Cortical information loss in diffuse low-grade glioma infiltrated cortex

Project Summary/ Abstract. Glioma, the most common primary brain tumor in adults, is a major cause of neurological morbidity and mortality, with no effective therapies. Low-grade gliomas invade healthy brain tissue over decades and as a result fundamentally alter cellular and circuit level interactions responsible for information processing. As a result, nearly all patients experience cognitive and behavioral impairments. New treatments have been obstructed by limited understanding of the cellular and circuit level mechanisms governing the integrity of neural circuits following low-grade glioma infiltration. The influence of glioma infiltration on neuronal circuits have traditionally assumed that neurological impairments occur because of glioma induced neuron death. However, it is now known that tumor cells make electrical and chemical synapses with excitatory glutamatergic neurons. Neuronal signaling within cognitive networks are however both balanced synchrony between excitatory and inhibitory signals and directional, enabling the transmission of information to be organized in a hierarchy. The extent to which whether low-grade gliomas cortical infiltration influences cortical laminar structure and GABAergic inhibitory signals remains incompletely studies. This knowledge gap contributes to a paucity of therapies. Our long-term goal is to accelerate the development of precision-medicine therapies to treat cognitive impairments through the modulation of neuronal inputs. The objective of this application is to determine how glioma infiltration influences cortical structure and function. The central hypothesis is that inhibitory GABAergic inputs are reduced within lower feedback layers of cortex (Aim 1). Furthermore, we propose that information processing of sensory representations (Aim 2) and speech production (Aim 3) will be demonstrated as loss of neuronal population tuning responses which may be recovered with GABAergic restoration. Aim 1 will define the cortical neuron laminar structure and excitatory-inhibitory transcriptional programs of glioma-infiltrated cortex using histology and spatially resolved transcriptomics for neuronal density and subtype within each cortical layer. Aim 2 will determine the functional consequences of glioma infiltration on information processing in sensory regions. High-density local field potentials will be recorded from superior temporal and somatosensory regions during speech perception and tactile tasks, examining task-related changes in neuronal responses. Aim 3 will identify the functional consequences of glioma infiltration on information processing in higher-order speech and motor regions. To do so, we will measure the spatial and temporal responses from ventral pre-motor and motor regions to five clinically administered language paradigms of varying complexity. We expect this work to advance understanding of information loss in low grade glioma. These results will motivate and clarify potential target mechanisms for future clinical trials focused on restoring excitatory-inhibitory balance to treat patients.