Radiation therapy plays a crucial role in the treatment of brain tumors. However, especially in young patients, successful treatment outcomes are unfortunately associated with long-term declines in cognitive function. However, remarkably little is known regarding the mechanisms of radiation-induced cognitive impairment. The ventral tegmental area (VTA), which connects the prefrontal cortex, hippocampus and other limbic brain regions, is critically important in cognitive functions including reward, motivation, decision making and learning, all of which may be impacted in patients treated with brain radiation. Although significant dysfunctions in the VTA dopamine system have been identified in...

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Radiation therapy plays a crucial role in the treatment of brain tumors. However, especially in young patients, successful treatment outcomes are unfortunately associated with long-term declines in cognitive function. However, remarkably little is known regarding the mechanisms of radiation-induced cognitive impairment. The ventral tegmental area (VTA), which connects the prefrontal cortex, hippocampus and other limbic brain regions, is critically important in cognitive functions including reward, motivation, decision making and learning, all of which may be impacted in patients treated with brain radiation. Although significant dysfunctions in the VTA dopamine system have been identified in variety of brain diseases with cognitive impairments, to our knowledge, no groups have studied the impact of radiation on dopaminergic signaling. Our goals in this project are to understand the role of the dopaminergic system, not only alterations at a neuronal level but also dysfunction in coupling with other brain regions, in radiation induced cognitive dysfunction. The current study is significant in that we, for the first time, seek to understand alterations in the midbrain dopamine system after brain radiation and the mechanisms underlying these changes. With this new knowledge, we then seek to prevent or reverse these changes using drugs already approved for patient use for other neurodegenerative conditions. As our previous CPRIT funding has, we expect this work will open new directions for future research and lead to the development of novel clinical trials. Ultimately this will improve functional outcomes and quality of life for pediatric brain tumor survivors.

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