A brain science breakthrough at UR

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University of Rochester researchers have unlocked the reasons behind cognitive impairment after cranial radiotherapy, a discovery that could pave the way for new therapies to protect the brain.

A new study shows that exposure to cranial radiation elicits an immune response that cuts off connections between nerve cells. Though a healthy brain can remodel links between neurons, radiation sets that process awry. This results in damage, seen with cognitive and memory problems faced by brain cancer patients 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,” says Kerry O’Banion M.D., a professor at UR’s Del Monte Institute for Neuroscience and senior author of the study, which was conducted on 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.”

Microglia, a cell in the immune system, is known to seek out and destroy infections and clean up damaged tissue after injury. Scientists are understanding microglia’s role in the process by which connections between neurons are wired and rewired to support functions such as sensory, memory and cognition.

Neuron-to-neuron junctions, also known as synapses, transmit and route signals to the target destination. Microglia interact with neurons at the synapse. When a connection is no longer essential, a signal tells these microglia to destroy the synapse and remove its link with another neuron.

In their study, O’Banion and his team—including URMC’s Joshua Hinkle, John Olschowka, Tanzy Love, and Jacqueline Williams—exposed the mice to radiation equivalent to the doses that patients experience during cranial radiotherapy. They found that the brain’s microglia were activated and removed nodes that form one end of the synaptic juncture—called spines—preventing the cells from making new connections. 

The microglia appeared to target less mature spines, which the researchers speculate could be important for encoding new memories, UR says, and may explain the cognitive difficulties that many patients experience. Male mice experienced more brain damage after radiation.

In 2019, there were an estimated 23,820 new cases of brain and nervous system cancers in the United States, according to the National Cancer Institute. Tumors that start in the brain are called primary tumors. The effects of cranial irradiation, the main treatment for primary and metastatic malignancies in the brain, are well-documented. Some side effects show up early while others can surface six months after radiotherapy. Though protocols and tools allow this therapy to be targeted and limit the brain’s exposure, UR’s study shows that the brain is at significant risk.

The team’s research, however, also pinpoints two ways to prevent damage to nerve cells. One could block a receptor that is responsible for synapse removal by microglia. The team found that when the CR3 receptor was suppressed in mice, the synaptic loss was absent. Another method could be lowering the brain’s immune response while a patient is undergoing radiation, limiting the microglia’s overactive ability.

Until researchers find ways to reduce cognitive dysfunction following cranial radiotherapy, it will remain a significant problem for patients, especially children.

Smriti Jacob is Rochester Beacon managing editor.

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