NeURoscience | Vol 17 | 2023

NE UR OSCIENCE

HALTING THE RISE OF PARKINSON'S

John J. Foxe, PhD

As another academic year enters its final weeks, I cannot help but reflect on the in-person interactions throughout the year. In-person seminars, guest speakers at a podium instead of on Zoom, retreats, and other gatherings brought together the great minds that study and investigate neuroscience here and around the world. There was another success from our Neuroscience Diversity Commission this semester. NEURO2ALL, the Commission’s community outreach group, held its first children’s event at the Rochester Museum and Science Center. The group also successfully launched a new course within the School of Medicine and Dentistry that provides community outreach opportunities to UR and URMC students at all levels. Some of the lessons developed in this class have already been shared with the community.

I am thrilled to share the incredible research highlighted in our cover story. Collaborators from across the University—including the new Institute for Human Health and the Environment—aim to understand how chemicals in the environment cause or contribute to neurodegenerative diseases

like Parkinson’s—the fastest-growing neurological condition in the world. You will also read about their research under the University of Rochester Intellectual and Developmental Disabilities Research Center (UR-IDDRC).

Our student spotlight shines on Mark Osabutey who was a physician in Ghana before coming to Rochester. His passion for basic science led him to study neuroscience at the School of Medicine and Dentistry. I look forward to you learning more about his aspirations and how a 13-year-old patient helped send him on this path.

Forever curious is the scientist and our faculty and students never cease to amaze me. You will see the breadth of peer-reviewed research recently published that brings each hypothesis closer to the ultimate questions—how does the brain work, and what can be done to prevent, treat, and care for neurodegenerative and neuropsychiatric disorders.

In Science,

John J. Foxe, PhD

Del Monte Institute for Neuroscience Executive Committee

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

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

NEUROSCIENCE

Editor/Writer

Kelsie Smith Hayduk Kelsie_Smith-Hayduk@ urmc.rochester.edu

Contributors

Mark Michaud, Barbara Ficarra

Feature Photography

John Schlia Photography

Designer Beth Carr

Kilian J. and Caroline F. Schmitt Chair in Neuroscience

Director, Ernest J. Del Monte Institute for Neuroscience

Professor & Chair, Department of Neuroscience

Can hearing loss be reversed?

Research reveals clues that could regrow the cells that help us hear

The most common cause of hearing loss is progressive because cochlear hair cells—the primary cells to detect sound waves— cannot regenerate if damaged or lost. People who have repeated exposure to loud noises, like military personnel, construction workers, and musicians, are most at risk for this type of hearing loss. But, it can happen to anyone over time. Birds and fish can regenerate these hair cells, and now researchers at the Del Monte Institute for Neuroscience are getting closer to identifying the mechanisms that may promote this type of regeneration in mammals, as explained in research recently published in Frontiers in Cellular Neuroscience

Researchers found how the activation of the growth gene ERBB2 pathway triggers a cascading series of cellular events by which cochlear support cells multiply and activate other neighboring stem cells to become new sensory hair cells. This is a significant advance toward the ultimate goal of generating new cochlear hair cells in mammals, according to the senior author of the study, Patricia White, PhD, professor of Neuroscience and Otolaryngology at the University of Rochester Medical Center.

Researchers identify neurons that "learn" to smell a threat

Whether consciously or not, when entering a new space, we use our sense of smell to assess whether it is safe or a threat. In fact, for much of the animal kingdom, this ability is necessary for survival and reproduction. Researchers are finding new clues to how the olfactory sensory system aids in threat assessment and have found neurons that “learn” if a smell is a threat.

In a paper published in the Journal of Neuroscience, researchers in the lab of Julian Meeks, PhD, associate professor of Neuroscience, describe that they were able to identify a specific set of neurons in the accessory olfactory system in mice that can learn the scent of another mouse that is a potential threat. The experiment abolished the ramping aggression that is typically exhibited by mice and indicates that this early sensory inhibitory neuron population plays a critical role in regulating the behavioral response to social smells.

Our eyes are never at rest. They remain in motion, even between our voluntary gaze shifts, through fixational eye movements—small, continuous shifts of the eye that we are not aware of making. Scientists have long sought to understand how humans can perceive the world as stable while our eyes are constantly moving. Past research has suggested that, in the intervals between voluntary gaze shifts, the human visual system builds a picture of a stable world by relying solely on sensory inputs from fixational eye movements. According to new research by a team at the University of Rochester published in Nature Communications, however, there may be another contributing factor.

