Neuroscience | Winter 2018-2019

NEUROSCIENCE University of Rochester | Ernest J. Del Monte Institute for Neuroscience Winter 2018-2019

The Future of an Epidemic Kerry O’Banion and Anton Porsteinsson on what’s next for Alzheimer’s research PG 4

University of Rochester | Winter 2019

Winter 2019

D I R EC TO R ’ S N OT E

Neuroscience on the March at the Del Monte Institute

John J. Foxe, Ph.D. Kilian J. and Caroline F. Schmitt Chair in Neuroscience Director, The Ernest J. Del Monte Institute for Neuroscience Professor & Chair, Department of Neuroscience

On the cover: Photo by Matt Wittmeyer

I am often asked what my favorite part of my job is, and I think I can reasonably speak for most all of the faculty in the neurosciences in saying that it is the interaction with our incredible students and postdocs, having the privilege to play a small role in their development as world class scientists and clinicians, that really floats my boat. There is nothing quite so satisfying as witnessing the emergence of new understanding, new skills, and novel ideas in these young vibrant minds. Two or three times each semester, usually after our late afternoon Monday neuroscience seminars, I get to take the students out for some less-than-nutritional snacks and a few beverages at a local establishment, and to hear from them about their experiences, concerns and aspirations. What I really love about these informal get-togethers is watching the interactions of the students from different labs and seeing the close friendships that have developed, friendships that I know from my own experience will stand the test of time. Our current crop of students are an amazing bunch of people, and their passion really energizes me and reminds me of the importance of the work we are engaged in here at the Del Monte Institute for Neuroscience. We have witnessed three extraordinary years of bumper classes in our Neuroscience Graduate Program and our recruitment numbers keep rising as budding young scientists from all over the country — well, actually from all over the world — seek out the University of Rochester for its superb neuroscience program. Our students are the lifeblood of the operation and it is simply great to see our program thriving and growing in the way that it is.

As we welcome in 2019, this is a great time to reflect on our achievements and to look with real excitement to the year ahead, to acknowledge the incredible progress we have made, and to set ourselves new targets and goals. We’ve welcomed a superb coterie of new faculty members to grow our basic and clinical research engines, finished a complete renovation of the Center for Advanced Brain Imaging and Neurophysiology (UR CABIN), and successfully competed for more than $20M in federal grant support for our work. As you will read in these pages, our newest faculty member, Kuan Hong Wang, Ph.D., has moved his research program from the NIMH where he was serving as the director of the Neural Circuits division, and will join a growing hive-mind of investigators employing murine models to understand neurological and neuropsychiatric diseases at the brain circuit level.

Work from our investigators has appeared in the very best journals in the field, has attracted national and international attention, and our scientists have been asked to chair major symposia and events around the world and serve as editors for some of the most significant publications in our field. In the 2019 U.S. News & World Report ranking for Best Global Universities, we are in the top 25 neuroscience programs nationally (at number 23) and in the top 50 globally (at number 44). We hope you enjoy reading this inaugural issue and look forward to providing you updates on a quarterly basis. As we continue to build and expand our efforts, the sky is the limit. From the offices of the Del Monte Institute, I wish you all a most productive and exciting year of cutting-edge research and amazing new discoveries in 2019.

In Science,

John J. Foxe, Ph.D. 2

NEWS BRIEFS

Study Points to Possible New Therapy for Hearing Loss Researchers have taken an important step toward what may become a new approach to restore hearing loss. In a recent study published in the European Journal of Neuroscience, scientists have been able to regrow the sensory hair cells found in the cochlea — a part of the inner ear — that converts sound vibrations into electrical signals and can be permanently lost due to age or noise damage.

Research conducted in the lab of Patricia White, Ph.D., in 2012 first identified a family of receptors – called epidermal growth factor – responsible for activating support cells in the auditory organs of birds. When triggered, these cells proliferate and foster the generation of new sensory hair cells. She speculated that this signaling pathway could potentially be manipulated to produce a similar result in mammals.

White is a research associate professor in the Del Monte Institute and lead author of the current study.

Above: Cochleae extracted from neonatal mice and cultured for 24 hours.

Below: Lineage tracing of murine cochlear supporting cells.

S T U D E N T S P OT L I G H T

Monique Mendes Monique S. Mendes, a neuroscience Ph.D. student, is the first URMC graduate student to receive a prestigious F99/K00 NIH Blueprint Diversity Specialized Predoctoral to Postdoctoral Advancement in Neuroscience (D-SPAN) fellowship from the National Institute of Neurological Disorders in Stroke. The award was created to provide outstanding young neuroscientists from diverse backgrounds a pathway to develop independent research careers. Unlike traditional graduate student fellowships, this award provides research funding for six years, including dissertation research and mentored postdoctoral research career development. Mendes currently works in the laboratory of Ania Majewska, Ph.D., and studies the role that the brain’s immune cells play in development, learning, and diseases like autism.

