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Image from study shows protein marker (green) that indicates activation of microglia (red) after exposure to radiation.

One of the potentially life-altering side effects that patients experience after cranial radiotherapy for brain cancer is cognitive impairment. Researchers now believe that they have pinpointed why this occurs and these findings could point the way for new therapies to protect the brain from the damage caused by radiation.

The new study -- which appears in the journal Scientific Reports -- shows that radiation exposure triggers an immune response in the brain that severs connections between nerve cells. While the immune system's role in remodeling the complex network of links between neurons is normal in the healthy brain, radiation appears to send the process into overdrive, resulting in damage that could be responsible for the cognitive and memory problems that patients often face after radiotherapy.

"The brain undergoes a constant process of rewiring itself and cells in the immune system act like gardeners, carefully pruning the synapses that connect neurons," said Kerry O'Banion, M.D., Ph.D., a professor in the University of Rochester Del Monte Institute for Neuroscience and senior author of the study which was conducted in mice. "When exposed to radiation, these cells become overactive and destroy the nodes on nerve cells that allow them to form connections with their neighbors."

The culprit is a cell in the immune system called microglia. These cells serve as the brain's sentinels, seeking out and destroying infections, and cleaning up damaged tissue after an injury. In recent years, scientists have begun to understand and appreciate microglia's role in the ongoing process by which the networks and connections between neurons are constantly wired and rewired during development and to support learning, memory, cognition, and sensory function.

Microglia interact with neurons at the synapse, the juncture where the axon of one neuron connects and communicates with another. Synapses are clustered on arms that extend out from the receiving neuron's main body called dendrites. When a connection is no longer required, signals are sent out in the form of proteins that tell microglia to destroy the synapse and remove the link with its neighbor.

In the new study, researchers exposed the mice to radiation equivalent to the doses that patients experience during cranial radiotherapy. They observed that microglia in the brain were activated and removed nodes that form one end of the synaptic juncture -- called spines -- which prevented the cells from making new connections with other neurons. The microglia appeared to target less mature spines, which the researchers speculate could be important for encoding new memories -- a finding that may explain the cognitive difficulties that many patients experience. The researchers also observed that the damage found in the brain after radiation was more pronounced in male mice.

While advances have been made in recent years in cranial radiotherapy protocols and technology that allow clinicians to better target tumors and limit the area of the brain exposed to radiation, the results of the study show that the brain remains at significant risk to damage during therapy.

The research points to two possible approaches that could help prevent damages to nerve cells, including blocking a receptor called CR3 that is responsible for synapse removal by microglia. When the CR3 receptor was suppressed in mice, the animals did not experience synaptic loss when exposed to radiation. Another approach could be to tamp down the brain's immune response while the person undergoes radiotherapy to prevent microglia from becoming overactive.

Additional co-authors of the study include Joshua Hinkle, John Olschowka, Tanzy Love, and Jacqueline Williams with the University of Rochester Medical Center (URMC). The research was funding with support from the National Institute of Allergy and Infectious Disease, NASA and the URMC Wilmot Cancer Institute.

Living microglia, genetically marked to glow green, in the cerebral cortex with magenta colored blood vessels from a mouse treated with URMC-099.

A new study published in the Journal of Neuroinflammation found that prophylactic treatment with URMC-099 -- a "broad spectrum" mixed-lineage kinase 3 inhibitor -- prevents neuroinflammation-associated cognitive impairment in a mouse model of orthopedic surgery-induced perioperative neurocognitive disorders (PND).

PND, a new term that encompasses postoperative delirium, delayed neurocognitive recovery, and postoperative neurocognitive disorder, is the most common complication after routine surgical procedures, particularly in the elderly. Following surgery, such as hip replacement or fracture repair, up to 50 percent of patients experience cognitive disturbances like anxiety, irritability, hallucinations, or panic attacks, which can lead to more serious complications down the line. Currently, there are no FDA-approved therapies to treat it.