Michele Rucci, PhD, a professor in the Department of Brain and Cognitive Sciences and at the University’s Center for Visual Science, and first author Zhetuo Zhao, a PhD student in Rucci’s lab— report that the visual system not only receives sensory inputs from fixational eye movements but also possesses knowledge of the motor behavior involved in those movements. The results of the research reveal that spatial representations—that is, the locations of objects in relation to other objects—are based on a combination of sensory and motor activity from both voluntary and involuntary eye movements, which is contrary to the prevailing understanding of this phenomenon.

Iron & the brain: Where and when neurodevelopmental disabilities may begin during pregnancy

Numerous studies have found that mothers with low iron levels during pregnancy have a higher risk of giving birth to a child that develops cognitive impairments like autism, attention deficit syndrome, and learning disabilities. The laboratory of Margot Mayer-Proschel, PhD, a professor of Biomedical Genetics and Neuroscience, was the first to demonstrate that the brains of animals born to iron-deficient mice react abnormally to excitatory brain stimuli, and that iron supplements given at birth do not prevent functional impairment that appears later in life.

Most recently, her lab has made significant progress in the quest to find the cellular origin for the impairment and has identified a new embryonic neuronal progenitor cell target for gestational iron deficiency as described in a study published in the journal Development

Through the eye of the beholder: People with autism may process illusory shapes differently

The process in our brain that allows us to see visual distinctions may not be happening the same way in the brains of children with autism spectrum disorder. Researchers in the Frederick J. and Marion A. Schindler Cognitive Neurophysiology Laboratory used visual illusions—groups of Pac-Man-shaped images that create the illusion of a shape in the empty space—and revealed that children with autism did not automatically process the illusory shapes as well as children without autism. It suggests that something is going awry in the feedback processing pathways in their brain.

“How our brain puts together pieces of an object or visual scene is important in helping us interact with our environments,” said Emily Knight, MD, PhD, assistant professor of Neuroscience and Pediatrics at the University of Rochester Medical Center, and first author on a study in the Journal of Neuroscience. “When we view an object or picture, our brains use processes that consider our experience and contextual information to help anticipate sensory inputs, address ambiguity, and fill in the missing information.”

Small, involuntary eye movements help us see a stable world

Halting the Rise of Parkinson’s

Quality of life, health, and longevity are being increasingly tied to someone’s zip code rather than their genetic code. Cancer, heart disease, neurodegenerative disorders, and even our ability to fight infection are linked to the myriad of chemicals we are exposed to, often unwittingly, over the course of our lives. The University of Rochester’s leadership in the field of environmental medicine stretches back to toxicology research programs developed at the University under the Manhattan Project. These programs also served as the basis for the formation of a NIEHS Center of Excellence in environmental toxicology and health that is one of the oldest in the country celebrating 50 years of sustained funding. This foundation and the decades of work that followed—coupled with the recognition that the public health

threat requires a collaborative commitment to research, education, and community engagement—led to the creation of the new Institute for Human Health and the Environment.

Paige Lawrence, PhD, the Wright Family Research Professor and chair of the Department of Environmental Medicine, is the founding director of the new Institute. “Genetics only explaining 10 to 15 percent of human health, which leaves the rest to the environment,” said Lawrence. “If we really want to have an impact on health, environmental influences need to be front and center.”

The new Institute will help power a team of neurologists, neuroscientists, toxicologists, epidemiologists, and researchers at the University of Rochester who are examining the impact of environmental chemical exposure on the brain. One disease in

particular stands out. Parkinson’s is the fastest growing neurodegenerative disease in the world, outpacing even Alzheimer’s, and a growing number of scientists are linking the disease’s rise to air pollution, pesticides, and a ubiquitous chemical pollutant.

Paige Lawrence, PhD, sits at a bench in her lab in the Institute for Human Health and the Environment at the University of Rochester Medical Center (URMC).

Up the nose it goes

Air pollution is associated with many health problems, including asthma, heart disease, stroke, low birth weight, and inflammation. While epidemiological studies have hinted at the link between air pollution and neurological disorders like Parkinson’s and Alzheimer’s, the route these chemicals use to make their way into the brain, and the damage caused once there, was until recently poorly understood.

