From the BRAIN Director: Looking Back and Looking Ahead

Dr. John Ngai in a lab

In years past, attending the annual late-fall meeting of the Society for Neuroscience (SfN) was a busy and at times tedious ritual. Months after submitting abstracts comes the frenzied work of putting together posters and slides and leaving our homes and labs for several days. Upon arrival, though, my mood quickly shifts to anticipation and excitement as new results are shared, new collaborations are hatched, and long-distance friendships are renewed or made anew. This year’s in-person SfN gathering in San Diego, CA was especially welcome, following three years of mostly remote work forced by the COVID-19 pandemic and its many limitations.

In addition to being a forum for new findings, meetings like SfN are also an important opportunity for scientists to learn about the BRAIN Initiative. As I wrote about recently, BRAIN strategically funds a variety of research: tool makers, individual labs testing new hypotheses, and large, team-based efforts aiming to catalyze neuroscience inquiry forward for everyone. BRAIN-funded science presented at SfN illustrates the diversity of science, scientists, and approaches that are providing hope for people with debilitating brain diseases and disorders. Among many talks and posters, I’ll mention just a few that stood out to me.

Dr. Hongkui Zeng from the Allen Institute for Brain Science updated us on the ongoing advances in defining cellular diversity. Various technologies continue to teach us what makes a brain cell different from its neighbor, why that matters, and how to understand the molecular properties of cells. As revealed by transcriptomics and other single cell methods, this work is shedding light on evolutionary relationships that in turn help to infer function. For example, Zeng’s recently published work revealed a previously underappreciated complexity of hippocampal cell types, drawing striking organizational parallels to the neocortex. The accomplishments of Zeng and her team highlight the power of team science and how it has propelled the BRAIN Initiative’s cell census program. It is extremely satisfying to look across the trajectory of this work, beginning eight years ago with the pilot projects of the BRAIN Initiative Cell Census Consortium, the scaled-up activities of the BRAIN Initiative Cell Census Network, all leading up to the recently launched BRAIN Initiative Cell Atlas Network. The success of this endeavor is emblematic of how sustained support of a community with a bold and common goal can enable remarkable progress buoyed by emerging technologies that drive innovation.

This year’s SfN meeting also featured a presentation about new ways to target, study, and repair the neural circuits that are affected in brain disorders. BRAIN-funded researcher Dr. Viviana Gradinaru from Caltech described putting engineering to work in the service of biology. Trained as an engineer, Gradinaru and her lab devised a clever suite of technologies to build new viral vectors for delivering genes with increasing precision to brain regions in both the central and peripheral nervous systems. Among the many fascinating vignettes she presented was her group’s trailblazing work with directed evolution and machine learning techniques to create new variants of adeno-associated virus capable of crossing the blood brain barrier. These re-tooled viruses can reach a broad spectrum of cell types in the brains of both rodents and non-human primates. The resources, which are openly available to the scientific community, are moving the field closer to gaining highly specific access to brain cell types for research and, eventually, precision gene therapies for treating human circuit disorders. Indeed, Gradinaru’s work embodies the goals of the Armamentarium for Precision Brain Cell Access, which supports her research.

Sharing new insights at SfN from innovative work I have highlighted in the past, BRAIN-funded Dr. Kafui Dzirasa from Duke University described progress on his protein-engineering based strategy to assess resilience at the level of neural circuits. He is using this model as a launchpad to intervene using customized gap junction proteins that can rewire a circuit toward a more resilient state. This coming year, Dzirasa’s and Gradinaru’s work and many other BRAIN-funded projects studying circuit function will get a significant boost from the BRAIN Initiative Connectivity across Scales (BRAIN CONNECTS) Network: one of three BRAIN-funded transformative projects that intend to help us learn how to map synapses and circuits across the entire mammalian brain.

Probably the most challenging mandate of the BRAIN Initiative is translating the language of synapses and circuits into human behaviors. What constellation of connections creates the ability to learn a language? Ride a bicycle? Play a guitar? Understanding (and ultimately manipulating) behaviors is a critical task for treating neuromuscular disorders, neuropsychiatric conditions, and other brain diseases. Recording behavior in living humans is central to this research. To catalyze this important work, through the recently announced Brain, Behavior, Quantification and Synchronization (BBQS) project, next year BRAIN will fund research to measure complex behaviors in both humans and other animal models while simultaneously recording activity in brain circuits. This will allow researchers to make more tangible links between activity coursing through neural circuits at any given moment and the behaviors that they generate.

For all of the endeavors I have described here, and across the entire portfolio of BRAIN-funded research, it is vital that the resources and tools that grow from our work will benefit all –  individuals of various ages and backgrounds, those who are members of NIH-designated U.S. health disparity populations, in diverse sociocultural settings, and in a range of disease states. This research will also benefit from diverse expertise including behavioralists, neurobiologists, social systems, computer scientists and data scientists, engineers, biostatisticians, and neuroethicists. Meaningful input from people with lived experience will be an essential component of these studies.

As this year draws to a close, I look back in awe of the work the BRAIN research community has accomplished. I deeply appreciate the intellect, the creativity, and the hard work amid significant challenges to everyday life that continue to test us as a scientific community, as a nation, and as a global society. But I am hopeful that as the world begins to open again after three tough pandemic years, we will use both planned and serendipitous encounters at conferences and other gatherings to celebrate our accomplishments and dream of new ways to understand the brain. I look forward with both optimism and excitement to what’s on the horizon as BRAIN continues on its steep trajectory of discovery driven by powerful new tools and diverse, creative minds.

With respect, gratitude, and best wishes for the holidays,

John Ngai, Ph.D.
Director, NIH BRAIN Initiative







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black and white image of people working on laptops at a counter height table on stools at the annual BRAIN meeting