Developed in the laboratory of Harris A. "Handy" Gelbard, M.D., Ph.D., director of the Center for Neurotherapeutics Discovery at the University of Rochester Medical Center, URMC-099 inhibits damaging innate immune responses that lead to inflammation in the brain and accompanying cognitive problems. Using animal models of diseases like HIV-1-associated neurocognitive disorders, Alzheimer's disease and multiple sclerosis, Gelbard has shown that the compound blocks enzymes called kinases (such as mixed lineage kinase type 3, or MLK3) that respond to inflammatory stressors inside and outside cells.

Gelbard and Niccolò Terrando, Ph.D., director of the Neuroinflammation and Cognitive Outcomes laboratory in the Department of Anesthesiology at Duke University Medical Center, used an orthopedic surgery mouse model that recapitulates features of clinical procedures such as a fracture repair or hip replacement, which are often associated with PND in frail subjects. In a pilot experiment, they treated one group of these mice with URMC-099 before and after surgery, and another group prior to surgery only. Gelbard and Terrando's teams, including first author Patrick Miller-Rhodes, a senior pre-doctoral student in the Neuroscience Graduate Program working in the Gelbard lab at URMC, measured the following:

• How the surgery affected the central nervous system and the immune cells (microglia) that reside there was evaluated using stereology and microscopy.
• Surgery-induced memory impairment was assessed using the "What-Where-When" and Memory Load Object Discrimination tasks.
• The acute peripheral immune response to surgery was assessed by cytokine/chemokine profiling and flow cytometry.
• Long-term fracture healing was assessed in fracture callouses using micro-computerized tomography and histomorphometry analyses.
• For additional details see the "Materials and Methods" section of the study

The team found that the surgery disrupted the blood brain barrier and activated microglia (a first line immune responder present in the inflamed brain), which led to impaired object place and identity discrimination when the mice were subject to the "What-Where-When" and Memory Load Object Discrimination tasks. Both URMC-099 dosing methods prevented the surgery-induced microgliosis (increase in the number of activated microglia) and cognitive impairment without affecting fracture healing.

"A major concern regarding the use of anti-inflammatory drugs for PND is whether they will affect fracture healing. We found that our preventive, time-limited treatment with URMC-099 didn't influence bone healing or long-term bone repair," said Gelbard and Terrando, professor of Neurology, Neuroscience, Microbiology and Immunology, and Pediatrics at URMC and associate professor of Anesthesiology at Duke University Medical Center, respectively. "These findings of improvement in cognition and normal fracture healing provide compelling evidence for the advancement of URMC-099 as a therapeutic option for PND."

"Right now we have nothing to treat this condition," said Mark A. Oldham, M.D., assistant professor in the department of Psychiatry at URMC who treats patients with PND. "We work hard to provide good medical care, including helping people sleep at night and making sure they are walking, eating and drinking, but it isn't clear that these efforts have any meaningful long-term impact."

According to Oldham, recent studies that track patients following an episode of PND show that many of them don't resolve completely, and that they have a new cognitive baseline after delirium.

"It is increasingly an accepted fact that after delirium, people have suffered some kind of neurological insult, which leaves them cognitively or functionally worse off than before the incident," he noted.

Next steps for the research include identifying definitive mechanisms for pain modulation, immune cell trafficking and neuro-immune characterization in PND. Gelbard and Terrando are tackling some of these questions with funds from the National Institutes of Health (RO1 AG057525). The current study was also funded by multiple grants from the NIH (P01MH64570, RO1 MH104147, RO1 AG057525 and F31 MH113504). The University of Rochester has four issued U.S. patents and multiple issued patents in foreign countries covering URMC-099.

Lynne Maquat, Ph.D., the J. Lowell Orbison Endowed Chair and Professor in the Department of Biochemistry and Biophysics, was honored with the International Union of Biochemistry and Molecular Biology (IUBMB) Jubilee Lectureship in September. The IUBMB unites biochemists and molecular biologists in 75 countries and is devoted to promoting research and education in biochemistry and molecular biology, giving particular attention to areas where the subject is still in its early development.

The IUBMB Jubilee Lectureship was established to commemorate the 50th anniversary of the First International Congress of Biochemistry that was held in Cambridge, England in 1949, at which the initial steps were taken that led to the formation of IUBMB. Maquat gave the keynote lecture at the IUBMB Molecular Biosystems Conference in Puerto Varas, Chile on September 30 and was presented with a medal in recognition of the event.