“We’ve known that air pollution has effects on the heart and the lung for a very long time, but it's really only been in about the past

ten years that attention has been directed to its effects on the brain,” said Debbie Cory-Slechta, PhD, a professor of Environmental Medicine, Neuroscience, and Public Health Sciences. Cory-Slechta’s colleagues at the University of Rochester, Guenter Oberdoerster, PhD, and Alison Elder, PhD, were among the first to show that ultrafine air pollution particles, called PM0.1, are able to hitch a ride directly into the brain via the nasal passage and olfactory nerves, bypassing the brain’s normal defenses.

Researchers are quick to point out that many challenges hinder the field of air pollution research, including the fact that they suspect damage to the brain is caused not by a single component but rather multiple

different chemicals acting together.

“Air pollution is a very complicated exposure,” said Cory-Slechta. “It is comprised of a mixture of gases and particles, and those particles carry other metals and organic toxins into the brain.”

Another factor is that several decades can pass between exposure and onset of symptoms, making the time, place, and “dose” of exposure difficult to identify. Unlike other forms of air pollution, there is not widespread and routine monitoring for ultrafine particles. Furthermore, exposure could be more dangerous for individuals already at higher risk for diseases like Parkinson’s, or when the exposure occurs during important, and vulnerable, development stages.

Debbie Cory-Slechta, PhD, checks the Harvard Ultrafine Concentrated Ambient Particle System (HUCAPS). HUCAPS takes in the outside air to be studied in real time. It is one of only a handful in use in the United States.

Modeling human exposure

This last question is one of the areas of focus of the lab of Marissa Sobolewski, PhD, an assistant professor of Environmental Medicine who is studying how a wide range of environmental pollutants—including those found in air pollution—act as endocrine active chemicals. These chemicals can disrupt normal hormonal function in newborns and mothers, potentially setting the stage for neurological and behavioral disorders later in life.

Her lab is also conducting experiments that model exposure to ultra-fine iron particles. This research project arose out of findings that showed that the air in some parts of the New York City subway system contain iron particles at levels 30 times higher than safe levels established by the EPA. Sobolewski points to this project as an example of the translational focus of her lab’s work.

“When we're trying to understand the influence of pollution on the brain and behavior, it is important that we are appropriately modeling the environmental toxic exposure and making our animal model as translationally relevant to what people are being exposed to in the everyday world,” said Sobolewski.

A key research tool that enables these studies is the Inhalation Exposure Facility at the University of Rochester, which can trace its origins to the Manhattan Project. The current facility brings together researchers in fields such as biology, chemistry, and physics to support research into how airborne agents, by themselves or in combination with other factors, contribute to cumulative health risk across the lifespan.

Cory-Slechta and Sobolewski are frequent collaborators and recently co-authored a commentary piece in

Nature Reviews Neuroscience pointing to the concerning and growing body of research linking air pollution to neurological disorders and calling for more stringent and targeted regulation of the sources of air pollution.

Parkinson’s is a global public health crisis

When James Parkinson first described the disease that bears his name in 19th century London, he reported six individuals with the disease. “Two hundred years later, the global burden of disease is now estimated to be more than 6 million people,” said Ray Dorsey, MD, the David M. Levy Professor of Neurology at the University of Rochester and coauthor of the book “Ending Parkinson’s Disease.” “The rates are growing far faster than aging could explain alone. It has to be environmental factors and air pollution, pesticides, and

industrial chemicals are all important contributors.”

The chemical burden contributing to Parkinson’s rise is a byproduct of industrialization, in the form of ongoing pollution and the toxic legacy of contaminated sites, as well as the introduction of synthetic chemicals for agricultural use. The association between Parkinson’s and industrial growth is strong. Countries that have experienced the least industrialization have the lowest rates of the disease, whereas those undergoing the most rapid transformation, such as China, have the highest rates of increase.

Paraquat, a widely used and highly toxic herbicide, and other pesticides are increasingly being linked with Parkinson’s disease. A landmark study in 2011 showed that occupational exposure to paraquat increases Parkinson’s risk by 150 percent. More recently, research by Cory-Slechta and

Marissa Sobolewski, PhD, uses tools in the Inhalation Exposure Facility in the Medical Center to study the effects ultra-fine iron particles have on the brain.

The core provides IDD investigators with tools and support to conduct, generate, and interpret data in both behavioral and neurophysiological assays in rodent models. These resources will enable investigator to study the neural underpinnings of IDDs.