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NEWS BRIEFS

ABCD Study Completes Enrollment, Already Making Impact on Community

Members of the Rochester ABCD Study Team: Back row (left to right): John Foxe, Ph.D., Brianne Roche, Allison Havens, and Ed Freedman, Ph.D. Front row (left to right): Preshetha Kanagaiah, Emily Richardson, and Nicole Vieyto

More than 300 Rochester-area children are participating in the Adolescent Brain Cognitive Development (ABCD) Study at URMC. The federally funded project officially completed enrollment in December 2018 with 11,874 total children, ages nine and 10, participating nationwide. URMC, one of 21 sites where the ABCD Study is being conducted, exceeded its enrollment target of 275 children in just over one year with a total of 339 youths from the Rochester area participating.

URMC achieved the ambitious recruitment goal with the assistance of numerous organizations and community members. The current participant pool includes children from the Rochester City School District, as well as surrounding suburban school districts including Webster, Greece, Brighton, Pittsford, and Newark. The study ultimately aims to understand how childhood experiences such as social media, video games, smoking, sleep and other factors impact brain development, academic achievement, and social behavior.

Researchers Harness Virtual Reality, Motion Capture to Study Neurological Disorders Neuroscientists at URMC have a powerful new state-ofthe-art tool at their disposal to study diseases like Autism, Alzheimer’s, and traumatic brain injury. The Mobile Brain/ Body Imaging system, or MoBI, combines virtual reality, brain monitoring, and Hollywood-inspired motion capture technology, enabling researchers to study the movement difficulties that often accompany neurological disorders and why our brains sometimes struggle while multitasking.

The MoBI platform is located in the Del Monte Institute’s Cognitive Neurophysiology Lab where it is currently being employed for several studies.

Study participants wear a black body suit fitted with reflective markers and are asked to walk on a treadmill in a room with 16 high speed cameras that record the position of the markers with millimeter precision (left). This data is mapped to a computer-generated 3D model that tracks movement (right).

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NEWS BRIEFS

UR Named National Center of Excellence for Parkinson’s Research UR has been selected as a Morris K. Udall Center of Excellence in Parkinson’s Disease Research by the National Institute of Neurological Disorders and Stroke. The $9.2 million award brings together researchers from industry and multiple academic institutions to focus on the development of digital tools to enhance understanding of the disease, engage broad populations in research, and accelerate the development of new treatments for Parkinson’s disease.

The new UR Udall Center will undertake research utilizing mobile technologies, such as smartphones, wearable sensors, and telemedicine to expand the reach and accessibility of clinical research and to develop objective measures of the progression of the disease and effectiveness of experimental therapies in real-world settings.

IN MEMORIAM

Tristram Smith Tristram Smith, Ph.D., whose research on behavioral interventions changed the landscape of care for children with autism spectrum disorders (ASD), died after suffering a heart attack on August 6 at the age of 57.

His research in the late ‘80s and early ‘90s, conducted alongside the late O. Ivar Lovaas, Ph.D., showed that many children with ASD could be successfully treated with behavior-based interventions, which allowed some to catch up to their peers in school.

The work helped move treatment of children with ASD away from psychotherapy — which had been used with nominal effectiveness for decades — and toward applied-behavior-based models.

The sea change in treatment paved the way for ASD screenings in schools and pediatricians’ offices and led to numerous additional studies on behavior-based interventions.

At the time of his death, Smith was serving as the HaggertyFriedman Professor in Developmental/Behavioral Pediatric Research at URMC, where he had worked since joining as a faculty member in 2000.

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W H AT ’ S N E X T FO R

Alzheimer’s Research

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bout ten years ago, most of what researchers knew about Alzheimer’s disease (AD) was turned on its head with a dramatic discovery. But, as assistant director of the Del Monte Institute for Neuroscience Kerry O’Banion, MD., Ph.D., puts it, “In some ways, that’s the best thing that can happen in science.”

Alzheimer’s is one of the most significant public health challenges facing the nation; by 2050, an estimated 13.8 million Americans will have the disease at an estimated annual cost of $1.1 trillion to the healthcare system. Since the early 1990’s, O’Banion has been researching AD, which begins in areas of the brain important for memory before spreading to areas critical for making decisions. Around the time that he

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started, it was assumed that inflammation in the brain was the driver of the damage that appears in AD. However, clinical trials intended to slow neuroinflammation with non-steroidal anti-inflammatory drugs were not successful.