The founding director of the University of Rochester's Center for RNA Biology, Maquat has spent her career deciphering the many roles that RNA plays in sickness and in health. She's an international leader in the field and is credited with several major discoveries that are informing a new generation of therapies for a wide range of genetic disorders.

Her lecture, titled "Nonsense-mediated mRNA Decay in Human Health and Disease," described her discovery of nonsense-mediated mRNA decay or NMD and how this important surveillance system protects against mistakes in gene expression that lead to disease. She also discussed ongoing work on how misregulation of NMD in Fragile X Syndrome, the most common single gene cause of intellectual disability and autism, results in neuronal defects that typify this disorder.

Science tells us that a lot of good things happen in our brains while we sleep -- learning and memories are consolidated and waste is removed, among other things. New research shows for the first time that important immune cells called microglia -- which play an important role in reorganizing the connections between nerve cells, fighting infections, and repairing damage -- are also primarily active while we sleep.

The findings, which were conducted in mice and appear in the journal Nature Neuroscience, have implications for brain plasticity, diseases like autism spectrum disorders, schizophrenia, and dementia, which arise when the brain's networks are not maintained properly, and the ability of the brain to fight off infection and repair the damage following a stroke or other traumatic injury.

"It has largely been assumed that the dynamic movement of microglial processes is not sensitive to the behavioral state of the animal," said Ania Majewska, Ph.D., a professor in the University of Rochester Medical Center's (URMC) Del Monte Institute for Neuroscience and lead author of the study. "This research shows that the signals in our brain that modulate the sleep and awake state also act as a switch that turns the immune system off and on."

Thank you, from the Center of RNA Biology members, to Dianne Edgar, MD and Terry Platt, PhD for their generous gifts to the Center over the years.

Dr. Edgar is a Clinical Professor in the Department of Obstetrics and Gynecology at the URMC, and a Pediatrician at Parkwest Women's Health. Dr. Platt is a Professor Emeritus of the Department of Biochemistry and Biophysics at the URMC.

The Center will use the gift toward an RNA-centric seminar in their names, a testament to their generosity. Thank you, Dr. Edgar and Dr. Platt!

Neuroscience students and faculty made a big splash at the 2019 School of Medicine & Dentistry Convocation Ceremony. The following were awarded and recognized for their achievements:

• Martha Gdowski, Ph.D., received the Manuel D. Goldman Prize for Excellence in First Year Teaching & the Marvin J. Hoffman Faculty Mentoring Award
• John Olschowka, Ph.D., received a Commendation for First Year Teaching
• Sergiy Nadtochiy, Ph.D., received a Commendation for First Year Teaching
• Sarah McConnell, Ph.D., received the Gold Medal Award for Excellence in Teaching
• Johanna Fritzinger, first year NGP student, received the Irving L. Spar Fellowship Award
• Sarah Yablonski, first year NGP student, received the Merritt & Marjorie Cleveland Fellowship & the Robert L. and Mary L. Sproull University Fellowship
• Suzanne Haber, Ph.D., received the Dean's Professorship
• Marc Halterman, M.D., received the Dean's Associate Professorship

Congratulations to all recipients!

Abstract: Perioperative neurocognitive disorders (PND), including delirium and postoperative cognitive dysfunction, are serious complications that afflict up to 50% of surgical patients and for which there are no disease-modifying therapeutic options. Here, we test whether prophylactic treatment with the broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents surgery-induced neuroinflammation and cognitive impairment in a translational model orthopedic surgery-induced PND. We used a combination of two-photon scanning laser microscopy and CLARITY with light-sheet microscopy to define surgery-induced changes in microglial morphology and dynamics. Orthopedic surgery induced microglial activation in the hippocampus and cortex that accompanied impairments in episodic memory. URMC-099 prophylaxis prevented these neuropathological sequelae without impacting bone fracture healing. Together, these findings provide compelling evidence for the advancement of URMC-099 as a therapeutic option for PND.