIDA scientists understand how drugs affect the brain,?from cellular to circuit levels. For example, NIDA’s BRAIN-inspired research programs are already producing exciting findings. One of them is?NIDA?Single Cell Opioid?Response in the Context of HIV, or SCORCH, which is applying single-cell sequencing-based approaches to inventory the cellular targets of drugs and the changes in those targets that drugs induce. A NIDA-funded team has recently identified a group of neurons in the dorsal peduncular nucleus, a brain region central to emotional regulation, reward, and motivation, that act as a master regulator of opioid reward.

Another NIDA initiative inspired by BRAIN is the?Neural Ensembles and Used Substances (NExUS) Collaboratory, which seeks to integrate molecular information from cell taxonomies with measurement of neuronal population dynamics in behaving animals. NExUS aims to decipher how activity within the mosaic of brain cells “encode” particular properties of misused substances, such as the analgesic versus addictive properties of opioids.?A NIDA-funded team has also recently used a mouse model to identify a brain circuit that mediates placebo pain relief.

In its 10 years, the BRAIN initiative has provided tools to visualize, monitor, and manipulate brain activity from molecular to network levels and has led to an exponential growth in understanding of how the brain functions. NIDA has been a key player in this effort, and our Institute continues to apply these new tools and emerging knowledge to inform research on urgent questions under its mission to advance the science of drug use and addiction.

View Nora's blog on NIDA's website.