Sobolewski published last year in the journal Toxicological Sciences shows that paraquat can enter the brains of mice via the olfactory nerve.

Safety concerns have led to the banning of paraquat in more than 30 countries. However, its domestic use continues to rise unabated and the weed killer is applied to millions of acres annually to aid the production of soybeans, corn, cotton, and other crops.

An investigative report published in the British newspaper The Guardian last year details how for decades paraquat’s manufacturer downplayed the chemical's toxic effects, hid its own research results, and discredited the work of other scientists. One of the scientists targeted by the company was Cory-Slechta, who was one of the first to show that paraquat killed dopamine-producing neurons in mice, hinting at its role in Parkinson’s disease. Internal documents show the company worked behind the scenes in 2005 to block her from serving on an Environmental Protection Agency’s (EPA) scientific advisory committee on pesticides.

Pollution’s Impact on the Developing Brain

The lab of Ania Majewska, PhD, a professor in the Del Monte Institute for Neuroscience and co-director of the UR-IDDRC, first began studying environmental risk factors for neurodevelopment and neurodegenerative diseases more than a decade ago, when she partnered with URMC toxicologist Lisa Opanashuk, PhD, (now the neuroscience program director) at the National Institute of Aging, to study the impact of BPA on brain development. The inspiration for this project was a research assistant professor in her lab at the time who was struck by how her small children were constantly surrounded by plastics, which they often chewed on, and was interested in how this could be affecting their brains.

This research quickly expanded into TCDD, a toxic pollutant that humans are exposed to primarily through the consumption of meat, dairy products, and fish. In a study published last year in the journal Brain, Behavior, and Immunity, Majewska’s lab showed that exposure to TCDD in utero could cause the brain’s immune system to go awry later in life, potentially damaging important brain circuits and potentially contributing to disorders like autism and ADHD. In the same study, her lab showed that a drug currently used to treat cancer could restore normal immune function in the brains of mice.

Her lab is also working in collaboration with Marissa Sobolewski, PhD, and Paige Lawrence, PhD, with the URMC Department of Environmental Medicine, to investigate how PFAS affect the brain’s immune system and its interactions with neurons to alter brain development. These chemicals, which are widely used and persistent in the environment, are only now starting to be regulated on the state level.

Sobolewski (left) stands with CorySlechta in the URMC IDDRC Animal Behavior and Neurophysiology (ABN) Core, which is co-led by Cory-Slechta and Krishnan Padmanabhan, PhD.

Ania Majewska, PhD

“Rather than remove this dangerous chemical from the market or develop a safer alternative, the company doubled down on its blockbuster product and sought to expand its use,” said Dorsey, who argues that the U.S. should join the European Union, UK, and China to ban paraquat.

A ubiquitous pollutant

For the last 100 years, the industrial solvent trichloroethylene (TCE) was widely used in a number of industrial, consumer, military, and medical applications, including to decaffeinate coffee, degrease metal, and dry-clean clothes. Its use in the U.S. peaked in the 1970s, when more than 600 million pounds of the chemical—or two pounds per American—were manufactured annually.

Countless Americans are exposed to the chemical through contaminated groundwater, drinking water, and indoor air pollution. TCE is found in half of the most toxic EPA Superfund sites and numerous military bases, including Camp Lejeune in North Carolina, where a million Marines, their families, and civilians were

exposed to the chemical in drinking water over a three-decade period. A growing body of epidemiological and lab-based research are linking TCE to Parkinson’s disease.

Dorsey and URMC neurologists Ruth Schneider, MD, and Karl Kieburtz, MD, recently co-authored a piece in the Journal of Parkinson’s

Disease pointing to TCE as an invisible cause of Parkinson’s. They call for urgent action: accelerated remediation, containment, and mitigation of contaminated sites; more research to understand how TCE contributes to Parkinson’s and other diseases; closer monitoring and disclosure of TCE levels in groundwater, drinking water, soil, and outdoor and indoor air; and banning TCE and its close chemical cousin perchloroethylene (PCE) in the U.S.

“The world’s fastest-growing brain disease may be largely preventable,” said Dorsey. “Pesticides are likely to blame for those who grew up in or live in rural areas, and industrial chemicals like TCE may be to blame in urban areas. Banning these toxic chemicals, containing contaminated sites and protecting homes, schools, and buildings at risk may all help create a world where Parkinson’s is increasingly rare, not common.”