Almost a decade later, O’Banion and his colleagues discovered that neuroinflammation might not be so bad — in fact, it might even help hold the disease at bay. After figuring out how to trigger the inflammatory process in the brain genetically, they applied this technique to mouse models of AD, expecting that the disease would get worse. Instead, what they found, remarkably, was that the pathology got better. This finding was unexpected, to say the least.

While O’Banion continued to investigate the link between neuroinflammation and AD, the pharmaceutical industry took a different direction, targeting the accumulation of toxic peptides that lead to a disease hallmark known as plaques.

Over the last several years, various promising drugs have failed in late stage clinical trials that focused on eliminating plaques. Billions of dollars later, the scientific community is still no closer to finding a way to reverse the course of the disease, leading many to conclude that new approaches are needed.

Fast forward to the present and researchers at the University of Rochester Medical Center (URMC) remain at the forefront of AD research. Collaboration among scientists across multiple departments and disciplines are being fostered by the Del Monte Institute for Neuroscience to tackle this complex disease.

Now considered a pioneer in the field, O’Banion is currently focused on investigating how to stop the inflammation in the brain that leads to memory problems and cognitive decline. He is exploring the idea of re-programming the microglia — a cell type that serves as the immune system’s ‘first responder’ — to harness the benefits of inflammation, while at the same time squelching the potentially toxic effects of these cells in an effort to halt the spread of disease.

Rusty Elliott, Ph.D., with the URMC Center for Vaccine Biology and Immunology has been collaborating with O’Banion and Olschowka, and together they’re working on mechanisms by which microglia could be harnessed to clear the plaques that accumulate in the brains of people with AD. The duo also works closely with Ania Majewska, Ph.D., or, as O’Banion fondly calls her, “The Microglia Guru.”

Together they have a pilot project through the Del Monte Institute that’s aimed at trying to modify microglia responses to AD. “We’re using a method that gets rid of all microglia and then allows them to start again to see if the newly-born microglia are better at their job than the old microglia,” said O’Banion.

Advancing clinical trials for Alzheimer’s disease In addition to basic research, there is wealth of clinical AD-focused research occurring at the University. Anton Porsteinsson, M.D., is the director of the Alzheimer’s Disease Care, Research and Education Program (AD-CARE) at URMC. At any given time, the AD-CARE program participates in about 15 national and international clinical trials for the disease.

The microglia dream team O’Banion and his longtime collaborator, John Olschowka, Ph.D., run laboratories that utilize mouse models to focus on the role of neuroinflammation in neurodegenerative disease and central nervous system injury.

“We’re looking at ways to modify the peripheral immune system so that it talks to microglia and makes them happier,” said O’Banion. “We’re using information about microglia that’s been gathered in the last few years and we’re very excited about what we’re learning.”

“It’s not something we’re doing in a vacuum. We’ve been very lucky to have willing and very competent collaborators in several departments.”

– Anton Porsteinsson, M.D.

O’Banion (left) and Porsteinsson (right) are just two of the many faculty members dedicated to Alzheimer’s research at the University of Rochester.

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W H AT ’ S N E X T F O R A L Z H E I M E R ’ S R E S E A R C H

Porsteinsson, a professor in the Departments of Psychiatry unique waste disposal process — to improve the brain’s and Neurology, is a 20-year collaborator of Bob Chapman, ability to remove the toxic proteins associated with the Ph.D., in the Department of Brain and Cognitive Sciences, disease. Rashid Deane, Ph.D., a research professor in the and for the past five years has partnered with Feng (Vankee) Department of Neuroscience, studies the different types Lin, Ph.D., R.N., in the School of Nursing. AD-CARE often of the APOE gene and their association with AD risk. Gail works closely with the Department of Imaging Sciences Johnson, Ph.D., a professor in the Department of Anesand also helps Del Monte Institute investigators John Foxe, thesiology, explores molecular mechanisms underlying the Ph.D., and Ed Freedman, Ph.D., recruit participants for their formation of tangles, another hallmark pathology of AD. AD research. It doesn’t stop there. Porsteinsson adds, “For Houhui (Hugh) Xia, Ph.D., an associate professor who our studies, we’ve also had to work closely with Dermatology holds the Paul Stark Professorship in the Department of for skin monitoring and with Ophthalmology for eye health Pharmacology and Physiology, investigates mechanisms monitoring. It’s not something we’re doing in a vacuum. underlying synaptic communication, a process fundamental We’ve been very lucky to have willing and very competent to learning and memory. Handy Gelbard, Ph.D., with the collaborators in several departments.”

