NeURoscience | Vol 20 | 2024

NEUROSCIENCE University of Rochester | Ernest J. Del Monte Institute for Neuroscience Vol. 20 - 2024

Transforming intellectual and developmental disabilities research PG 3

F R O M T H E D I R EC TO R ’ S D E S K

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John J. Foxe, PhD Kilian J. and Caroline F. Schmitt Chair in Neuroscience

Director, Ernest J. Del Monte Institute for Neuroscience

Professor & Chair, Department of Neuroscience

here is something about the start of a new year that inspires change.

Many make resolutions. In academia, a new year means a new semester, classes, projects, and questions. This year, more change is on our doorstep as the University of Rochester Medical Center (URMC) CEO and School of Medicine and Dentistry Dean, Dr. Mark Taubman, retires. We in the neurosciences, especially those who study intellectual and developmental disabilities, owe him a great debt of gratitude. He was a driving force in helping the University secure the Intellectual and Developmental Disabilities Research Center (UR-IDDRC) designation in 2020, built on decades of research, and launched the University into a small but mighty group of institutions that have the trifecta of NIH funding that supports research, community outreach, and training in this realm. We dedicated this issue's cover story to the work that’s been accomplished since receiving that designation (page 3). Thank you, Dr. Taubman, for your leadership and dedication to making the community and world healthier. And for your support of advancements in our understanding

Del Monte Institute for Neuroscience Executive Committee

ON THE COVER: Toxicology graduate student Elizabeth Plunk (back) and Neuroscience graduate student Alexis Feidler (front) use a confocal microscope in the Cell and Molecular Imaging (CMI) scientific core of the University of Rochester Intellectual and Developmental Disabilities Research Center.

John Foxe, PhD, Chair, Department of Neuroscience Bradford Berk MD, PhD, Professor of Medicine, Cardiology Robert Dirksen, PhD, Chair, Department of Pharmacology & Physiology Diane Dalecki, PhD, Chair, Department of Biomedical Engineering Jennifer Harvey, MD, Chair, Department of Imaging Sciences Robert Holloway, MD, MPH, Chair, Department of Neurology

of IDDs. It simply would not have happened without you.

Now, I am delighted to welcome Dr. David Linehan to the helm. He becomes the second person to hold both titles–URMC CEO and SMD Dean–and he is also senior vice president (SVP) for Health Sciences. As a surgeon and a very accomplished clinical researcher, Dr. Linehan's leadership will usher in a new era of excellence and growth.

I am very much looking forward to working with him in this next chapter for URMC and SMD. We had a wonderful time at the annual Society for Neuroscience Conference in Washington, D.C., in November. The Conference was vibrant, and I enjoyed seeing many familiar faces at our annual social event. It was also a thrill to bring many of the high school students from our Diversity Commission’s NEUROEAST program to the Conference for the first time.

In Science,

John J. Foxe, PhD

Paige Lawrence, PhD, Chair, Department of Environmental Medicine Hochang (Ben) Lee, MD, Chair, Department of Psychiatry Shawn Newlands, MD, PhD, MBA, Chair, Department of Otolaryngology Webster Pilcher, MD, PhD, Chair, Department of Neurosurgery Steven Silverstein, PhD, Professor, Department of Psychiatry Duje Tadin, PhD, Chair, Department of Brain & Cognitive Sciences

UNIVERSITY OF ROCHESTER | ERNEST J. DEL MONTE INSTITUTE FOR NEUROSCIENCE

NEUROSCIENCE Editor/Writer Kelsie Smith Hayduk Kelsie_Smith-Hayduk@ urmc.rochester.edu Contributors Mark Michaud James Miller Feature Photography John Schlia Photography Designer Beth Carr

NEWS BRIEFS

Researchers identify path to prevent cognitive decline after radiation Researchers at the Del Monte Institute for Neuroscience at the University of Rochester find that microglia—the brain’s immune cells—can trigger cognitive deficits after radiation exposure and may be a key target for preventing these symptoms. These findings build on previous research showing that after radiation exposure microglia damage synapses, the connections between neurons that are important to cognitive behavior and memory. Using several behavioral tests, M. Kerry O’Banion, MD, PhD, professor of Neuroscience and senior author of the study published in the International Journal of Radiation Oncology Biology Biophysics, investigated the cognitive function of mice before and after radiation exposure. Female mice performed the same throughout, indicating a resistance to radiation injury. However, researchers found male mice could not remember or perform certain tasks after radiation exposure. This cognitive decline correlates with the loss of synapses found damaged by microglia following the treatment.

