Abstract
In vivo two-photon microscopy was used to image in real time dendrites and their spines in a mouse photothrombotic stroke model that reduced somatosensory cortex blood flow in discrete regions of cortical functional maps. This approach allowed us to define relationships between blood flow, cortical structure, and function on scales not previously achieved with macroscopic imaging techniques. Acute ischemic damage to dendrites was triggered within 30 min when blood flow over >0.2 mm2 of cortical surface was blocked. Rapid damage was not attributed to a subset of clotted or even leaking vessels (extravasation) alone. Assessment of stroke borders revealed a remarkably sharp transition between intact and damaged synaptic circuitry that occurred over tens of μm and was defined by a transition between flowing and blocked vessels. Although dendritic spines were normally ~13 μm from small flowing vessels, we show that intact dendritic structure can be maintained (in areas without flowing vessels) by blood flow from vessels that are on average 80 μm away. Functional imaging of intrinsic optical signals associated with activity-evoked hemodynamic responses in somatosensory cortex indicated that sensory-induced changes in signal were blocked in areas with damaged dendrites, but were present ~400 μm away from the border of dendritic damage. These results define the range of influence that blood flow can have on local cortical fine structure and function, as well as to demonstrate that peri-infarct tissues can be functional within the first few hours after stroke and well positioned to aid in poststroke recovery.
Highlights
Previous magnetic resonance imaging and histological studies have provided valuable information on the histopathology and the development of ischemic brain damage [1,2,3,4]
Synapses were tightly coupled to small brain blood vessels, on average only 13 lm away
We find that normal synaptic structure can be maintained by flowing blood vessels at a much greater distance of 80 lm
Summary
Previous magnetic resonance imaging and histological studies have provided valuable information on the histopathology and the development of ischemic brain damage [1,2,3,4]. Based on insight from these macroscopic imaging approaches, therapeutic strategies for stroke involve not saving the ischemic core, but the surrounding penumbral tissues showing partial blood flow or oxygenation [5,6]. To better determine the link between dendritic structure and blood flow, we have imaged individual dendrites and spines of somatosensory cortex neurons in vivo within the ischemic core and surrounding penumbral tissues of transgenic mice expressing yellow or green fluorescent protein. To provide an index of the functional integrity of ischemic cortex, we have mapped somatosensory stimulus-evoked hemodynamic responses using intrinsic optical signal (IOS) imaging [10,11]
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