Multi-modal assessment of neurovascular coupling during cerebral ischaemia and reperfusion using remote middle cerebral artery occlusion

Hyperacute changes in cerebral blood flow (CBF) during cerebral ischemia and reperfusion is an important determinant of injury. CBF is regulated by neurovascular coupling (NVC), and disruption of NVC contributes to brain plasticity and repair problems. However, it is unknown how NVC is affected hyperacutely during cerebral ischemia and reperfusion. We have developed a remote middle cerebral artery occlusion (MCAO) model in the rat, which enables multi-modal assessment of NVC immediately prior to, during and immediately following reperfusion. Male Wistar rats were subjected to remote MCAO, where a long filament was advanced intraluminally through a guide cannula in the common carotid artery. Transcallosal stimulation evoked increases in blood flow, tissue oxygenation and neuronal activity, which were diminished by MCAO and partially restored during reperfusion. These evoked responses were not affected by administration of the thrombolytic alteplase at clinically used doses. Evoked CBF responses were fully restored at 24 hours post-MCAO indicating that neurovascular dysfunction was not sustained. These data show for the first time that the rat remote MCAO model coupled with transcallosal stimulation provides a novel method for continuous assessment of hyperacute NVC changes during ischemia and reperfusion, and offers unique insight into hyperacute ischemic pathophysiology

Moderate Traumatic Brain Injury Causes Acute Dendritic and Synaptic Degeneration in the Hippocampal Dentate Gyrus

Hippocampal injury-associated learning and memory deficits are frequent hallmarks of brain trauma and are the most enduring and devastating consequences following traumatic brain injury (TBI). Several reports, including our recent paper, showed that TBI brought on by a moderate level of controlled cortical impact (CCI) induces immature newborn neuron death in the hippocampal dentate gyrus. In contrast, the majority of mature neurons are spared. Less research has been focused on these spared neurons, which may also be injured or compromised by TBI. Here we examined the dendrite morphologies, dendritic spines, and synaptic structures using a genetic approach in combination with immunohistochemistry and Golgi staining. We found that although most of the mature granular neurons were spared following TBI at a moderate level of impact, they exhibited dramatic dendritic beading and fragmentation, decreased number of dendritic branches, and a lower density of dendritic spines, particularly the mushroom-shaped mature spines. Further studies showed that the density of synapses in the molecular layer of the hippocampal dentate gyrus was significantly reduced. The electrophysiological activity of neurons was impaired as well. These results indicate that TBI not only induces cell death in immature granular neurons, it also causes significant dendritic and synaptic degeneration in pathohistology. TBI also impairs the function of the spared mature granular neurons in the hippocampal dentate gyrus. These observations point to a potential anatomic substrate to explain, in part, the development of posttraumatic memory deficits. They also indicate that dendritic damage in the hippocampal dentate gyrus may serve as a therapeutic target following TBI