Researchers then targeted the pathway in microglia important to synapse removal. Mice with these mutant microglia had no cognitive decline following radiation. And others that were given the drug, Leukadherin-1, which is known to block this same pathway, during radiation treatment, also had no cognitive decline.

Calcium channel blockers key to reversing myotonic dystrophy muscle weakness, study finds New research has identified the specific biological mechanism behind the muscle dysfunction found in myotonic dystrophy type 1 (DM1) and further shows that calcium channel blockers can reverse these symptoms in animal models of the disease. The researchers believe this class of drugs, widely used to treat several cardiovascular diseases, holds promise as a future treatment for DM1. John Lueck, PhD, an assistant professor at the University of Rochester Medical Center (URMC) in the Departments of Pharmacology and Physiology, and Neurology, led the study published in the Journal of Clinical Investigation. When the team treated mice with verapamil, a calcium channel blocker used to treat hypertension and chest pains, the mice quickly recovered muscle function and began to resemble their healthy, wild type peers.

The researchers were quick to emphasize that verapamil is NOT an appropriate treatment for DM1 in humans due to its potential cardiac side effects. They are now looking for an appropriate and safe calcium channel blocker to potentially use in this way.

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NEWS BRIEFS

Manipulating fluid flows in the brain could save lives, improve recovery post-TBI Research led by Maiken Nedergaard, MD, DMSc, co-director of the University of Rochester Center for Translational Neuromedicine finds a cocktail of drugs already approved to treat high blood pressure quickly reduces brain swelling and improves outcomes, in animal models of brain injury. Cerebral edema, the dangerous brain swelling that occurs after traumatic brain injury (TBI), can increase risk of death tenfold and significantly worsen prospects for recovery in brain function. Physicians have very few tools at their disposal that are effective in treating cerebral edema, which is one of the leading causes of in-hospital deaths and is associated with long-term neurological disability. This study published in Nature points to the potential to repurpose the glymphatic system to act as an emergency pressure release valve. Using fluorescent microspheres, the researchers traced cerebrospinal fluid originating from the site of the swelling as it exited in bulk from the brain via the lymphatic vessels, carrying with it debris from the injury to the lymph nodes.

Once the drugs were administered, the result was an almost immediate elimination of cerebral edema and a sustained return to normal intracranial pressure in the animals. The treatment resulted significant recovery of cognitive, behavioral, and motor function.

Researchers find neurons work as a team to process social interactions Researchers have discovered that a part of the brain associated with working memory and multisensory integration may also play an important role in how the brain processes social cues. Previous research has shown that neurons in the ventrolateral prefrontal cortex (VLPFC) integrate faces and voices—but new research, led

by Lizabeth Romanski, PhD, associate professor of Neuroscience at the Del Monte Institute for Neuroscience at the University of Rochester, shows that neurons in the VLPFC play a role in processing both the identity of the “speaker” and the expression conveyed by facial gestures and vocalizations. While showing short videos to non-human primates, researchers recorded the activity of more than 400 neurons in the VLPFC and found that individually, the cells did not exhibit strong categorical responses to the expressions or the identities of the macaques in the videos. However, when the researchers combined the neurons as a population a machine learning model could be trained to decode the expression and identity in the videos based only on the patterns of neural activity, suggesting that neurons were collectively responding to these variables. These findings, published in the Journal of Neuroscience, suggest that the VLPFC is a key brain region in the processing of social cues.

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UNIVERSITY OF ROCHESTER | ERNEST J. DEL MONTE INSTITUTE FOR NEUROSCIENCE

F E AT U R E

The University of Rochester Intellectual and Developmental Disabilities Research Center is transforming the landscape of exploration.

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atten disease is a devastating rare genetic disorder. While the genetic flaw that causes this disease is well known, scientists do not fully understand the connection between this mutation and the disease’s symptoms like behavioral changes, cognitive impairment, seizures, and vision loss. John Foxe, PhD, co-director of the University of Rochester Intellectual and Developmental Disabilities Research Center (UR-IDDRC), recently described a potential neuro marker for the disease that could represent a way to better understand this complex disease and, ultimately, help researchers measure outcomes in clinical trials.

“We [researchers] know it is a genetic single gene mutation that causes Batten disease and as a scientist that really gives us something to focus on,” said Foxe, who is also director of the Del Monte Institute for Neuroscience at the University of Rochester. “But clinically, what we do not fully understand is how the mutation changes connections in the brain. Our work has been aimed at developing a much better understanding of these changes and developing ways to measure these accurately. If we can figure out how to treat Batten disease, there's a very good chance we will gain insight into how to treat other rare diseases.”

