The Board of Directors of The McKnight Endowment Fund for Neuroscience is pleased to announce it has selected seven neuroscientists to receive the 2021 McKnight Scholar Award.
The McKnight Scholar Awards are granted to young scientists who are in the early stages of establishing their own independent laboratories and research careers and who have demonstrated a commitment to neuroscience. “This year’s class of Scholars showcases the diversity of young, brilliant, innovative neuroscientists from across the nation,” says Kelsey C. Martin MD, PhD, chair of the awards committee and dean of the David Geffen School of Medicine at UCLA. Since the award was introduced in 1977, this prestigious early-career award has funded more than 250 innovative investigators and spurred hundreds of breakthrough discoveries.
“Together, the McKnight Scholars are tackling some of the most exciting questions in neuroscience today,” says Martin. “Using an array of experimental and computational approaches, they are elucidating how sensory experience shapes the brain during development, how brain circuits give rise to sex-specific behaviors, how sound is perceived and processed during behavior, how sleep influences cognition and brain health, how cell biological mechanisms control circadian rhythms, and how neural circuits process information and learn. On behalf of the entire committee, I would like to thank all the applicants for this year’s McKnight Scholar Awards for their contributions and creativity.”
Each of the following seven McKnight Scholar Award recipients will receive $75,000 per year for three years. They are:
|Lucas Cheadle, PhD
Cold Spring Harbor Laboratory
Cold Spring Harbor, NY
|Uncovering the Molecular Basis of Microglial Function in the Stimulated Brain – Researching how microglia shape synaptic function in response to visual stimuli.|
|Josie Clowney, PhD
University of Michigan
Ann Arbor, MI
|A Feminist Framing of Fruitless: Maleness as a Suppression of Female Neural Programs – Examining how male fruit fly brains develop sex-specific circuits, and whether they are formed by suppressing parts of a female “base.”|
|Shaul Druckmann, PhD
|How Does the Brain Compute Using Activity Distributed Across Populations and Brain Areas? – Exploring how sensory and motor computations occur simultaneously across brain regions, and how new methodologies might aid in researching this and other brain-wide phenomena.|
|Laura Lewis, PhD,
|Imaging Neural and Fluid Dynamics in the Sleeping Brain – A study of the effects of sleep on neural computation and physiology, with an emphasis on the role of cerebrospinal fluid and how it synchronizes with neural slow waves.|
|Ashok Litwin-Kumar, PhD
New York, NY
|Connectome-Constrained Models of Adaptive Behavior – Identifying connectivity motifs in neural wiring diagrams and using them to explore how sensory data reaches neurons that guide behavior.|
|David Schneider, PhD
New York University
New York, NY
|Coordinate Transforms in the Mouse Cortex – Researching how the brain learns to anticipate the sound of movements, and the effects of that anticipation on behavior.|
|Swathi Yadlapalli, PhD
University of Michigan
Ann Arbor, MI
|Cellular Mechanisms Controlling Circadian Rhythms – An in vivo study to uncover how our circadian clocks are regulated at the subcellular level.|
There were 70 applicants for this year’s McKnight Scholar Awards, representing the best young neuroscience faculty in the country. Faculty are only eligible for the award during their first four years in a full-time faculty position. In addition to Martin, the Scholar Awards selection committee included Gordon Fishell, PhD, Harvard University; Loren Frank, PhD, University of California, San Francisco; Mark Goldman, PhD, University of California, Davis; Richard Mooney, PhD, Duke University School of Medicine; Jennifer Raymond, PhD, Stanford University; Vanessa Ruta, PhD, Rockefeller University; and Michael Shadlen, MD, PhD, Columbia University.
Applications for next year’s awards will be available in August and are due on January 10, 2022. For more information about McKnight’s neuroscience awards programs, please visit the Endowment Fund’s website at https://www.mcknight.org/programs/the-mcknight-endowment-fund-for-neuroscience
About The McKnight Endowment Fund for Neuroscience
The McKnight Endowment Fund for Neuroscience is an independent organization funded solely by The McKnight Foundation of Minneapolis, Minnesota, and led by a board of prominent neuroscientists from around the country. The McKnight Foundation has supported neuroscience research since 1977. The Foundation established the Endowment Fund in 1986 to carry out one of the intentions of founder William L. McKnight (1887-1979). One of the early leaders of the 3M Company, he had a personal interest in memory and brain diseases and wanted part of his legacy used to help find cures. The Endowment Fund makes three types of awards each year. In addition to the McKnight Scholar Awards, they are the McKnight Technological Innovations in Neuroscience Awards, providing seed money to develop technical inventions to enhance brain research; and the McKnight Neurobiology of Brain Disorders Awards, for scientists working to apply the knowledge achieved through translational and clinical research to human brain disorders.
2021 McKnight Scholar Awards
Lucas Cheadle, PhD Assistant Professor, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Uncovering the Molecular Basis of Microglial Function in the Stimulated Brain
Much of developmental neuroscience has historically focused on the hard-wired aspects of neural development – how cells are genetically “programmed” to develop a certain way or provide a particular function. And until recently, research has more closely examined the neurons themselves, with many of the tools and techniques commonly used being optimized to study mechanisms intrinsic to neurons. In his research, Dr. Cheadle is turning attention to lesser-studied areas of neurology: a late-stage of neural development that is influenced by external environmental factors, and the role played by brain immune cells called microglia in this process.
In his research, Dr. Cheadle is specifically studying the development of visual neural connections using a mouse model in which some mice are reared in a light-free environment during a crucial stage of development. His previous research shows that microglia essentially “sculpt” the visual system, culling synaptic connections that are less beneficial. As a result, the physical ordering of that part of the neural system is different in mice reared in the dark than those reared in light. In his ongoing work, Dr. Cheadle will seek to identify at the molecular level how microglia are stimulated by external factors (such as light) and the mechanisms by which they then sculpt synapses.
The research offers several novel approaches, including using gene-editing technology to knock out specific microglial genes to define their roles in visual circuit development, as well as creating a transgenic line of mice that tags functionally active microglial cells in the brain, both tactics most often applied to neurons that Dr. Cheadle is adapting to study microglia for the first time. Dr. Cheadle hopes his research can help uncover new insights about the roles of non-neuronal cells in the brain, which may lead to future breakthroughs into the origins and treatment of neural disorders, especially those such as autism and schizophrenia that arise relatively late in development and have some indication of an immune component.
Josie Clowney, PhD, Assistant Professor, University of Michigan, Department of Molecular, Cellular and Developmental Biology, Ann Arbor, MI
A Feminist Framing of Fruitless: Maleness as a Suppression of Female Neural Programs
The differences between male and female brains may seem subtle and affect only 2-5% of the brain – after all, most functions of living creatures of both sexes are the same, including the need to eat, sleep, learn, and move – but those differences are crucial to survival of a species. A great deal of research has been behavioral, such as the performance of mating rituals, but less is understood about how the genes that drive those rituals are tuned in the brain.
Dr. Clowney hypothesizes that the process is one of subtraction – that the code for the brains of both sexes starts out largely the same, and then certain genes are switched off in certain patterns for each sex, resulting in male and female brains. Furthermore, her studies to date using a fruit fly model suggest that the male brain may result from the removal of neural programs from a “base model” that is much closer to the female brain, rather than the creation of new programs. Key to the process is a fruit fly transcription factor called “Fruitless,” a protein created only in male fruit fly brains that regulates whether sex-specific genes in the brain switch on or off, and which have a role in driving sex-based instincts even in adults.
In her research, Dr. Clowney will seek to identify the genetic targets of Fruitless in developing and adult brains; how inhibitory neural circuits regulate male courtship by preventing males from performing mating rituals to other males; and how males lose the neural circuits for laying eggs. The experiments involved use a variety of techniques to observe the gain or loss of sex-associated circuits and behaviors in animals with or without Fruitless. Through this, she can shed light on the process of brain development, which may lead to new insights about how our brains know which innate behaviors to perform and which not to perform, and possibly help researchers of neurological and psychiatric disorders, many of which are more common is one sex or another.
Shaul Druckmann, PhD, Assistant Professor of Neurobiology and of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA
How Does the Brain Compute Using Activity Distributed Across Populations and Brain Areas?
After decades of research, we still have a limited understanding of how the brain performs computations across regions. This very fundamental question is at the heart of Dr. Druckmann’s work, which takes advantage of the increasing scope and detail of brain activity recording to explore what happens in the brain between stimulus and response, specifically when the response is delayed and short-term memory is engaged.
In one set of experiments, mice are trained to lick in one of two directions some time after a stimulus is presented and then removed. Since the stimulus is no longer present, the brain needs to store the memory of it, plan motion, withhold the action for a certain time, and then act. During those seconds, brain activity is recorded in multiple brain regions simultaneously. Preliminary data show that activity is present and changing across regions and in different neuronal populations, and Druckmann aims to show that this collective activity is interacting across brain areas and the ways that interactions can “fix” the necessary memories and motion intention, even when a single region or population’s activity might be erroneous. A second line of research using humans tracks cross-regional brain activity during speech – an extraordinarily complex activity – in experiments that get at the same question of how calculations are made across the brain.
Dr. Druckmann sees these experiments as first steps towards having a model for how the brain works as a whole. At the same time, he also hopes to expand the way researchers work; his project involves intense collaboration with several other researchers, and he hopes to be able to explore both basic science and also pursue clinical applications for his findings, specifically through his participation in a collaborative clinical trial project that is working on neural interfaces. The ability to decode how brain activity translates into a complex activity like speech could lead to technology that can restore some function for people with degenerative diseases such as ALS.
Laura Lewis, PhD, Assistant Professor, Boston University, Department of Biomedical Engineering, Boston, MA
Imaging Neural and Fluid Dynamics in the Sleeping Brain
Sleep is critically important to brain health in both the short and long term. Both neural activity and the fluid dynamics of cerebrospinal fluid (CSF) change during sleep, with varied consequences – sensory systems shift away from awareness of external stimuli and towards memory reactivation, and CSF flows into the brain and clears away toxic proteins that build up during waking hours. Intriguingly, the two processes are closely correlated. In her research, Dr. Lewis will investigate the connection between neural and fluid dynamics during sleep and the connection of each to brain health.
The key to Dr. Lewis’ research is the ability to study patients during non-rapid eye movement (NREM) sleep and observe both brain activity and fluid dynamics in short timescales. To do so, Dr. Lewis is using an innovative combination of EEG with fast functional magnetic resonance imaging (fMRI), improved using an algorithm she developed to eliminate noise, allowing her to observe synchronized, precise neural activity and CSF flow. Her research will explore first how these slow waves are activated in the brain and which neural networks are involved, using auditory stimuli that can enhance slow waves. Second, she will examine the link between these slow waves and CSF flow; a hypothesis is that slowed neural activity decreases blood demand, essentially drawing CSF into the brain as blood recedes. Using the combined imaging technique, Dr. Lewis will be able to observe coupled blood flow and CSF flow moment by moment in 3D throughout the brain.
The implications for this interplay are profound. During these slow waves, the brain’s neural network is reorganized in a way that is critical to memory reactivation and short-term brain health; the CSF flow that is linked to the slow waves is important for long-term brain health. Understanding how these systems work will help future sleep researchers understand when something goes wrong, of particular interest in studies of neurological and psychiatric disorders, including Alzheimer’s, which may be linked to disrupted slow wave sleep.
Ashok Litwin-Kumar, PhD, Assistant Professor, Department of Neuroscience and Zuckerman Institute, Columbia University, New York, NY
Connectome-Constrained Models of Adaptive Behavior
With new electron microscopy (EM) wiring diagrams of ever-more complex nervous systems, researchers are on the verge of unlocking a deeper understanding of how these systems lead to behavior. The challenge: How to make use of these vast datasets, known as connectomes, which in the case of the fruit fly include tens of thousands of neurons and tens of millions of synapses. Accomplishing this task is difficult as many successful approaches for modeling behavior, including techniques inspired by machine learning, use models that don’t reflect the reality of how brains and nervous systems are wired.
In his research, Dr. Litwin-Kumar aims to develop a methodology to bring the worlds of the connectome and functional models of behavior together by developing ways to identify relevant structures within a connectome that can constrain the behavioral models – for example, by limiting the models so they only use synaptic connections that physically exist in the connectome, rather than making physically impossible leaps between neurons.
To test and refine this approach, Dr. Litwin-Kumar is first focusing on the connectome of a part of the fruit fly brain called the mushroom body, a well-mapped region that is a center for associative learning. Sensory inputs received by Kenyon cells are projected to output neurons, which trigger behaviors such as approach or avoidance reactions. Using advanced modeling, the team will seek to efficiently identify structure within the connectome that reflects how information is relayed to the mushroom body. Then they will test deep learning models constrained by those connections to see how effectively they predict responses to stimuli, compared to unconstrained models. Further tests will explore the role of dopamine neurons in more complex learning. Collectively, this research will lay the groundwork for using connectomes of increasing complexity along with learning models to reflect more accurately the behavior of real organisms.
David Schneider, PhD, Assistant Professor, New York University, Center for Neural Science, New York, NY
Coordinate Transforms in the Mouse Cortex
One of the many remarkable abilities found in the brains of advanced organisms is the ability to predict the future, not just on long time scales, but moment by moment, constantly tallying and recording data from sensory inputs and creating predictive models based on past experience. These predictive models help us more effectively navigate and interact with the world – and just as importantly, identify aberrations from the expected that might be a sign of danger or opportunity. Dr. Schneider’s work focuses on how motor control and sensory regions of the brain work together in this way and will work to uncover how the brain learns and forms memories that form the basis of what is expected.
In his experiments, Dr. Schneider focuses on a seemingly counterintuitive pathway found in mouse brains (and human brains): a conduit connecting a motor control region to an auditory sensory region. Whenever a movement is made, the two regions communicate in a way that tells the auditory system to disregard sound created by that movement, almost like a photo negative that cancels the sound out. In his experiments, mice will be conditioned to expect a certain sound when they push a lever. Neural activity and behavioral responses will be recorded when the expected sound is experienced, and then again when the sound is subtly changed.
These experiments will help identify the role of specific neurons in anticipating sensory responses, how motor control and sensory centers of the brain interact, and how the pathways between the motor and sensory regions change when a new sound becomes “expected.” Further research will block certain pathways in the brain to determine their role in making predictions, and also see how the brain uses visual input to help anticipate self-generated sounds. Understanding how these predictive and learning systems work may help guide future research into a range of neurological disorders.
Swathi Yadlapalli, PhD, Assistant Professor, University of Michigan Medical School, Department of Cell and Developmental Biology, Ann Arbor, MI
Cellular Mechanisms Controlling Circadian Rhythms
Circadian clocks – the 24-hour internal clocks that drive many of the rhythms of our biological system, such as when we sleep, wake, how we metabolize, and much more – are found in almost all cells of our body. But exactly what is happening within any given cell to create that rhythm is poorly understood. Previous biochemical and genetic research had identified crucial proteins that are transcription factors, either positive or inhibitory, with a role in circadian rhythms, but didn’t address exactly how they function in a live cell at the subcellular level, the biological equivalent of having a parts list but not understanding how they fit together.
Dr. Yadlapalli has developed innovative methods of performing single-cell, high-resolution visualization of these proteins and how they interact over a 24-hour period in the living cells of fruit flies for the first time, and the preliminary findings have already revealed unexpected insights. Specifically, one of the key inhibitory transcription factors, called PER, gathers to form foci evenly distributed around the envelope of the cell nucleus, and play a role in altering the nuclear location of clock genes during the cycle. Previously, it was assumed these proteins were free-floating or randomly distributed. These studies highlight an important new layer of regulation in the circadian clock system.
In a series of experiments, Dr. Yadlapalli will determine the mechanisms involved in this process – how the foci form and where they localize, and how they promote the repression of clock-regulated genes. Understanding more about the working of these fundamental, powerful cellular processes, which have effects all the way up to the behavior and health of the whole organism, will provide a starting point for research into many sleep and metabolic disorders and neurological diseases.