Harvard Neurobiologist Wins Major Award for Brain Plasticity Research – Harvard Gazette

Neurobiologist at Harvard Medical School Michael Greenberg have earned Brain Awards 2023 For his lifelong research on brain plasticity.

Greenberg, Nathan Marsh Pusey Professor of Neurobiology at the Bravatnik Institute at HMS, received the award alongside Christine Holt, Professor of Developmental Neuroscience at the University of Cambridge, and Erin Schumann, Director of the Max Planck Institute for the Brain. .

Three scientists work together to uncover cellular and molecular mechanisms that enable the brain to remodel itself in response to external stimuli as it adapts, learns and even recovers from injury. We have made great progress in doing so.

Considered the world’s most important award for brain research, the Brain Prize includes approximately €1.3 million, shared among the three winners. This award is given 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 and elucidated 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 key discoveries in 20th-century neuroscience. David Ginty, Chair of Neurobiology, HMS. “Mike’s work, extending into the 21st century, explains how this fundamental feature of brain function is achieved at the molecular, cellular, and circuit levels.”

Brain plasticity, or the brain’s ability to rewire itself in response to new information throughout life, is a hallmark of the brain. It functions for decades and is central to an organ’s ability to restore or regain function after injury.

To accomplish this feat, the brain must continually create new neural circuits and modify existing ones whenever it encounters information from the environment. This highly complex and dynamic process requires the brain to carefully coordinate numerous 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. That is, we have explored how genes cooperate with life experiences and external cues to support brain development and maintain the brain’s adaptability or plasticity over time.

“Mike’s sophisticated research highlights the power of fundamental discovery as the most important fuel for scientific progress. It shows how much is possible when you unwaveringly follow your scientific passion.”

Convergence of Insights

Greenberg and co-winners Holt and Schumann each study different aspects of protein production in 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 within the brain are formed and maintained over time. increase. She showed that proteins must be locally made and degraded to guide the growth of the pyramidal cells needed for vision. To do so also requires a continuous supply of locally produced protein. Holt’s work reveals how neural connections are established and how axons are maintained throughout life.

Schumann is interested in the processes that control how proteins are made and degraded in neuronal structures distant from the cell body, such as axons and branched dendrites extending to synapses. She showed that neurons localize cellular machinery, namely ribosomes and proteasomes, to axons and dendrites. She also established that a dendrite-made protein is required for synaptic plasticity and detailed the mRNA and ribosomal molecules involved. Her lab has developed new tools to label, purify, identify and visualize newly made proteins in neurons and other cells.

“Brain Prize 2023 winners have made groundbreaking discoveries by showing how the synthesis of new proteins is triggered in different neuronal compartments, thereby extending brain development and plasticity across our lifetimes. “We have guided them in ways that influence their behavior,” said Professor Richard Morris. He holds a PhD in Neuroscience from the University of Edinburgh and chaired the selection committee.

protein and plasticity

As a postdoctoral fellow in the lab of Edward Ziff, a professor of biochemistry and neuroscience at the New York University School of Medicine, Greenberg began studying the genetic changes that occur inside mammalian cells when they are stimulated externally. . He found that cells began to express themselves within minutes of stimulation. a gene called c-fosresulting in increased production of the associated Fos protein.

This turned out to be a breakthrough discovery.

Emily Osterweil, Professor of Molecular Neuroscience at the University of Edinburgh, commented on the study, saying, “The idea that changes in gene expression could be induced on such a rapid timescale is beyond the reach of neuroscience. It was a paradigm shift that ushered in a new era.” Out of 3 winners.

Greenberg continued this line of research as an assistant professor at HMS.In particular he Connections between neurotransmitters — chemical messengers flowing from one neuron to the next — and changes in gene activity. He described a signaling cascade that begins with the release of neurotransmitters and leads to a calcium spike in neurons receiving the message.This calcium influx activates neurons c-fos Other genes that make proteins initiate downstream signaling.

Greenberg more fully defined the signaling pathways that neurotransmitters use to activate genes and identified the specific proteins involved. Other lab studies suggest that one of these proteins, CREB, is an important mediator of long-term memory. Building on Greenberg’s research, scientists have also identified hundreds of stimuli that induce Fos production in the brain during various behaviors, demonstrating the protein’s ubiquity and importance to brain function. I’m here.

Greenberg is now working to further characterize the gene products regulated by neural activity, including how these gene products interact. For example, he learned that Fos works with another protein, NPAS4, to modulate neuronal on-off signals in response to stimuli, thereby regulating the expression of specific genes. His findings provide new possible mechanisms of long-term brain plasticity that may underlie associative learning and spatial navigation. He also established that Fos plays a role in remodeling the genetic material in cells in conjunction with a protein complex called BAF, which has been implicated in neurodevelopmental disorders such as autism. bottom.

Greenberg’s efforts have provided insight into the mechanisms by which activity-related genes control synaptic maturation, pruning, and stability. This is the small gap where neurons connect and communicate. Greenberg linked the gene transcription programs he was studying to key aspects of experience-dependent brain maturation and plasticity. This includes the formation of context-dependent memories and the plasticity of the developing visual system. His research sheds light on the origin of disorders in which the mechanisms of neuroplasticity are disrupted.

Greenberg’s research also resulted in important technological advances. His discovery of Fos induction provided researchers with tools now widely used to identify neurons and neural circuits that mediate behavior. His findings also lead to innovative methods to capture these neurons and assess their function in neural circuits, as well as new strategies for making detailed observations of the molecules and mechanisms that mediate learning, memory, and behavior. is also connected.

“For me, this is how our sensory experiences influence the genome of neurons, modulating brain maturation and plasticity that underlie long-term memory, and how these processes fail in neurological disorders.” It’s the culmination of 40 years of adventure aimed at understanding how the system works,” said Greenberg.

Greenberg holds a BS in Chemistry from Wesleyan University and a PhD from Rockefeller University. After his postdoctoral work at NYU, he became an assistant professor in the Department of Microbiology and Molecular Genetics at HMS He, and then Director of the FM He Kirby Center for Neurobiology at Boston Children’s Hospital. In 2008, he became chairman of his HMS neurobiology, 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 is the recipient of the McKnight Prize for Technical Advancements in Neuroscience, his 2015 Gruber Prize in Neuroscience, his 2019 Ralph W. Gerald Prize in Neuroscience, and the 2022 Edward M. Skolnick Prize in Neuroscience. and many other awards.

The Lundbeck Foundation has awarded The Brain Prize annually since 2011. Winners are selected by a panel of her nine leading neuroscientists from around the world with expertise in various neuroscience fields.