Consequences of Neurovascular Coupling Impairment on Cortical Processing and Sensory Encoding

Abstract

The brain consumes a remarkable amount of energy, receiving 20% of the total cardiac output yet comprising only 2% of total body mass. While total cerebral blood volume remains constant, the cerebrovascular network dynamically matches local blood flow to active neural populations in a process known as neurovascular coupling (NVC). This feature of the cerebral vasculature generates a spatial and temporal relationship between neuronal activity and vasomotion. While NVC is widely accepted to be essential for normal brain function and health, it remains poorly understood how NVC supports neuronal activation. I characterized a genetic mouse model of NVC impairment and investigated the consequences on sensory-evoked cortical activity. Using a combination of histological and imaging approaches, I demonstrated that NVC could be reliably blunted across cortical areas through genetic recombination of caveolin-1 in arterial endothelial cells. NVC impairment was observed within one month of gene deletion, and this phenotype was generalizable across the somatosensory and visual cortices. Using electrophysiology, I demonstrated that NVC impairment was associated with increased cortical firing at the population level during sensory activation. In the primary visual cortex, orientation selectivity was diminished, and neurons displayed wider tuning curves to distinct sensory cues after NVC was impaired. These functional changes were not accompanied by observable markers of cellular stress or apoptosis. Finally, NVC-impaired mice underperformed on behavioral tasks designed to measure cognition. Together, these data directly link NVC to neuronal function for the first time. Emerging evidence supports the notion that multiple signaling pathways are likely integrated to produce robust vasodilation during active neuronal signaling. As such, it is of interest to develop a range of tools that impair NVC through targeting different pathways. I investigated a series of mouse models with the aim of screening for additional tools to selectively impair NVC. This work revealed novel insights on the molecular players underlying NVC and uncovered pathways through which vascular proteins may affect neuronal circuits at the cortical level. I also identified several unexplored candidates in vascular cells that could serve as new research targets for the mechanistic understanding of NVC, and potentially new tools for manipulating NVC strength. These findings pave the way for new lines of investigation and advance our understanding of NVC, offering critical insights on its role in brain function.