Recent studies have revealed that crosstalk between glioma cells and the brain microenvironment is a crucial regulator of cancer initiation and progression. A vast majority of glioma patients suffer from seizures, and this pathological neuronal activity has been proposed to contribute to increased glioma cell proliferation. Glioma patients also suffer from additional neurological symptoms, including deficits in attention, concentration, memory, and language. These neurological effects of gliomas along with the limited therapeutic options underscore the need for novel therapies.
This thesis investigates the neuronal alterations at the margins of glioma which contribute to the neurological symptoms (Chapter 2), and on the effect of sensory stimulation on the glioma cells and microglia in the glioma microenvironment (Chapter 3). The work describes the development of new mouse models in which glioma cells are infiltrating the somatosensory cortex in mice that express GCaMP in neurons or microglia. Methodologies include a combination of in vivo two-photon calcium imaging and tissue-based analysis to determine the glioma-induced alteration on whisker stimulation-evoked responses of these different cell types.
This work also tests the effects of pharmacologically inhibiting mTOR signaling on neuronal responses (Chapter 2) or purinergic signaling on microglial responses (Chapter 3). Together these studies demonstrate that glioma infiltration induces local effects in functionally-responsive cortex, and that many of these glioma-induced effects on neurons and microglia are ameliorated by pharmacological inhibition of mTOR or purinergic signaling. This reveals a highly dynamic and plastic nature of the glioma-induced alterations, and points towards new strategies to treat glioma-associated neurological symptoms while potentially slowing tumor progression.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/d2a1-6f91 |
| Date | January 2024 |
| Creators | Goldberg, Alexander |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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