The University is a recognized leader in Batten disease research and care and has been at the forefront of efforts to understand and treat this condition. The University of Rochester Batten Center (URBC) is designated as a Center of Excellence by the Batten Disease Support and Research Association (BDSRA), highlighting its commitment and expertise in advancing both research and treatment for this disease.

In 2020, when the National Institute of Child Health and Human Development (NICHD) designated the University as an IDDRC, the disease became the Center’s principal project, and researchers identifying biomarkers to evaluate the effectiveness of experimental treatments became a renewed focus for faculty at the Medical Center. Foxe’s latest research, published in the Journal of Neurodevelopmental Disorders, is one example of how the IDDRC designation is transforming the IDD research landscape at the Medical Center.

Above: MD/PhD student Emily Isenstein (right) is with a subject in EEG booth in CABIN. Isenstein is using new advancements to understand how the brain responds to active and passive touch.

This could improve therapies for people with autism that could make passive touch less unpleasant.

From left: Ania Majewska, PhD, co-director of the UR-IDDRC, Sherry Mentor, administrative director, UR-IDDRC, John Foxe, PhD, co-director of the URIDDRC.

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Delivery day: 9.4T MRI is lifted by crane as it begins its journey into CABIN.

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UNIVERSITY OF ROCHESTER | ERNEST J. DEL MONTE INSTITUTE FOR NEUROSCIENCE

Upgrading resources, uniting teams The structure of the UR-IDDRC has propelled the relationship between discoveries at the bench and clinicians.

The Center has four scientific cores—Human Clinical Phenotyping and Recruitment, Translational Neuroimaging and Neurophysiology, Animal Behavior and Neurophysiology, and Cell and Molecular Imaging. These cores enhance access to resources, equipment, data, and expertise, advancing research at the University in new ways.

The Cell and Molecular Imaging (CMI) core provides access to state-of-the-art equipment and expert support for those looking to utilize it. Currently, research utilizing CMI is developing a human model of iron deficiency using brain organoids—a mass of cells, in this case, that represents a brain that is so small a microscope is needed to study it. This research led by Margot Mayer-Proschel, PhD, professor of Biomedical Genetics and Neuroscience, and supported by a UR-IDDRC pilot grant, builds on her lab’s previous work that identified a new embryonic neuronal progenitor cell target for gestational iron deficiency. This research could inform the connection between gestational iron deficiency and IDDs, change health care recommendations, and provide potential targets for future therapies. It is well understood that low levels increase the risk of cognitive impairments like autism, attention deficit syndrome, and learning disabilities.

Some of the first images captured by the Ania Majewska, 9.4T MRI that is part of the Translational PhD, professor of Neuroimaging and Neurophysiology core Neuroscience and of the UR-IDDRC. co-director of the UR-IDDRC, is also the co-director of the CMI core. The URIDDRC has fostered new collaborations for her and her lab’s IDD-related research, particularly in understanding how the environment impacts the brain.

“I have always studied basic neurodevelopment, how circuits get set up and remodeled naturally and by the environment; this fed into the IDD space,” said Majewska.

“The UR-IDDRC has been fantastic for finding people who are already at the University and Medical Center to collaborate with, like Marissa Sobolewski, PhD, and Paige Lawrence, PhD, who is the director of the Institute for Human Health and the Environment. Our labs are working together on research related to per- and polyfluoroalkyl or PFAS, also known as

From left: Neuroscience Graduate Student Mark Stoessel works with Ania Majewska, PhD, at bench in her lab at the Medical Center.

‘forever chemicals’. In fall 2023, a new 9.4T MRI arrived at the Center for Advanced Brain Imaging and Neurophysiology (CABIN) at the Medical Center. This state-of-the-art imaging system is available to investigators through the Translational Neuroimaging and Neurophysiology core. It joins the ranks of Mobile Brain/Body Imaging or MoBI and high-density electroencephalogram or EEG. “It [UR-IDDRC] has provided absolutely critical infrastructure through the scientific cores and then through all its activities,” Foxe said. “Our successful symposiums have brought researchers from around the world to Rochester.

The IDDRC has also brought scholarship opportunities and students. It has coalesced the IDD community at the University like never before.”

Subject on Mobile Brain/Body Imaging machine in CABIN. It is one of the tools in the Translational Neuroimaging and Neurophysiology core.

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“I

think it’s a very exciting thing to be partnering with people who look at the same thing from a very different

perspective. We learn from each other and share resources.”

– John Foxe, PhD

The University is one of eight institutions with the trifecta of federal awards related to IDDs, giving a nod to its research, training, care, and community partnerships.

