Medical School neurobiologist wins prestigious Brain Prize

Harvard Medical School neurobiologist Michael Greenberg has won The Brain Prize 2023 for his lifelong research into brain plasticity: the ability of the organ to change, adapt, and learn over time.

Greenberg, who is the Nathan Marsh Pusey Professor of Neurobiology in the Blavatnik Institute at HMS, shares the award with Christine Holt, professor of developmental neuroscience at the University of Cambridge, and with Erin Schuman, director of the Max Planck Institute for Brain Research.

Collectively, the three scientists have made significant advances in unveiling the cellular and molecular mechanisms that enable the brain to restructure itself in response to external stimuli as it adapts, learns, and even recovers from injury.

The Brain Prize, considered the world’s most significant prize for brain research, includes approximately €1.3 million to be shared by the three recipients. The prize is awarded annually by the Danish Lundbeck Foundation to researchers who have made highly original and influential discoveries in brain research.

Greenberg’s research focuses on understanding how the brain responds to signals from the outside world to modulate the activity of genes that make proteins essential for brain plasticity. Throughout his career, Greenberg has delved into the details of this process, elucidating the identities, roles, and relationships of the various genes, proteins, and molecules involved.

“That our sensory experiences shape the structure and function of the brain is one of the profound discoveries in the field of neuroscience in the 20th century,” said David Ginty, chair of neurobiology at HMS. “Mike’s work, which has extended into the 21st century, has explained how this fundamental feature of brain function is achieved at a molecular, cellular, and circuit level.”

Brain plasticity, or the brain’s ability to rewire itself in response to new information throughout life, is a hallmark of the brain; central to the organ’s ability to function over many decades and to recover or regain function after damage.

To achieve this feat, the brain must continuously create new neural circuits and modify existing ones as it encounters information from the environment. This highly complex and dynamic process requires the brain to carefully orchestrate a multitude of molecules that communicate in signaling pathways and form the cellular basis of learning and memory.

Throughout his career, Greenberg has explored the role of genes in this process — how they work together with life experiences and external signals to support brain development and to ensure that the brain remains adaptable, or plastic, over time.

“Mike’s elegant research highlights the power of basic discovery as the most essential fuel for scientific progress. His impressive accomplishments, which now include this wonderful accolade, show just how much is possible when researchers unwaveringly follow their curiosity and scientific passions,” said HMS Dean George Q. Daley.

A convergence of insights

Greenberg and co-recipients Holt and Schuman are each studying different aspects of protein production within the context of brain plasticity.

Holt’s research focuses on the vertebrate visual system — specifically, the neurons that extend from the eye to the brain — to understand how neural connections in the brain form and are maintained over time. She has shown that proteins must be made and degraded locally to guide the growth of cone cells needed for vision. A continuous supply of locally made proteins is also required to maintain axons — the long fibers that transmit information down neurons. Holt’s work sheds light on how neural connections are established and how axons are sustained throughout life.

Schuman is interested in the processes that control how proteins are made and degraded in neuron structures that are distant from the cell body, including axons and branching dendrites that extend into synapses. She has shown that neurons have localized cellular machinery — namely, ribosomes and proteasomes — in axons and dendrites. She has also established that proteins made in dendrites are needed for synaptic plasticity and revealed molecular details of the mRNA and ribosomes involved. Her lab has developed new tools to label, purify, identify, and visualize newly made proteins in neurons and other cells.

“Together, the Brain Prize 2023 winners have made groundbreaking discoveries by showing how the synthesis of new proteins is triggered in different neuronal compartments, thereby guiding brain development and plasticity in ways that impact our behavior for a lifetime,” said Richard Morris, a professor of neuroscience at the University of Edinburgh and chair of the selection committee.

Of proteins and plasticity

As a postdoctoral researcher in the lab of Edward Ziff, a professor of biochemistry and neural science at New York University School of Medicine, Greenberg began studying the genetic changes that occur inside a mammalian cell when it is stimulated from the outside. He discovered that within minutes of stimulation, the cell begins to express a gene called c-fos, which, in turn, boosts the production of the associated Fos protein.

This turned out to be a milestone discovery.

“The idea that gene expression changes could be induced on such a rapid timescale was a paradigm shift that ushered in a new era for neuroscience,” wrote Emily Osterweil, a professor of molecular neuroscience at the University of Edinburgh, in a commentary about the work of the three winners.

Greenberg continued this line of research as an assistant professor at HMS. Notably, he established a connection between neurotransmitters — chemical messengers that flow from one neuron to the next — and changes in the activity of genes. He described a signaling cascade that starts with the release of neurotransmitters and leads to a spike in calcium in the neuron receiving the message. This influx of calcium induces the neuron to activate c-fos and other genes that make proteins, which, in turn, initiate downstream signaling.

Greenberg went on to more fully define the signaling pathways that neurotransmitters use to activate genes and identify the specific proteins involved. The work of other labs suggests that one of these proteins, CREB, is an important mediator of long-term memory. Building on Greenberg’s work, scientists have also identified hundreds of stimuli that induce Fos production in the brain during different behaviors, thus demonstrating the protein’s ubiquity and importance for brain function.

Greenberg is now working to further characterize the products of genes controlled by neural activity, including how these gene products interact. For example, he learned that Fos works with another protein, NPAS4, to regulate the expression of certain genes by modulating the on-off signals in neurons in response to stimuli. His findings offer a new possible mechanism for long-lasting brain plasticity that may underlie associative learning and spatial navigation. He also established that Fos plays a role in remodeling genetic material inside cells in conjunction with a protein complex called BAF, which has been implicated in neurodevelopmental disorders such as autism.

Greenberg’s efforts have provided insight into the mechanisms by which activity-related genes control the maturation, pruning, and stability of synapses — the small gaps where neurons connect and communicate. Greenberg has linked the gene transcription programs he is studying to key aspects of experience-dependent brain maturation and plasticity, including the formation of context-dependent memories and the plasticity of the visual system during development. His work sheds light on the origins of disorders in which mechanisms of neural plasticity are disrupted.

Greenberg’s research has also yielded important technical advances. His discovery of Fos induction provided researchers with a tool that is now widely used to identify the neurons and neural circuits that mediate behavior. His discoveries have also led to innovative ways of trapping these neurons to assess their function in neural circuits, and new strategies for making detailed observations about the molecules and mechanisms that mediate learning, memory, and behavior.

“For me, this is the culmination of a 40-year odyssey aimed at understanding how our sensory experiences impinge on the neuronal genome to orchestrate brain maturation and the plasticity that underlies long-term memory and how these processes go awry in disorders of the nervous system,” Greenberg said.

Greenberg earned a bachelor’s degree in chemistry from Wesleyan University and completed his PhD at Rockefeller University. Following his postdoctoral research at NYU, he became an assistant professor in the Department of Microbiology and Molecular Genetics at HMS, and later, director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital. In 2008, he became the chair of neurobiology at HMS, a position he held for 14 years.

Greenberg is a member of the American Academy of Arts and Sciences, the National Academy of Sciences, and the National Academy of Medicine. He has received numerous other awards, including a McKnight award for technological advances in neuroscience, the 2015 Gruber Prize in Neuroscience, the 2019 Ralph W. Gerard Prize in Neuroscience, and the 2022 Edward M. Scolnick Prize in Neuroscience.

The Lundbeck Foundation has awarded The Brain Prize annually since 2011. Winners are selected by a committee of nine leading neuroscientists from around the world who have expertise in diverse neuroscience disciplines.