Center for Neurotherapeutics DiscovURMC is considered a top recruiting ery is investigating a compound that site for the federally-funded Alzheiturns off a specific enzyme that sets the mer’s Disease Neuroimaging Initiative neuroinflammatory process in motion (ADNI) study, a mark of distinction in diseases like Alzheimer’s. that Porsteinsson says speaks volumes Investigators who are conducting paabout the commitment of the Rochtient-oriented research include Vankee ester community. “It reflects tremenLin, Ph.D., R.N., an associate professor dously, not only on our operation and of Nursing with a cross-appointment in the University, but also on the willingNeuroscience, who is examining how ness of this community to participate computer-based brain fitness activities in clinical trials and push back against may help slow cognitive and functionAlzheimer’s disease,” he said. “There’s al decline in older adults with mild really a special goodwill in this area.” cognitive impairment, and in those at ADNI is a long-term study that tracks risk for developing AD and other forms The glymphatic system pumping cerebral brain aging through neuroimaging of dementia. In the Del Monte Instispinal fluid (blue) into the brain, which and is now focused on investigating tute’s Cognitive Neurophysiology Lab, flushes away toxic proteins associated with how fast cognition and brain function John Foxe, Ph.D., and Ed Freedman, Alzheimer’s. change over the course of the disease.

Ph.D., are working on developing a While there are a host of studies curpotential diagnostic method to identify rently active in the AD-CARE portfolio, Porsteinsson said he people at risk for AD using a novel Mobile Brain/Body Imagis particularly excited about a few prevention investigations. ing (MoBI) approach.

The program is involved in three different studies that look Like many complex neurological disorders, there is growat cognitively normal individuals who have either biomarker ing recognition that there may not be one single approach evidence of an evolving AD process in their brain or genetic that’s successful for prevention and treatment in Alzheimarkers that significantly increase their risk for AD and intermer’s. Successful treatment strategies will likely require a vene with different treatments targeting the evolving increased combination of therapies, preventative approaches, and amyloid burden. advanced neuroimaging to address the growing prevalence “We’re looking forward to closer collaboration with basic of the disease as the population ages. The Del Monte Instiand translational science at the Del Monte Institute,” adds tute for Neuroscience has identified tackling this devastating Porsteinsson. “It gives us a number of very exciting potential disease as one of its key 10-year objectives and is supportavenues.” ing research through pilot grant funding and encouraged collaboration. Together with the Rochester community A campus-wide effort and numerous departments, laboratories and investigators There are many other investigators at the University engaged across the University, the Institute is determined to remain in AD research. Maiken Nedergaard, M.D., D.M.Sc.,with at the forefront of the battle against Alzheimer’s disease and the Center for Translational Neuromedicine is investigating tackle the epidemic head-on. Q how to manipulate the glymphatic system — the brain’s 6

F A C U LT Y P R O F I L E

Q&A with Kuan Hong Wang, Ph.D. Kuan Hong Wang, Ph.D., joined the Del Monte Institute for Neuroscience as a professor at the start of the year. Wang comes to the University of Rochester from the National Institute of Mental Health (NIMH) where he served as chief of neural circuits and adaptive behaviors research for over a decade. We sat down with Wang to talk about his research, his love for classical music, and why he is excited to immerse himself in the rich scientific environment at the University.

Del Monte: Why did you decide to come to the University of Rochester?

KHW: The University of Rochester is known for its excellence in research and emphasis on education, and I’m highly excited to come here. I have been doing research for a couple of decades, and my investigations cover a wide spectrum of topics, from the molecular biology of nerve cells to the developmental origin and functional architecture of the brain. While NIMH was a great biomedical research environment for me to start out as an investigator, my program has been growing and has become more cross-cutting. Conducting these innovative types of projects requires extensive interdisciplinary collaboration and there are some limitations to that when working for government agencies.

Rochester has a great collegial environment and I’m very much looking forward to becoming a part of its scientific community. The collaborative nature of the Del Monte Institute for Neuroscience is impressive; the leadership is extremely visionary, with great ambition for moving neuroscience forward. It will be fantastic to work with people in different research areas, from biomedical genetics to cognitive science, and come up with cutting-edge research questions. Another draw are the strong engineering, computer science, and optics programs. These disciplines are necessary for making innovation and progress in neuroscience research. Additionally, the University supports diverse experimental organisms, allowing and encouraging researchers to look at rodent and non-human primate models. Such comparative perspectives are essential for cross-species translation of basic biological discoveries into medical insights and benefits.