Ray Dorsey, MD, holds a telemedicine visit with a patient with Parkinson's disease. Technology allows him to conduct research and provide care around the world.

Mark Osabutey

Mark Osabutey, MBChB, is a 2nd-year Neuroscience graduate student at the University of Rochester Medical Center. Osabutey has a medical degree from the Kwame Nkrumah University of Science and Technology in Ghana. He completed his undergraduate studies in Human Biology at the same institution. Before coming to Rochester, Osabutey was a physician for three years in Kumasi, Ghana.

“During my preclinical years, I found love for science, specifically basic science,” said Osabutey. “It was there I discovered research, but it wasn’t until my physician intern years when I was working with a neurologist that I got into neuroscience.” During that rotation, Osabutey helped diagnose a 13-year-old boy with neuromyelitis optica—a central nervous system disorder that, in this case, had caused the boy to have sight problems and paralysis from his waist down. With this diagnosis, the boy was prescribed a therapeutic and walked again in about a week. Today, he is attending university.

“I was very happy to see that the basic science knowledge led to this patient being well managed," said Osabutey. “For many of our patients [in Ghana], the epidemiology of neurological conditions differs from what is in the United States. But basic neuroscience research is not studied as extensively in Ghana like here in the U.S. This is why I’m now pursuing my PhD.”

Osabutey is currently in the O-labs, the labs of M. Kerry O’Banion, MD, PhD, and John Olschowka, PhD. His

research interests primarily focus on neuroinflammation and attendant cognitive changes that occur after the brain is exposed to ionizing radiation and possible therapeutic approaches to mitigate such changes.

“I want to understand the role that microglia play in the context of dendritic spine loss and how this may be linked to the observed cognitive deficits that occur after exposure to ionizing radiation,” said Osabutey. “This intends to identify mechanisms that are targetable by therapeutic agents.”

Osabutey recently traveled to Texas to present at a NASA conference on behalf of the O-Labs. While there, he received a grant augmentation from NASA to study the populationlevel changes in microglia after exposure to galactic cosmic radiation. It is an important step in the field because space radiation has been shown to cause cognitive decline and loss of fine motor skills, which pose risks of impairing performance in mission-critical tasks in space. Using singlecell RNA sequencing in mice exposed to space radiation, he aims to identify subpopulations of microglia and their molecular differences based on sex.

Osabutey’s long-term goal is to establish a neuroscience research center in Ghana. “I chose to pursue my doctoral degree in neuroscience at the University of Rochester School of Medicine and Dentistry because of the exceptional research facilities, the remarkable mix of scientists and physician-scientists, and the supportive and nurturing environment for graduate students. The NGP at URMC is at the forefront of neuroscience research, and I am proud to be a part of such a vibrant community of scholars and researchers.”

Osabutey (second from left) working as a medical officer (general physician) stands with physician assistant trainees on his clinical team after ward rounds at the University Hospital, Kwame Nkrumah University of Science and Technology, Ghana.

Mark Osabutey, MBChB

NEURO2ALL holds first outreach event at RMSC

The Neuroscience Diversity Commission group NEURO2ALL held an event to teach kids, and adults, about the brain at the Rochester Museum and Science Center (RMSC). The group set up experiments to show how the brain works with our eyes and ears and even how it helps us taste. Kids were also given a backpack with brain facts and experiments to continue to learn about the brain at home. NEURO2ALL fosters curiosity around brain science, empowering the next generation of neuroscientists.

The stars in the brain may be information regulators

Graduate students participating in the new course Science Outreach to All at the University of Rochester School of Medicine and Dentistry helped organize this interactive event.

Long thought of as “brain glue,” the star-shaped cells called astrocytes may be a key player in the brain’s ability to process external and internal information simultaneously—a task essential to our very survival. Nathan Smith, PhD, associate professor of Neuroscience, published a paper in Trends in Neuroscience that explores how astrocytes may play a crucial role in brain processing information. Previous research has shown astrocytes sense the moment neurons send a message and can simultaneously sense sensory inputs. These external signals could come from various senses such as sight or smell. Astrocytes respond to this influx of information by modifying their calcium Ca2+ signaling directed towards neurons, providing them with the most suitable information to react to the stimuli. The authors hypothesize that this astrocytic Ca2+ signaling may be an underlying factor in how neurons communicate and what may happen when a signal is disrupted. But much is still unknown in how astrocytes and neuromodulators, the signals sent between neurons, work together.