A conversation about neuroscience

Nature research journal editors speak with Eric Nestler and Robert Greene about neurobiology and the Society for Neuroscience (SfN) 2017 annual meeting.

A conversation about neuroscience
presented by Nature Methods, Nature Neuroscience & Nature Communications

Sachin Ranade and Jean Zarate

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In advance of the 2017 annual meeting of the Society for Neuroscience, Jean Mary Zarate, an editor at Nature Neuroscience and Sachin Ranade , an editor at Nature Communications (photo, upper left) had the opportunity to speak with Eric Nestler, President of the Society for Neuroscience and researcher at the Icahn School of Medicine at Mt. Sinai and Robert Greene, a scientist at the University of Texas Southwestern Medical Center (photo, upper right).

Watch the video here

Brain initiatives galore, smiles aplenty

Vivien Marx reports on the Society for Neuroscience meeting in San Diego and the big brain projects in the EU and US.

SfN attendance sign

The Society for Neuroscience annual meeting in San Diego clocked record attendance.{credit}Vivien Marx{/credit}

The brain is hot.

Despite dismay about the recent 16-day US government shutdown, the impact of automatic budget cuts–the sequester–taking effect in light of federal budget disagreements in Washington, and the general economic malaise, there is palpable excitement. New large-scale initiatives are getting underway around the world to develop technologies to empower neuroscientists.

This year’s Society for Neuroscience (SfN) meeting in San Diego that has just ended, clocked a record attendance of over 30,000 attendees, noted society president Larry Swanson to attendees with a broad smile in one of his conference announcements. “It is an inspirational time to be a neuroscientist,” he said, with the field drawing attention, for example, across the European Union and in the White House. In a town hall meeting for the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, there was no lack of critical comments and suggestions of aspects to include in BRAIN. But smiles stayed plentiful as funders explained their plans.

The fact that the US president chose neuroscience as his multi-year, signature project is something “we should all be pretty excited about,” says Tom Insel, director of the National Institutes of Mental Health. In addition to projects in the US, such as  (BRAIN) Initiative and the EU’s Human Brain Project, large neuroscience projects are just emerging in Australia, China, Japan and Israel. “This is beginning to feel like a global movement,” he says. And projects are unfurling in the private sector, too.

The new tools, says Story Landis, director of the National Institute of Neurological Disorders and Stroke, will help neuroscientists do their work “bigger, better, faster” and expand the research strides made in recent years.

Much remains to be done. Compared to what is known about the kidney or heart, very little is known about the brain, says Insel. Adding to the neurological diseases, he noted, are the “invisible wounds of war” such as traumatic brain injury and post-traumatic stress disorder. Tools to help diagnose these illnesses are urgently needed.

Nora Volkow, director of the National Institute of Drug Abuse says that the BRAIN initiative stands to “act like a catalyst” in ways not unlike the decoding of the human genome and its successive “avalanche of discovery.”

Besides attending SfN’s hundreds of sessions and 17,000 posters, scientists had the chance to get up close and personal with representatives from the funding agencies and to hear about and discuss the new opportunities. Here is a snapshot of some of the announcements.

European Union
As Daniel Pasini from the European Commission’s programme on future and emerging technologies explained, the 10-year European Human Brain Project has invited the scientific community to present “grand ideas” for a massive effort to computationally reconstruct the human brain using supercomputers.

The model will help to study brain-related diseases, which are a major health challenge, an economic and social burden, and to pool data and expertise more effectively and translate results for treatments.

The project, which took three years of planning, involves over 250 scientists across Europe in 135 research groups in 22 countries, including groups in the US and Asia. The program began officially in October and has a budget of $1.6 billion. Half of the money will come from the EU the other will come from national funding sources, Pasini says. The first phase is slated to last 30 months and is funded with $100 million.

Six platforms are to be developed including, for example, the neuroinformatic platform as a single point of access to all neuroscience and clinical data along with software tools. The other platforms involve brain simulation, high performance computing, medical informatics, neuromorphic projects and neurorobotics. The idea is to keep improving the model as new data become available. All tools and data are set to be made available to the global scientific community. The plan is to create the ‘CERN for brain research.’ Not unlike a telescope facility or a super-collider, scientists will be able to perform experiments and use this platform to help continue to expand the model.

