Title: Interrogating spatiotemporal patterns of resting state neuronal and hemodynamic activity in the awake mouse model
Description: Since the advent of functional magnetic resonance imaging (fMRI) and the rise in popularity of its use for resting state functional connectivity mapping (rs-FCM) to non-invasively detect correlated networks of brain activity in human and animal models, many resting state FCM studies have reported differences in these networks under pathologies such as Alzheimer’s or schizophrenia, highlighting the potential for the method’s diagnostic relevance. A common underlying assumption of this analysis, however, is that the blood oxygen level dependent (BOLD) signal of fMRI is a direct measurement of local neural activity. The BOLD signal is in fact a measurement of the local changes in concentration of deoxy-hemoglobin (HbR). Thus, it is imperative that neurovascular coupling—the relationship between neuronal activity and subsequent hemodynamic activity—be better characterized to enable accurate interpretation of resting state fMRI in the context of clinical usage. This dissertation first describes the development and utility of WFOM paradigm for the robust and easily adaptable imaging of simultaneous neuronal and hemodynamic activity in awake mouse models of health or disease in strains with genetically encoded fluorescent calcium reporters.

Subsequent exploration of resting state WFOM data collected in Thy1-GCaMP3 and Thy1-GCaMP6f mouse strains is then presented, namely the characterization of spatiotemporal patterns of neuronal and hemodynamic activity and different modulatory depths of neuronal activity via a toolbox of unsupervised blind source separation (e.g. k-means clustering) and supervised (e.g. non-negative least squares, Pearson correlation) analysis tools. The presence of these different modulatory depths of neuronal activity were then confirmed in another Thy1-jRGECO1a mouse strain using the same imaging scheme. Finally, the dissertation documents the application of the WFOM paradigm and select analysis tools to a novel mouse model of diffusely infiltrating glioma, through which neuronal and hemodynamic activity changes during diffusely infiltrating glioma development which impact temporal coherence of the tumor region activity relative to non-tumor regions activity were recorded and analyzed. The paradigm also allowed for recording of numerous spontaneous occurrences of interictal neuronal activity during which neurovascular coupling is modified in the tumor, as well as occurrences of non-convulsive generalized seizure activity (during which neurovascular is non-linear and cortex eventually suffers hypoxia).

The detection of spatiotemporal patterns and different modulatory depths of activity in the awake mouse cortex, as well as observation of changes in functional activity in the context of diffusely infiltrating glioma, provide us with new insights into the possible mechanisms underlying variations in resting state connectivity networks found in resting state fMRI studies comparing health and disease states.