2022 Theses Doctoral

The impact of cortical perturbations on neurovascular dynamics

Zhao, Hanzhi

Neurons and the underlying vascular structure that maintains the nutrients necessary for their normal function are intrinsically linked. The relationship between neural activity and its accompanying blood flow is called neurovascular coupling. Our understanding of the intricacies of this relationship has evolved over the years from one of pure supply and demand to one that is highly complex and involves various cell types. While the exact mechanisms underlying neurovascular coupling still remains unresolved, altered coupling has been implicated in a variety of pathological conditions. The overall motivation of this thesis was to uncover how specific perturbations to either the neural or vascular system affect the resulting interplay between them. Our hope is that the results could act as a framework for guiding more specific mechanistic dissections in the future.Until recently, technological constraints have precluded the ability to comprehensively characterize neurovascular coupling on a large scale. Much of our understanding of the coupling relationship on a circuit level has been inferred from individual measurements of either neuronal firing or blood flow dynamics. Our lab has the ability to study coupling more directly through simultaneous imaging of both neural and hemodynamic activity. In this thesis, I set out to characterize how coupling could be differentially altered at a mesoscopic level by specifically perturbing either blood flow or cortical circuit organization. Thus, this work is split into two projects. The first investigates the downstream effects of an acute ischemic injury and the second focuses on how a developmental change in neuronal circuit structure alters function.

My work in the acute ischemia model allowed us to capture a curious phenomenon called cortical spreading depolarization (CSD). CSDs have been implicated in a range of acute brain injuries, including ischemia. Despite being a neural event, CSDs have a profound impact on the cerebrovascular. Unfortunately, existing work in this field has been discordant and the results have been difficult to interpret. We used wide-field optical mapping to characterize the dynamics and impact of ischemia-triggered CSDs. Our imaging technique revealed that CSDs had a spatially heterogeneous impact on tissue depending on factors such as baseline metabolic condition and spatiotemporal properties of the CSDs themselves. Furthermore, we observed that CSDs were not isolated events and that multiple could occur in succession in a short period of time. By tracking each and every CSD, we were able to characterize the cumulative effects of CSDs on tissue oxygenation. Our results provide a contextual framework that reconciles some of the observed experimental variabilities. We conclude that an ischemic insult triggers a CSD and consequently, a combination of CSD dynamics and the tissue’s metabolic condition begets more CSDs. This pushes the brain deeper into a feedback loop of exacerbating damage.

The second study was done in collaboration with Dr. Ewoud Schmidt and Dr. Franck Polleux, and looks at the functional changes mediated by expression of a human-specific gene duplication, SRGAP2C. The human brain exhibits unique features that enable its enhanced cognitive abilities. The Polleux lab found that humanized SRGAP2C mice showed similar features that characterize the human brain, such as increased synaptic density and delayed synaptic maturation. This ultimately led to increased local and long-range cortico-cortical connectivity and even improved the behavioral performance in a texture discrimination task. Thus, we were motivated to investigate the functional underpinnings that may explain and link these structural and behavioral differences. We used two-photon imaging to determine whether SRGAP2C expression changed neuronal firing dynamics and found that it increased response reliability and selectivity to whisker inputs, thus improving accuracy of sensory coding. This improvement may help to explain why SRGAP2C mice performed better in a cortex-dependent task that actively relies on engagement of multiple cortical regions. Moreover, by using a humanized SRGAP2C mouse model, our results provide a small step towards better understanding how experimental studies can be interpreted for and translated to humans.