Glioblastoma (GBM), the most common primary brain tumor in adults, has a dire prognosis, with a median survival of less than 1.5 years and no significant advancements in therapy within the last two decades. The emerging field of cancer neuroscience reveals that the formation of direct connections, known as neural synapses, from non-cancerous brain cells onto GBM cells, plays a significant role in tumor growth and migration. These connections help the tumor grow and spread, but scientists still don’t fully understand how they affect the rest of the brain. Since GBM often develops in the brain’s outer layer (the cortex), it’s possible these tumor-neuron connections could disrupt brain function even in areas far from the tumor itself. I propose to extend previous work mapping neural inputs to cortically transplanted GBM, focusing on neuromodulatory brainstem areas that control processes like mood, sleep-wake cycles, and basic bodily function. The overall goal is to determine whether brainstem neurons and their associated circuitry are disrupted upon synapsing with tumor cells. Because GBM and brain activity can fuel each other in a vicious cycle, breaking any part of this loop, including hyperactivity of neural circuits, could not only improve neurocognitive symptoms but also limit tumor progression. Additionally, understanding the role of different neuromodulatory systems has the potential to reveal novel therapeutic targets. Ultimately, this research could change how we think about brain tumors, showing that they might cause symptoms in far-off brain areas without ever spreading there.