Deconstructing Henry

The Brain Observatory at UC San Diego is running ‘Deconstructing Henry’ an examination of the Brain of patient H.M.{credit}Vivien Marx{/credit}

US Defense Advanced Research Projects Agency (DARPA)
“Yes, we build guns and bombs, that is true,” says Colonel Geoffrey Ling of DARPA more generally. He is a neurologist who also served in Afghanistan and Iraq and currently deputy director of DARPA’s division responsible for defense sciences, which does not build bombs and guns. He and many other neuroscientists want to cure diseases ranging from Alzheimer’s to schizophrenia to post traumatic stress disorder to traumatic brain injury. DARPA is indeed “zeroed in” on the problems facing soldiers returning from the battlefield.

Speaking directly to fellow panelists from NIH, he says: “I wish they would double the budget yet again for you guys,” which was greeted by SfN attendees with vigorous applause.

Two DARPA solicitations for proposals are now open, offering “real money,” as Ling says, collecting projects that relate to memory dysfunction and psychiatric disorders. More solicitations are “in the works,” he says. “It’s not for us to decide what you’re going to build,” he says, highlighting the importance of imagination and taking a diversity of approaches.

The funding model at DARPA is shaped by use cases to assure that what is developed serves his constituency, the servicemen and women.

Multidisciplinary research, for example, is not achieved with the collaboration of a cellular neuroscientist, a neurophysiologist, and a neurologist. Rather, for DARPA interdisciplinary efforts can be a team comprised of a mathematician, a physicist and “a crazy guy in his backyard putting together some Rube Goldberg thing,” says Ling.

Unlike NIH, DARPA issues no grants but rather contracts, which are “deliverables-driven,” and may seem more rigid that NIH. But he sees strength in the synergy of the different funding approaches by NSF, NIH and DARPA. DARPA is committed to this project over the next decade, says Ling.

Data-sharing provisions are built into each contract, which DARPA takes “extremely seriously,” and breach of contracts are pursued. The DARPA solicitations issued are just the beginning, he says.

Systems based Neurotechnology for Emerging Therapies (SUBNETS)
Deadline: Dec. 17, 2013
This project seeks proposals to develop devices, perform model organism based research, or enable modeling of human neural systems, which are geared to help treat patients with neuropsychiatric and neurologic disease.

Restoring Active Memory (RAM)
Deadline: Jan. 6, 2014
This project seeks proposals in the area of analyzing and decoding neuronal signals which can be used to help patients recover memory function after injury.

SfN attendee bag

Companies in the neuroscience field may benefit from funding in the emerging large-scale projects. Here a scientst at SfN wears one company’s advertisement.{credit}Vivien Marx{/credit}

National Institutes of Health (NIH)
No grants have yet been awarded through the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. But grants are in the pipeline. True, says Insel, some see the project as a perhaps $40 billion dollar challenge, but he views the funding in 2014 as an “initial investment.”

The first report of the BRAIN initiative’s working group, says Landis, offers a guide for how the project could begin to move forward in its first year. The working group, is the advisory committee to the NIH director is chaired by Rockefeller University’s Cornelia Bargmann and Stanford University’s Bill Newsome. Landis says excitement is high in the Obama administration and across NIH. The hope is that this enthusiasm would be reflected in the budget allocations.

The NIH first year funding is “a down payment,” she says.

Insel says that the NIH’s $40 million to be allocated in 2014 is drawn from the following sources:

  • $10 million are coming from the NIH Director’s discretionary fund
  • $10 million are from the NIH Blueprint Neuroscience a program to enhance collaboration across NIH institutes
  • $20 million are split among four NIH agencies: National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Mental Health (NIMH), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institute of Drug Abuse (NIDA)

These monies were previously slated for initiatives of the individual institutes’ choice. As Landis explains, these four agencies agreed that the BRAIN Initiative was the one they selected for fund allocation. She says she and her colleagues are “optimistic” that the excitement, opportunities and promise of the BRAIN initiative will power the budgets of the future. Throughout sessions at SfN, she, Insel and others were quick to squelch fears that BRAIN would draw funding away from investigator-driven grants.

The first NIH Requests for Applications (RFAs) are currently begin hashed out with cross-communication happening across NIH, NSF and DARPA, says Insel.

All BRAIN Initiative projects will be peer-reviewed and perhaps unlike the more classic grants, they will have milestones and there will be expectations of data-sharing. “That’s going to be baked into everything we do in this project,” says Insel. Evaluations will accompany the projects after they are funded.