Along with the IDDRC, it has long been a University Center of Excellence in Developmental Disabilities Education, Research, and Service (UCEDD) and Leadership Education in Neurodevelopmental and Related Disabilities (LEND). The UCEDD focuses on training and community service, while the LEND focuses on education. The three entities continue to innovate new collaboration opportunities. Most recently, a retreat brought more than two dozen people from across the three entities together to brainstorm, collaborate, and strengthen relationships.

(Center) Laura Silverman, PhD, program director of LEND, presents at recent retreat.

Tackling a challenge protects the vulnerable

(Center) Suzannah Iadarola, PhD, director of UCEDD presents to group at recent retreat.

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Within a year of receiving the IDDRC designation, the resources and expertise at the University were tested. As the COVID pandemic raged, the NIH looked to IDDRCs to help its efforts in understanding the impact of the virus on the IDD community. UR-IDDRC and Mary Cariola Center, an education and life skills center for people with severe IDDs and complex medical needs, teamed up and took on the $4 million project, funded by the NIH Rapid Acceleration of DiagnosticsUnderserved Populations (RADx-UP) program.

“This was an unbelievably successful project,” Foxe said.

“We were able to respond in a matter of weeks to a critical need in our community because we already had infrastructures set up and community partners in place.”

The access to testing allowed Mary Cariola to comply with state mandates and provide real-time results to researchers that kept COVID out of classrooms on several occasions by identifying asymptomatic cases. The data collected by this

UNIVERSITY OF ROCHESTER | ERNEST J. DEL MONTE INSTITUTE FOR NEUROSCIENCE

Emily Knight, MD, PhD, and lab technician Nishant Joshi Dinesha collect EEG data from subject in the Spectrum Brain Lab in CABIN.

study will inform how airborne illnesses are responded to and hopefully mitigated in this type of setting.

The future: From bench to bedside The UR-IDDRC continues to support research progress through new equipment and pilot funding, while attracting new talent to the University and the field. “The IDDRC designation is elevating the awareness of what we are doing in this space,” said Majewska. “And it has certainly helped with recruiting students. People get very excited about it. The IDDRC has become the nucleus of the work that has been underway at the University for decades. It has strengthened it, allowed us to purchase new state-of-the-art equipment, fostered new collaborations, and given resources to investigators here to take their research in new and exciting directions.”

Thirty peer-reviewed research papers have been supported by the Center since 2020, and faculty have established

new labs. Emily Knight, MD, PhD, assistant professor of Pediatrics and Neuroscience and principal investigator of the Spectrum Brain Lab, is a physician-scientist who was a fellow in the LEND program before becoming a faculty member in 2022. She was recently awarded a UR-IDDRC pilot grant to investigate the deficits in mechanisms in the auditory processing system that impact how children with autism process language in a noisy environment.

The IDDRC designation has leveraged the already robust IDD research at the University. It has established a clear pathway from bench to bedside by uniting the IDD research underway at the University with the already well established UCEDD and LEND programs. “I think it’s a very exciting thing to be partnering with people who look at the same thing from a very different perspective,” Foxe said. “We are learning from each other and sharing resources. I’m energized by what we’ve been able to accomplish so far and am looking forward to the future.”

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

Q&A with

Archan Ganguly, PhD for synaptic communication are trafficked from the cell body of the neuron, where they are synthesized, along these long axons, all the way to the synapses where they function. I am primarily interested in examining the molecular mechanisms essential for the trafficking of these synaptic proteins and how trafficking changes when neurons communicate with each other, or when learn a new task or age. I am also very interested in establishing if this transport of synaptic proteins is altered in patients carrying mutations associated with neurodevelopmental and neurodegenerative disorders.

Archan Ganguly, PhD, is an assistant professor of Neuroscience at the University of Rochester Medical Center.

He received his undergraduate degree in Zoology from the University of Delhi and completed his PhD in Neuroscience at Ohio University. He went on to complete his postdoctoral training at the University of California, San Diego. He came to the Medical Center in late 2019, and his research aims to understand how proteins essential for synaptic communication between neurons are trafficked from the cell body of the neuron to the synapses where they function, and how this process may be altered, including by gene mutations in the context of neurodegenerative and neurodevelopmental disorders.

Please tell us about your research.

Communication between neurons forms the basis for a whole host of functions we perform in our daily lives, including learning, memory, and social communication.

Neurons communicate with each other through specialized structures called synapses. At these synapses, hundreds of proteins work synchronously to release packets of peptides (called neurotransmitters) which encode the information necessary for effective communication between neurons.

Since the neurons are long and polarized, synapses are typically hundreds of microns away from the neuron’s cell body, to which they are connected by specialized tubes called axons. My research aims to define how proteins essential

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How did you become interested in your field?

