It Begins with Basic Science

In my Director’s messages, I’ve written about the breadth of research funded by NIMH. I’ve written about services research, learning what it takes to ensure that effective treatments can be delivered in real-world settings; about translational research aimed at finding biomarkers and novel therapeutics; and, about how we are trying to use the latest genetic information to understand how psychiatric dysfunction is encoded in our genomes. These are all important, directed efforts to explore the mechanisms of mental illnesses, with the expectation that these discoveries will lead to novel treatments or the better application of existing ones.

Biomedical scientists, however, have long recognized that some of the most important advances in the understanding and treatment of diseases come not from such directed efforts, but from basic research aimed at simply understanding the complex biological processes that make the human body work. Indeed, it was basic science research into the biochemistry of how cells reproduce that led to chemotherapies for cancer; investigations into how the inner ear works that led to cochlear implants for deafness; and, curiosity-driven studies of microorganisms that led to antibiotics for bacterial infections. Knowing this history, NIMH supports a robust program of basic neuroscience studies that aim to discover how the brain works.

Basic neuroscience was on full display earlier this month at the annual meeting of the Society for Neuroscience (SfN) , the largest gathering of neuroscientists in the world. Nearly 30,000 of us attended, viewing thousands of scientific presentations, sharing findings yet to be published, celebrating successes, and learning from failures. Those of you who follow me on Twitter (@NIMHDirector ) saw snippets of these goings-on, which I’ll elaborate on here.

Let’s start with a really basic question: How do neurons work together in circuits to drive behavior? This question is one that neuroscientists have been asking since we realized the brain drives behavior and is made up of neurons. For the longest time, we tried to answer this by recording a single neuron at a time. We made a lot of progress this way—for example, we learned how visual features are encoded in neurons in the primary visual cortex—but we also learned that studying neurons one at a time doesn’t give you all the information you need to understand how the brain works. Hence, the creation of the BRAIN Initiative , an all-out attempt to develop novel neuroscience tools such as those that will permit what we call “massively multiparallel neural recordings”—recording from large numbers of neurons at a time. Much of this type of recording was on display at the SfN meeting.

One of the holy grails of massively multiparallel recording is the ability to record all of the neurons in an organism at once during an interesting behavior. Attempts to do this in model organisms such as Drosophila (the fruit fly) and zebrafish (small vertebrates) have made some progress. But what intrigued me at SfN was a beautiful demonstration of what might be possible in an even simpler marine organism—the hydra. Currently under development in the Columbia University laboratory of Dr. Rafael Yuste, M.D., Ph.D., this project aims to simultaneously record the activity of all the neurons and muscles of the hydra, to learn how this organism drives its motor and sensory behaviors. Dr. Wataru Yamamoto, Ph.D., a postdoc in the Yuste lab, showed beautiful videos of the hydra, illuminating the activity of all of the neurons and musculature during free swimming. Dr. Yamamoto hopes to use these images to understand how the dynamics of the hydra’s nervous system guide behavior.

Of course, we’d love to learn what we can about more complex behaviors, even if we can’t yet study the activity of every neuron in a more complex brain. One of the most interesting behaviors to study is decision-making: How does the brain decide between multiple behavioral outputs? Several presentations on this subject drew my attention at SfN. Dr. Christine Constantinople, Ph.D., an early career scientist newly appointed to the faculty of New York University as an assistant professor, talked about her work with Dr. Carlos Brody, Ph.D., of Princeton University, showing how rats choose between sure bets and risky decisions in a gambling-like task. Dr. Constantinople told us about her work recording hundreds of neurons at a time using advanced imaging and neuromodulation technologies. Her research revealed a subset of neurons in the orbitofrontal cortex, an area of the frontal lobe that is thought to play a role in value-based decisions, that react to winning by encouraging further risk-taking. This striking study helps us understand a piece of the puzzle as to why people choose to take risks, whether it be in gambling or in other aspects of life—there is a piece of our brain that says, “I won! Let’s win more!”

From junior investigators to senior sages, all kinds of neuroscientists from around the world took part in SfN. Continuing the decision-making theme, Dr. Zachary Mainen, Ph.D., of the Champalimaud Center for the Unknown (what a great name for an institute aimed at studying the brain!) in Lisbon, Portugal, gave one of the Special Lectures on the role of serotonin, a neurotransmitter that plays important roles in decision-making (and in many psychiatric illnesses). Dr. Mainen showed a packed house of thousands of eager neuroscientists how serotonin neurons act as a kind of thermostat for learning. The neurons do this by setting the rate at which we update our understanding of how the world works, based on how many mistakes we make. If we make a lot of mistakes, serotonin neurons increase their activity. This increased activity signals the potential need for more learning, cranking up neural plasticity—the ability of neurons to change their connections and activity patterns in order to encode new information. Serotonin essentially acts to increase flexibility—a trait especially well-developed in us humans. We have tremendous ability to flexibly respond to changes in our environment, a gift that is at least partially facilitated by serotonin.

Trainees in neuroscience know all about flexibility and learning, and SfN is one place they get to show off what they have learned. Every year, I look forward to talking with trainees during the poster sessions, where (typically but not exclusively junior) scientists present their research and engage in an enriching, empowering, and exhausting marathon of presentations and discussions over the course of a 4-hour session. These are amazing opportunities to engage in give-and-take discussions, informal mentoring, and lots and lots of learning. I had the great pleasure of engaging with Héctor Bravo-Rivera, an outstanding graduate student in the laboratory of Dr. Gregory Quirk, Ph.D., at the University of Puerto Rico. Dr. Quirk is a long-time NIMH grantee who has been a supportive and effective mentor, training numerous undergraduate and graduate students who have gone on to stellar neuroscience careers. Dr. Quirk and his crew of trainees, Shantée Ayala-Rosario and Albit Cabán-Murillo, presented a poster on decision-making under conditions of threat.

Of course, SfN was full of directed, psychiatrically-relevant neuroscience as well, including studies of prenatal stress and how it affects the maternal and infant microbiome; the neurobiology of social behavior, depression, psychosis, and more; and, promising genetic models for the study of autism and schizophrenia. Although SfN offers a wealth of research, the highlight of this conference will always be basic research. Will exploring the neural activity patterns of hydra ever tell us about neural activity patterns in schizophrenia? Will understanding how rats make risky decisions using serotonin and their amygdalo-prefrontal-accumbens networks help us restore faulty decision-making that occurs with obsessive-compulsive disorder (OCD) or depression? You never know… and that’s the point.