A number of awards are likely to be cooperative agreements, which are part way between a contract with deliverables and R01s, says Landis. These agreements are accompanied by milestones. If researchers do not share data and that provision is in their notice of grant award “there can be consequences,” she says.

Update: In mid-December NIH announced six funding opportunities. Approximately $44 million will finance six new funding opportunities.

Sunset at SfN

Two of the 30,000 attending scientists take a break outside the SfN conference halls.{credit}Vivien Marx{/credit}

National Science Foundation (NSF)
Cora Marrett, the acting director of the NSF says her agency will “very energetically” support the BRAIN Initiative. She says that funders need to take “the long view” to let the forces of scientific discovery play out with a long-term commitment. “I’m feeling very optimistic, too, about what the long-run prospects for additional resources will look like.”

Evidence of NSF’s engagement with neuroscience in general can be seen in the recent $25 million grant to fund the Center for Brains, Mind and Machines at the Massachusetts Institute of Technology. The intent is to blend computer science, math, robotics, neuroscience and cognitive science.

The BRAIN Initiative will require intense collaboration across disciplines and scales, she says. Neuroscience has been more devoted to small science, she says, the work of individual principal investigators and small lab groups. Marrett agrees with Alan Leshner, the executive publisher of Science, that neuroscience’s strides will benefit from a change in the culture toward larger-scale, interdisciplinary efforts.

At the same time, this shift will occur without prescriptions that all work needs to be on “the huge scale” of a particle accelerator, for example. Indeed neuroscientists will need to integrate findings across the scales of their research and link physiology, biophysical and genetic data with cognitive and behavioral findings (see Leshner Editorial in Science).

The projects will require data management plans of the grantees, she says, to explain how they will handle data-sharing, which is to the benefit of the entire enterprise.

The NIH’s BRAIN Initiative interim report – notes and thoughts

The first official report lists the scientific priorities that will be funded by the NIH as part of the BRAIN Initiative

brain_map

{credit}Margrie & Osten, Nat. Methods{/credit}

Yesterday evening we heard the first official report that delivered some details about what scientific areas the BRAIN Initiative (at least the part coordinated by the National Institutes of Health) will focus on and what its general approach to science funding will be.

Cori Bargmann and Bill Newsome (co-chairs of the NIH-appointed panel that is advising the NIH-director about the plan) spoke through a webcasted seminar to explain the conclusions that arose from the series of scientific workshops and meetings that have been taking place over the summer to discuss what could be the scientific priorities of the BRAIN Initiative. These priorities will set the ground of the research areas to be funded by the BRAIN initiative NIH funding in Fiscal Year 2014 (with a budget of US $40M).

The overall goal of the project was summarized as focusing of developing tools and resources for analyzing neuronal circuits and their function in living organisms.

The two scientists delved on a number of principles that applied to the overall initiative, such as promoting platforms for data sharing, promoting interdisciplinary research and focusing on a variety of experimental organisms and studies across temporal and spatial scales.

The specific areas that will be funded through the Initiative are summarized below:

  1. Generate a census of cell types in the nervous system. Including neurons and glia and techniques for targeting them. To be attempted in parallel in human and animal samples. Methods developed for this should apply across species.
  2. Create structural maps of the brain. This means cell to cell level connections in different animal models. This would complement the Human Connectome project (based on macroscale neuroimaging approaches).
  3. Develop new large scale methods for recording chemical and electrical activity of neurons. Scaling up of electrophysiological and imaging methods as well as completely new technologies.
  4. Develop a suite of tools for circuit manipulation and perturbation of circuit function. A push for the development of technologies like optogenetics that enable manipulating nervous activity in ways that resemble natural activity patterns.
  5. Linking brain activity to behavior. Activity monitoring at the same time that behavior is monitored. Highlighting the importance of making simultaneous measurements during long periods of time and during different types of behaviors.
  6. Integrating theory, statistics and computation with experimentation. Importance of theoretical frameworks that could explain principles of brain function.
  7. Delineate mechanisms underlying macroscale brain imaging technologies, as used in humans.
  8. Create mechanisms to enable collection of human data.
  9. Provide training so that new methods reach the community and promoting interdisciplinary research.

Although these FY2014 research priorities are presented as 9 independent entities, the goal is really to integrate these approaches as much as possible —but how exactly this integration will take place or be promoted is to be revealed by June 2014.  The goals are also highly ambitious and will require much more funding than the BRAIN Intiative’s current budget.

The speakers noted that the goals were not “to develop tools for tools sake” but tools that could have applicability. Innovative tools, thoroughly validated and applied in real nervous systems, improved through iterations and to ensure that they are disseminated efficiently to the community.

The commission also highlighted that their goal was not to deliver the solutions but the problems. Solutions to addressing these challenges are to come from ‘bottom-up’ approaches proposed by the community of scientists.

Tools for studying individual cells in the brain or the entire brain as a whole exist and continue to be very useful. But methods for understanding how connected networks of cells in the brain work and relate to behavior are still largely missing. Even maps of these connected entities remain unknown. Focusing funding on better tools to close this gap will be exciting and productive for advancing neuroscience as a whole.

The conclusions disclosed in this interim report are very much in line with what was expected of the project as announced a few months ago. They also largely agree with the main scientific goals that were deemed to be the top funding priorities for the National Science Foundation for the BRAIN Initiative (which will have US$20M to contribute, as well). Indeed, many of the topics covered in these 9 areas were things we and others discussed in editorials and commentaries related to the BRAIN Initiative in our pages and in this blog. The working group that has developed these priorities has had an inclusive, overarching frame of mind and included most of the major challenges that neuroscience currently faces, as most scientists would probably agree.

As we’ve said before, a push for technology development in neuroscience, with clear goals and challenges that these tools need to tackle, will surely be an efficient way of advancing the science of the brain.

It’s time to map the brain

A special complimentary focus on technology for large scale mapping of anatomy and function of brain circuits at Nature Methods
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These are exciting times in neuroscience. The technology available for  large-scale anatomical and functional brain mapping is advancing at a very high speed and it is foreseeable that these brain maps will have a profound impact on our understanding of how the brain works. Because of the importance of this topic, we devote a special focus to it.

To understand the brain we need to know how and when neurons fire in the living animal while it performs naturalistic behaviors. We need to know the underlying wiring patterns and anatomical configuration of the circuits and we need to be able to develop testable models of how behaviors arise from the underlying function of the cells in the brain.

Obtaining this type of systems-level information about the brain has not been easy up to now. But thanks to technological development, this is rapidly changing.

Rendering the connectivity maps of entire areas of the mammalian nervous system, like the retina, at nanometer resolution is now feasible in a few years work. These structural maps will contain unique information about the characteristics of neural circuits. But in addition to anatomical information, we need to monitor the brain at work at cellular level and we need to gather molecular information about its components. Together, the compilation of functional, structural and molecular data about the circuits in the living brain and their relation to behavior opens new posibilities for neuroscience.

Data-gathering alone will not, however, deliver the answers. Neuroscientists will need help from statisticians and mathematicians to make the information understandable and interpretable. After all, the data is only a tool that one hopes will lead to testable theories and models about how the brain works.

Because of the exciting moment at which the technology for mapping the brain is, we have put together a collection of Reviews, Perspectives and Commentaries in which experts discuss the state of the art technologies available for mapping the brain, the challenges and the potential of this endeavor. All the materials in this focus are freely available (thanks to our sponsors)—you can also read more about our views on the importance of this topic for neuroscience in our editorial.

We hope that these pieces will inform, inspire and incite discussions about mapping the brain and its potential to help us advance towards a deeper understanding of our own minds.

An era for BRAIN technology

President Barack Obama has just proposed large investments in a project aiming to develop technologies that enhance our understanding of brain function.

In an official announcement from the White House, US President Obama just launched the BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative project. This basic research project is expected to receive large sums of public and private funding to promote technologies that expand our knowledge of brain function.

This was a much awaited announcement. From what can be read in the White House’s official Press release, the BRAIN Initiative will be a collaboration between the US National Institutes of Health, the Defense Advanced Research Projects Agency and the National Science Foundation, with an initial injection of funds going up to $100 million for 2014.

To set the goals and timeline of this project, the NIH will establish a working group composed of 60-80 scientists co-chaired by Cori Bargmann of Rockefeller University and Bill Newsome from Stanford University. Through workshops and meetings that will take place in 2013, the working group will define the detailed scientific goals and establish a multi-year scientific plan for achieving them. The workshops are to start in about one month.

In addition, the project will have several private sector partners: the Allen Institute for Brain Science, the Howard Hughes Medical Institute (HHMI), the Kavli Foundation and the Salk Institute for Biological Studies. Most of these institutions have already been investing in technology development to address the challenges of understanding the brain for some time. In fact, Nature Methods recently published work from HHMI investigators showing the first whole brain imaging of neural activity at the single-cell level. As the details of the goals and timelines of the BRAIN Initiative become clearer over the next few months, we will likely have a more concrete idea of how the budget for BRAIN will be projected in the coming years.

What is unique about BRAIN compared to other previous ‘big science’ projects like the Human Genome Project is that it is advocating for technology development first as it lays out its broad goals without indicating a particular biological idea or concept. The need for technology development is so dear in neuroscience that in our view devoting substantial resources to this is essential for understanding brain function, a view that appears to be shared by the HHMI as evidenced by the substantial technology development they are funding for brain research at the HHMI Janelia Farm Research campus.

As we have discussed in previous posts on this site and in our April Editorial, to understand the brain we will need technologies that help large scale mapping of the structural wiring diagrams in the brain, that record the activity of whole brains in action at resolutions that mirror those of physiology and behavior and that link function and behavior. In all these areas, we first need to improve our tools and methods.

The progress that can be made by promoting technological development cannot be underestimated. Once more powerful methods are in the hands of researchers, knowledge will advance at a much higher speed and investments in science will be more productive and efficient.

Whole brain cellular-level activity mapping in a second

It is now possible to map the activity of nearly all the neurons in a vertebrate brain at cellular resolution in just over a second. What does this mean for neuroscience research and projects like the Brain Activity Map proposal?

In an Article that just went live in Nature Methods, Misha Ahrens and Philipp Keller from HHMI’s Janelia Farm Research Campus used high-speed light sheet microscopy to image the activity of 80% of the neurons in the brain of a fish larva at speeds of a whole brain every 1.3 seconds. This represents—to our knowledge—the first technology that achieves whole brain imaging of a vertebrate brain at cellular resolution with speeds that approximate neural activity patterns and behavior.

Click on the image to view the video.

Brain activity imaging of a whole zebrafish brain at single-cell resolution. Click on image to view video [20 MB].

Interestingly, the paper comes out at a time when much is being discussed and written about mapping brain activity at the cellular level. This is one of the main proposals of the Brain Activity Map—a project that is being discussed at the White House and could be NIH’s next ‘big science’ project for the next 10-15 years. [Just for clarity, the authors of this work are not formally associated with the BAM proposal].

The details of BAM’s exact goals and a clear roadmap and timeline to achieve them have yet to be presented, but from what its proponents have described in a recent Science paper the main aspiration of the project is to improve our understanding of how whole neuronal circuits work at the cellular level. The project seeks to monitor the activity of whole circuits as well as manipulate them to study their functional role. To reach these goals, first and foremost one must have technology capable of measuring the activity of individual neurons throughout the entire brain in a way that can discriminate individual circuits. The most obvious way to do this is by imaging the activity as it is occurring.

With improvements in the speed and resolution of existing microscopy setups and in the probes for monitoring activity, exhaustive imaging of neuronal function across a small transparent organism was bound to be possible—as this study has now shown.

The study has also made interesting discoveries. The authors saw correlated activity patterns measured at the cellular level that spanned large areas of the brain—pointing to the existence of broadly distributed functional circuits. The next steps will be to determine the causal role that these circuits play in behavior—something that will require improvements in the methods for 3D optogenetics. Obtaining the detailed anatomical map of these circuits will also be key to understand the brain’s organization at its deepest level.

These are some of the types of experiments described in the BAM proposal and they are clearly within reach in the next 10 years–whether through a centralized initiative or through normal lab competition and peer review. While it is expected that in mice, too, functional circuits will span large brain areas, performing these types of experiments in mice will require more methodological imagination. It will not be possible to place a living mouse brain within the microscope system used by Ahrens and Keller to image the zebrafish brain. The mouse brain is significantly bigger, is largely impenetrable to visible light and is surrounded by a skull. Realistically, we may not see methods that enable whole brain activity mapping in mammals at the cellular level for quite a while.

But there is much worth learning about brain function in smaller organisms such as the zebrafish and drosophila, and microscopy systems such as this will be capable of providing important fundamental insights into brain function that are relevant to our understanding of the human brain.

Whether it will be through BAM or not, the neuroscience community has important challenges to tackle ahead. At Nature Methods, we have been actively involved in supporting technology development in the neurosciences from the very beginning and we look forward with enthusiasm to doing so during this exciting period in neuroscience research.

Update: We just published an Editorial on this topic in our May issue.