During my years in middle school back in my hometown in India, I had the opportunity to volunteer for a school for kids with special needs. The question which haunted my mind after this experience was why and how is neuronal communication so drastically altered in these kids? This sparked my natural curiosity in understanding how the human brain works and pursuing a research track in neuroscience.

While genome sequencing has identified genes linked to neurodevelopmental disorders and answered the ‘why’ part of the question, the biology underlying how these mutations effect wiring and communication between neurons remains poorly understood. This question of how Ganguly at Letchworth State Park, synapses fail to located about 40 miles south of form and function Rochester. He enjoys time with his appropriately remains family and watching songbird migration (particularly at Letchworth the driving motivation State Park) when he’s not in the lab. for my research.

UNIVERSITY OF ROCHESTER | ERNEST J. DEL MONTE INSTITUTE FOR NEUROSCIENCE

What brought you to the University of Rochester?

I came to the University of Rochester when my wife was recruited to the Wilmot Cancer Center. It was our first choice since it was the only place which gave me the liberty to work on publishing my post-doctoral work while also working on developing my own independent research ideas. Additionally, the diverse nature of neuroscience research here along with the very collaborative nature of the University was a strong draw.

I already have collaborations underway with Dr. Christoph Proschel in the Department of Biomedical Genetics and

Dr. Krishnan Padmanabhan in Neuroscience and look forward continuing to grow that list.

What is your favorite piece of advice?

A phrase from one of my favorite Dylan songs ‘Love Minus Zero/No Limit’ sums up my favorite advice. It goes: “There is no success like failure and failure is no success at all”.

The fun in science (according to me) is all about doing the hardest experiments and persevering through your failures and learning from every mistake you make.

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

John Gonzalez-Amoretti John Gonzalez-Amoretti is a 4th year Neuroscience graduate student. Gonzalez-Amoretti received his degree in Chemistry from Universidad Ana G. Mendez in Gurabo, Puerto Rico. He is currently working in the lab of Adam Snyder, PhD, in the Brain and Cognitive Sciences Department at the University of Rochester where he is studying visual attention and how the brain uses information about an object to find its location.

The National Eye Institute (NEI) awarded GonzalezAmoretti an F31 to study how neural populations in the prefrontal cortex of the brain use feature information of an object, such as its color and shape, to assign it a location that eases the search for that object. “I’m really interested in how the brain creates representations of the world around us and how those are used to enable cognitive mechanisms, such as attention,” Gonzalez-Amoretti said. “Basically, when you’re at a concert and go to the bathroom, how do you find your group of friends—you may be on the lookout for specific clothing to identify the potential places in the crowd where you may find them.”

Gonzalez-Amoretti is thrilled to receive this funding opportunity. “It feels good to have the support from the NEI for my research. It is awesome to have this kind of validation for my ideas and hard work, I would have never pictured myself here.”

He attributes his success in science to his innate curiosity.

“I have this impulse to grab things and examine them up close, now it’s more under control but I used to get scolded all the time as a kid for touching things,” Gonzalez-Amoretti said. “Stargazing was a common hobby of mine, which led to

many questions about space and the nature of things. It led me to study chemistry, where my desire to pursue a career John Gonzalez-Amorett in research became clear early on. However, philosophy sparked my interest in consciousness and perception. It eventually led me to shift my research interests, which led me to pursue a career in neuroscience.” His future goal is to pursue research focused on neural dynamics of conscious perception and how psychedelics may influence these dynamics.

Outside the lab, Gonzalez-Amoretti is active in the Society for Advancement of Chicanos/Hispanics and Native Americans in Science (SACNAS) at the University of Rochester and the Del Monte Institute for Neuroscience Diversity Commission. “I have had to work really hard and take initiative to get where I am today. There were many times where I had to hustle to find resources and opportunities. I wasn’t surrounded by people who could point me to the right direction to pursue higher education, let alone research. I had to go out of my way to find that. Now, I want to do what I can to contribute to improving the accessibility to educational resources and opportunities that can fulfill the potential of future firstgeneration STEM leaders.”

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Highlights from SfN 2023!

It was a busy Society for Neuroscience conference between booth visits, poster presentations, and talks.

Neuroscience Graduate Program booth.

Congratulations to our 2023 Neuroscience Alumni Award recipient, Colin Combs, '96 (PhD)! Pictured with (from left) M. Kerry O’Banion, MD, PhD, Lisa Opanashuk, '85, '92 (MS), '95 (PhD), Combs, and John Foxe, PhD.

(From left) William Merigan, PhD, and Frank Garcea, PhD, at poster presentation.

For the first time, the Neuroscience Diversity Commission brought NEUROEAST students along for the conference.