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Redgrave P, Mayhew JE. Fine detail of neurovascular coupling revealed by spatiotemporal analysis of the hemodynamic response to single whisker stimulation in rat barrel cortex.

The blood-brain barrier (BBB) is by far the most important target in developing new approaches to improve delivery of drugs and diagnostic tools into the Central Nervous System (CNS). Here we report the engineering of pH- sensitive polymersomes (synthetic vesicles formed by amphiphilic copolymers) that exploit endogenous transport mechanisms to traverse the BBB, enabling delivery of large macromolecules into both the CNS parenchyma and CNS cells. We achieve this by targeting the Low Density Lipoprotein Receptor-Related Protein 1 (LRP-1) receptor. We show that LRP-1 is associated with endothelial transcytosis that does not involve acidification of cargo in membrane-trafficking organelles. By contrast, this receptor is also associated with traditional endocytosis in CNS cells, thus aiding the delivery of relevant cargo within their cytosol. We prove this using IgG as a model cargo, thus demonstrating that the combination of appropriate targeting combined with pH-sensitive polymersomes enables the efficient delivery of macromolecules into CNS cells.

Modern neuroimaging techniques rely on neurovascular coupling to show regions of increased brain activation. However, little is known of the neurovascular coupling relationships that exist for inhibitory signals. To address this issue directly we developed a preparation to investigate the signal sources of one of these proposed inhibitory neurovascular signals, the negative blood oxygen level-dependent (BOLD) response (NBR), in rat somatosensory cortex. We found a reliable NBR measured in rat somatosensory cortex in response to unilateral electrical whisker stimulation, which was located in deeper cortical layers relative to the positive BOLD response. Separate optical measurements (two-dimensional optical imaging spectroscopy and laser Doppler flowmetry) revealed that the NBR was a result of decreased blood volume and flow and increased levels of deoxyhemoglobin. Neural activity in the NBR region, measured by multichannel electrodes, varied considerably as a function of cortical depth. There was a decrease in neuronal activity in deep cortical laminae. After cessation of whisker stimulation there was a large increase in neural activity above baseline. Both the decrease in neuronal activity and increase above baseline after stimulation cessation correlated well with the simultaneous measurement of blood flow suggesting that the NBR is related to decreases in neural activity in deep cortical layers. Interestingly, the magnitude of the neural decrease was largest in regions showing stimulus-evoked positive BOLD responses. Since a similar type of neural suppression in surround regions was associated with a negative BOLD signal, the increased levels of suppression in positive BOLD regions could importantly moderate the size of the observed BOLD response.