Looking to the Future of Fundamental Neuroscience

By Walter J. Koroshetz, M.D., Director, NINDS and Lyn Jakeman, Ph.D., Director of the Division of Neuroscience in Extramural Programs at NINDS

The nervous system is exceedingly complex and our lack of understanding of how it works stymies our efforts to develop treatments for neurological disorders. The brain, composed of 85 billion neurons and trillions of connections with an equal number of glial, vascular and immune cells, functions as an interrelated web to process information. Besides the connections within the nervous system, there is also a complex interplay with other body systems, especially since the nervous system supplies nerves to our organs. Nervous system cells themselves are unique in many ways: most dramatic are the long, sometimes feet long, thin processes that need to be nourished by cell bodies that are only a few microns in diameter. Understanding how the nervous system develops and carries out its complex functions is one of the greatest challenges in science and is critical for developing treatments for neurological disorders and diseases. While neuroscientists have made great discoveries since the days of Ramón y Cajal and colleagues, important fundamental questions remain.

Since NINDS’s formation in 1950, we have long recognized the importance of supporting basic discovery or fundamental neuroscience (FN) research, and that work continues today. A great example is NINDS’s participation in the Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative that is revolutionizing our ability to understand how neural circuits process information. We are always seeking new ways to stimulate innovation and reinforce the bedrock of neurological advances through FN research. To address this goal, we recently convened a Fundamental Neuroscience Working Group (FNWG) of the National Advisory Neurological Disorders and Stroke (NANDS) Council to provide recommendations on how we can create opportunities to catalyze and accelerate discoveries in important fields of FN research. We are grateful to share that at our most recent Council meeting, the FNWG recommendations were approved.

Recommendations from the Fundamental Neuroscience Working Group(pdf, 915 KB):

  1. Prioritize research into the organization of macromolecular complexes within cells from a few nanometers to one micron in length by developing tools and research programs to create a dynamic Macromolecular Cartography that analyzes subsets of proteins known to be part of functional subcellular units.

  2. Enable quantitative approaches to characterize protein and molecule turnover timescales and location in vivo to advance understanding of molecular interactions, their contribution to cellular stability and plasticity.

  3. Support approaches for capturing and imaging cell movement and cell-cell interaction during development of the nervous system.

  4. Ensure adequate resourcing of tool development for in vivo measurement of cellular activity.

  5. Promote interdisciplinary team science and collaborations with technical expertise across diverse disciplines.

  6. Support the mentoring of the next generation of FN researchers.

The FNWG was charged to: 1) look to the future of FN by identifying critical gaps, key unanswered questions, and new opportunities in FN research, 2) evaluate the effectiveness and potential of current NINDS programs to support the breadth of FN research, and 3) propose and prioritize concepts and strategies that could enhance the overall impact of NINDS FN research over the next 5-10 years.

The FNWG, led by Drs. Yishi Jin and Timothy Ryan, included FN investigators from across the country. Given that FN research is characteristically driven by open curiosity and infinite topical areas, the group focused discussion on generating cross-cutting ideas and themes at the level of cellular and molecular neuroscience. This approach was motivated by the relatively untapped microscopic research scale, with a potential to be highly impactful in addressing a broad range of fundamental questions. To carry out their charge, the FNWG formed seven subgroups across cellular and molecular neuroscience domains, including: neural development; genomic organization and regulation; inter-tissue interactions; metabolism; lipid stasis; atomic organization of machinery; and subcellular organization of machinery. Each subgroup considered critical knowledge gaps, ideas to foster mechanistic investigation, technology hurdles, and perceived funding difficulties, towards an overarching goal of identifying high-priority themes and concepts that could be considered cross-cutting, with applications to many domains.

The FNWG’s recommendations intend to advance a mechanistic understanding of neurobiology at the cellular and molecular level and to generate new hypotheses addressing the molecular machineries that form, drive, and maintain the organization and function of the nervous system. The first four recommendations focus on research tool development in cellular and molecular neuroscience with the FNWG’s consideration that technological solutions and microscopic capabilities are close to fruition for breakthroughs in these four areas. The FNWG conveyed that addressing common research bottlenecks can enable broad reaching opportunities for investigators seeking to pursue all sorts of research questions driven by individual curiosity. A similar approach has been taken to advance groundbreaking research spurred by the NIH BRAIN Initiative's focus on understanding neural circuits.

The last two recommendations were considered absolutely essential for invigorating the current basic research workforce and community. FNWG recommended that NINDS support initiatives that enhance team science and cross-disciplinary efforts between neuroscientists and experts in other fields such as cell biology, protein chemistry and biophysics, as these cross-disciplinary approaches could be uniquely valuable to the proposed efforts. In the same vein, the FNWG recommended that NINDS support the cultivation and interdisciplinary training of a diverse pipeline of the next generation of FN scientists. This cultivation should begin specifically with support for and engagement of research at the undergraduate level and encompass trainees with diverse perspectives and broad interests.

During Council discussion, some members wondered about the ability to facilitate research approaches that are spontaneous and untargeted as well as team science. Others were curious about whether a perceived emphasis on descriptive biology studies could also be reconciled with the focus on hypothesis testing to answer mechanistic questions. Alongside the recommendations, NINDS will explore these issues carefully as we work to implement the group’s recommendations, identifying how we can best foster fundamental neuroscience research for cellular and molecular neuroscience. In addition, we will be looking for opportunities and partnerships to support tool development and dissemination that can advance cellular and molecular neuroscience while continuing to support all areas of FN. We will work to identify ways to bring together diverse teams and trainees to address the big questions and challenges in FN.

These recommendations complement the NINDS five-year strategic plan, which underscores the unique value of FN and our commitment to supporting investigator-initiated discovery research across the neuroscience spectrum. To help inform our implementation of the FNWG recommendations, we want to hear from you, too. In addition to the resources below, you are encouraged to submit comments to NINDS at fn@nih.gov regarding FNWG’s report or any points related to promoting FN research.

We thank the Working Group members for their hard work over the last year, as well as the NINDS staff who facilitated and supported their deliberations. A richer understanding of all facets of fundamental neuroscience, including the cellular and molecular machineries that make up the nervous system, will benefit the entire neuroscience community and ultimately improve neurological health for all people.

Related Resources: