The Board of Directors of The McKnight Endowment Fund for Neuroscience is pleased to announce it has selected six neuroscientists to receive the 2022 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 Scholars exemplify the creativity and technical sophistication of today’s leading young neuroscientists from across the country,” said Richard Mooney, PhD, chair of the awards committee and George Barth Geller Professor of Neurobiology at the Duke University School of Medicine.
“Leveraging approaches from structural biology, optics, genetics, physiology, computation and behavior, the Scholars seek to gain insights into topics ranging from the biophysics of neuronal signaling to the large-scale structure of neuronal circuits, and to elucidate the neuronal basis of decision making, sensory processing and flight,” Mooney said. “On behalf of the entire committee, I congratulate all of the applicants on their impressive efforts at the leading edge of neuroscience research.”
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. Each of the following McKnight Scholar Award recipients will receive $75,000 per year for three years.
| Christine Constantinople, Ph.D. New York University New York City, NY |
Neural Circuit Mechanisms of Inference – Researching how internal models of the world are represented in the brain and how these representations contribute to decision-making, especially when an individual enters a new and complex environment. |
| Bradley Dickerson, Ph.D. Princeton University Princeton, NJ |
Proportional-Integral Feedback in a Biological ‘Gyroscope’ – Examining how the fruit fly uses mechanosensory feedback from its wings and specialized gyroscopic halteres to both maintain stable flight and rapidly maneuver when navigating through complex environments, and how this process plays out at neural and whole-body scales. |
| Markita Landry, Ph.D. University of California – Berkeley Berkeley, CA |
Illuminating Oxytocin Signaling in the Brain with Near-Infrared Fluorescent Nanosensors – Building and deploying optical sensors that can detect in real-time the presence of the neuropeptide oxytocin, and using these sensors to help better diagnose chemical imbalances in the brain. |
| Lauren Orefice, Ph.D. Massachusetts General Hospital / Harvard Medical School Boston, MA |
Development, Function, and Dysfunction of Somatosensory and Viscerosensory Systems in Autism Spectrum Disorder – Researching the role of peripheral sensory dysfunction as a contributor to ASD phenotypes, and seeking therapies that restore normal function to those peripheral systems to ameliorate these phenotypes. |
| Kanaka Rajan, Ph.D. Icahn School of Medicine at Mount Sinai New York City, NY |
Multiscale Neural Network Models to Infer Functional Motifs in the Brain – Building novel computational models that bridge neural connectivity, dynamics and behavior using datasets from multiple organisms (e.g., zebrafish, fruit flies, mice), and using these models to discover universal functional motifs that link brain structure and function across species. |
| Weiwei Wang, Ph.D. University of Texas Southwestern Medical Center Dallas, TX |
Understanding the Construction and Function of Glycinergic Post-Synaptic Assemblies – Studying the molecular structure and function of the glycine receptor, a major class of inhibitory receptor in the brain, how synaptic receptors are organized on the neural surface and how dense clusters of these receptors enable synaptic signaling between neurons. |
There were 53 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 Mooney, the Scholar Awards selection committee included Gordon Fishell, Ph.D., Harvard University; Mark Goldman, Ph.D., University of California, Davis; Kelsey Martin, M.D., Ph.D., Simons Foundation; Jennifer Raymond, Ph.D., Stanford University; Vanessa Ruta, Ph.D., Rockefeller University; and Michael Shadlen, M.D., Ph.D., Columbia University.
The schedule for applications for next year’s awards will be available in early September. For more information about McKnight’s neuroscience awards programs, please visit the Endowment Fund’s website.
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.
2022 McKnight Scholar Awards
Christine Constantinople, Ph.D., Assistant Professor, New York University Center for Neural Science, New York City, NY
Neural Circuit Mechanisms of Inference
The animal brain is marvelously well adapted to making decisions based on inference – an understanding of how the world works that helps guide whether or not to take a given action in a given situation. If an animal has an internal “model” of the world, a decision can be made based on that model. But how do neurons come to represent things in the world? What actual circuits and processes are involved? And in a dynamic world, where choices need to be made with incomplete or unrecognized information, how do animals decide how to place a “bet” on the best action?
In her research, Dr. Constantinople is working with a rat model to uncover what parts of the brain are involved in inferring things about the world, and the neurological differences between making a cognitive decision in an uncertain environment or falling back on habitual action. The experiment involves waiting for a known water reward, or “opting out” in hopes that the next reward offered is more worthwhile. There are different reward amounts, and they are presented in a pattern that lets the rat build a model of what range of outcomes to expect, although he can’t be certain, because some of the rewards are ambiguous about the state of the task.
By monitoring brain activity in multiple regions and in specific projections during both predictable and unpredictable periods and the transitions between them, and inactivating specific brain regions and neural pathways in different trials, Dr. Constantine proposes to identify the mechanisms involved in inference. She proposes that different processes are involved when choosing action based on a mental model vs. model-free decisions; that different thalamic nuclei encode the rewards and the rat’s history separately; and that the orbitofrontal cortex (OFC) integrates these two overlapping but distinct inputs to infer unknown states. This work may help future research involving conditions, such as schizophrenia or obsessive-compulsive disorder, in which sufferers seem to have an impaired internal model of the world to help guide behavior.
Bradley Dickerson, Ph.D., Assistant Professor, Princeton Neuroscience Institute, Princeton University, Princeton, NJ
Proportional-Integral Feedback in a Biological ‘Gyroscope’
The nervous system collects and acts on incoming information within milliseconds – sometimes with hard-wired reflexes, sometimes with intention. But studying how these signals affect motion in a living animal presents challenges. There has been work at the level of individual neurons, as well as at the scale of whole-body motion. Dr. Dickerson proposes to bridge these different scales and also resolve the level of control fruit flies have over certain wing muscle assemblies through an experiment that studies specialized mechanosensory organs unique to flies known as halteres.
The halteres detect rotational forces affecting the fly and provide involuntary instructions directly to wing muscles to compensate, acting as a sort of automatic gyroscope. But in earlier research, Dr. Dickerson showed the haltere also can activate precise wing steering actions in the absence of rotations, responding to active control instructions from the brain. In his new research, he will explore the control motifs of flight maneuvers when the flies are exposed to sensory input. These flies are tethered in an arena and monitored by an epiflourescent microscope that can detect neuronal activity in the haltere muscles. In separate experiments, a two-photon microscope above the fly will monitor brain activity, with a camera below tracking wing motion. Visual stimuli appear before the fly, prompting steering events, and allowing Dr. Dickerson to observe on multiple scales how the motion comes about.
Dr. Dickerson proposes that the haltere has separate control mechanisms that can be recruited during perturbations to offer the fly maximum control. In controls engineering lingo, he believes the haltere can react to both proportional (the size of a perturbation) and integral (how the perturbation changes over time) feedback – a greater sophistication than previously believed. Beyond this, he hopes to document how all these systems work together, learning what neurons send what signals to which muscles, and how this leads to specific motions – creating a model of how brains, neurons, and muscles communicate that can advance our understanding of how movement is controlled.
Markita Landry, Ph.D., Assistant Professor, University of California – Berkeley, Department of Chemical and Biomolecular Engineering, Berkely, CA
Illuminating Oxytocin Signaling in the Brain with Near-Infrared Fluorescent Nanosensors
Chemical imbalances in the brain are believed to be associated with a wide range of neurological disorders in humans, but it is currently impossible to see what chemicals are present in a brain with cellular precision. In her research, Dr. Landry seeks to create a nanosensor that can detect oxytocin, one of a class of neuropeptides believed to have a role in modulating mood and behavior, and so enable research that can help confirm the role of neuropeptides in day to day life, and more precisely diagnose neurochemical imbalances that can lead to mental health ailments.
Dr. Landry’s work involves the creation of “optical probes” – miniscule carbon nanotubes with a peptide bound to the surface that will fluoresce in near-infrared light when in the presence of oxytocin. This fluorescence can be detected with high precision on a millisecond timescale, letting researchers see exactly where and when it is present in a brain, and so identify under what conditions oxytocin release might be impaired (and thus treatable) in mood, behavior, and social disorders. Dr. Landry has created similar probes for serotonin and dopamine, but creating a new probe for oxytocin will not only allow research into its effects on the brain, but for a whole class of neuropeptides like it.
Importantly, these nanotubes can be introduced into brain tissue externally; the fluorescence is not the result of genetic encoding, so it can be used on animals that have not been modified. Because they emit near-infrared light, it is possible that the light can be detected through the cranium, which would enable minimal disturbance to the subjects. In Dr. Landry’s experiment, the development of the nanosensors and detectors will be validated by in vitro testing using brain slices, and finally applied in vivo, at which point it will be determined if through-skull imaging is possible. With these sensors as a tool, Dr. Landry hopes to help improve diagnosis of neurological disorders and so destigmatize and improve treatment of many such conditions.
Lauren Orefice, Ph.D., Massachusetts General Hospital / Harvard Medical School, Boston, MA
Development, Function, and Dysfunction of Somatosensory and Viscerosensory Systems in Autism Spectrum Disorder
Autism Spectrum Disorder (ASD) is a highly prevalent but very complex neurological disorder, often associated with alterations in social behavior. In many cases, ASD is associated with certain genetic changes, and it often comes with certain co-morbidities, some of the most common of which include hypersensitivity to touch and a range of gastrointestinal issues.