I received much of my early research experience at academic institutions, including my B.A. from Harvard, Ph.D. from the University of California San Francisco, and a postdoc at MIT. I really missed working with students after moving to NIMH, so I’m looking forward to again conducting exciting investigations with students from different 7

Tracing connected neurons (red) and activity-dependent gene expression patterns (green) in mouse brain.

backgrounds and departments. I love to brainstorm with colleagues and serve as a teacher and mentor to students and staff. Outside of my duties as a professor, I plan to participate in activities that lend themselves to general science outreach and education.

What areas of neuroscience will you focus on at the University of Rochester?

My personal research interest lies in how our complex behaviors are generated from the underlying nervous system.

To adaptively interact with a complex and changing environment, our brain needs to select appropriate sensory signals and integrate them with internal goals to control actions.

Dysfunctions in this cognitive control process are found in many debilitating psychiatric and neurological conditions such as schizophrenia, autism, neuropathic pain, and addiction. Over the past decade, I have taken on an ambitious research direction to define neural mechanisms of cognitively-controlled motor action, with the hope to identify and investigate a new set of prodromal markers and therapeutic targets for brain disorders.

My future research will continue to focus on the developmental origins and functional plasticity of brain circuits involved in the cognitive control of sensorimotor functions.

How does the cerebral cortex send descending projections to the brainstem and spinal cord to take control of our body?

How do the ascending neuromodulatory inputs to the cerebral cortex convey our internal drive and influence cognitive maturation? Can we harness the plasticity of these circuit modules to treat brain disorders? We hope to address these questions by linking the molecular mechanisms regulating circuit formation to the functional logic of circuit organization, using both rodent and primate research models.

A deeper understanding of neural mechanisms underlying cognitive control will help us to identify translational and 8

clinical opportunities. Treatment for a range of brain disorders like intellectual disability, autism, ADHD, and schizophrenia will benefit from our investigation of the functional development of cognitive control circuits. These disorders tend to emerge at different stages in life — congenitally in the case of most intellectual disabilities, but in adolescence or early adulthood in the case of schizophrenia. My hope is that by examining vulnerabilities of the brain in different stages and genetic models we can better understand why symptoms occur when they do and what approaches could potentially help reverse brain deficits.

How did you become interested in neuroscience?

In high school I participated in math and chemistry competitions. When I was an undergraduate at Harvard University I started to become interested in neuroscience. I had a lot of great research opportunities there, which led me to wonder more deeply about the underlying basis of mental activities that we humans have. I thought that I needed to start with something basic, like molecular signal transduction. Then, I gradually expanded the scale of my investigation from nerve cells to neural circuits and behaviors. I feel extremely fortunate that I now have the luxury and freedom to conduct research and get an integrative view into how the brain functions. I believe that neuroscience represents one of the ultimate frontiers in human knowledge.

What do you like to do for fun outside of the lab?

I have always enjoyed all different genres of music, especially classical. Some composers have such an abstract and unique sense of beauty. I think it’s amazing how music can evoke a strong emotional response in people, and how we can enjoy it from an intellectual perspective as well. I also love to hike, ski, and play badminton. And, now that I’m up north in Rochester, I’m looking forward to trying cross country skiing. Q

Del Monte Institute for Neuroscience Executive Committee

John J. Foxe, Ph.D.

Diane Dalecki, Ph.D.

Director, The Ernest J. Del Monte Institute for Neuroscience

Distinguished Professor of Biomedical Engineering

Kilian J. and Caroline F. Schmitt Chair in Neuroscience

Chair, Department of Biomedical Engineering

Professor and Chair, Department of Neuroscience

Webster H. Pilcher, M.D., Ph.D.

Robert G. Holloway, M.D., M.P.H.

Ernest & Thelma Del Monte Distinguished Professor in Neuromedicine

Edward A. and Alma Vollertsen Rykenboer Chair in Neurophysiology

Professor and Chair, Department of Neurosurgery

Professor and Chair, Department of Neurology

Gregory C. DeAngelis, Ph.D.

Bradford Berk, M.D., Ph.D.

Hochang B. (Ben) Lee, M.D.

George Eastman Professor

Director, The University of Rochester Neurorestoration Institute

John Romano Professorship in Psychiatry

Chair, Brain and Cognitive Sciences

Professor of Medicine, Cardiology

Professor and Chair, Department of Psychiatry

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Paths of Least Resistance

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22K and 12K gold, dye, mica, and metal powder on stainless steel 96” X 40”, 2017 Greg A. Dunn, PhD