ASD has traditionally been thought to be caused solely by abnormalities in the brain, but in her research, Dr. Orefice has found that alterations in peripheral sensory neurons contribute to the development of ASD symptoms in mice, including hypersensitivity to touch of the skin and altered social behaviors. Her current research will focus on whether peripheral sensory neurons of the dorsal root ganglia (DRG) that detect stimuli in the gastrointestinal tract are also abnormal in mouse models for ASD, and if this contributes to gastrointestinal problems like increased gastrointestinal pain that are remarkably common in ASD.
Dr. Orefice’s work has identified that touch hypersensitivity during development leads to changes in social behaviors in adult mice. Like humans, many aspects of mouse social behaviors involve the sense of touch. In a second part of her research, Dr. Orefice hopes to understand how alterations in somatosensory circuit development due to peripheral sensory neuron dysfunction result in changes to connected brain circuits that regulate or modify social behaviors.
Finally, Dr. Orefice will focus on translating her findings from preclinical mouse studies to understanding ASD-associated sensory issues in humans. Dr. Orefice will first test whether approaches that reduce peripheral sensory neuron excitability can improve touch over-reactivity and gastrointestinal problems in mice. She will leverage these findings in mice to better understand human physiology using studies of cultured cells taken from people with ASD. Dr. Orefice’s work also aims to use studies in mice and human-derived cells to identify compounds that target peripheral sensory neurons as a tractable approach for improving sensory issues and related ASD behaviors.
Kanaka Rajan, Ph.D., Assistant Professor, Department of Neuroscience & Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai, New York City, NY
Multiscale Neural Network Models to Infer Functional Motifs in the Brain
With the rise of artificial intelligence (AI) and machine learning, neuroscientists are leveraging these tools to build computational models that can help us understand how the brain works. But the big question is: What is the right level to study neural systems? Is it at the level of individual neurons, brain circuits, layers, regions, or some combination?
Dr. Rajan is tackling this question by harnessing the power of AI-based models and combining them with datasets acquired from recordings in multiple species to make better, more predictive representations of the brain. Using recurrent neural network models (RNNs), Dr. Rajan has discovered that placing more constraints on computational models resulted in more consistent findings and smaller, more robust solution spaces. She has since turned to developing multi-scale RNNs where the constraints are neural, behavior, and anatomical data from real experiments, and are simultaneously applied. Her next step will be to create multi-scale RNNs using such data recorded from multiple species well-studied in neuroscience—larval zebrafish, fruit flies, and mice—to create models.
Ultimately, using datasets from different species will allow Dr. Rajan to identify “Functional Motifs” and use them to discover unexpected commonalities and divergences across these systems. These common, discrete ensembles of active neurons that are linked to similar behaviors and states, regardless of species, will help us to infer how brains operate at a fundamental level without biases or assigning structures like brain regions with specific functions a priori. With the data available, these models can run many scenarios and identify what changes in structure or neural activity result in different behavioral outcomes. This has the potential to shed light on neural dysfunctions associated with a wide range of neuropsychiatric diseases. With the advent of much larger and more detailed datasets in neuroscience, the increasing accessibility of greater computing power, and advances in mathematics and algorithms, Dr. Rajan believes we are at the cusp of a revolution in what computational models and theory can teach us about the brain.
Weiwei Wang, Ph.D., Assistant Professor, University of Texas Southwestern Medical Center, Dallas, TX
Understanding the Construction and Function of Glycinergic Post-Synaptic Assemblies
The way neurons communicate with each other is remarkably intricate: neurotransmitters are passed from one neuron to the next across synapses, signaling synaptic receptors on the receiving neuron to open and form channels that allow ions to pass through, and so transmitting an electrical signal. However, if the synapses fail to work or fail to form, the impairment of these signals can contribute to neurological disorders. Dr. Wang seeks to broaden our understanding of these synapses, how they form, and how they work – in particular, how they organize synaptic receptors into clusters, and why it matters that the receptors assemble in high concentrations – by studying in detail the glycinergic synapse.
Despite being fairly well-documented, many questions remain about the glycinergic synapse. There are a number of subtypes (one of which is present only very early in brain development) with different roles and distributions whose structure is unclear, as is the mechanism by which they react to a scaffolding protein to form clusters. The role of forming in a cluster is itself a mystery – it’s unclear if they need to be together in a certain density to work correctly, and if so, why. Each of these unknowns presents another point at which some dysfunction could cause a neurological disorder, such as hyperekplexia (called “startle syndrome”) and possibly inflammatory pain.
Dr. Wang will systematically aim to learn more about each of these mysteries, using cryo-electron microscopy to precisely identify the molecular structure of each sub-type that has not yet been resolved and so identify how each functions; testing how the scaffolding that the glycine receptors cluster on is formed from the proteins gephyrin, neuroligin-2, and collybistin; and finally testing purified receptors on an artificial membrane, first in isolation, then bound to the scaffold, and then bound to the scaffold in a cluster to see how the function changes. While research has been done into how solitary ion channels work, this study of the effect of clustering may open new avenues of understanding, since synaptic receptors are most often clustered in a living neuron.
