During a cerebrovascular accident (or stroke), the blood supply to part of the brain is interrupted. This is often caused by a blood clot which blocks an artery that carries blood to the brain. Consequently, neurons in the affected region of the brain die because they are deprived of oxygen.
Stroke has several characteristic symptoms: slurred speech, paralysis and weakness on the right side of the body, and weakness and drooping of the face. These typically develop within minutes, and occur because stroke often affects the motor cortex in the left hemisphere, which controls the movements of the muscles in the opposite side of the body, and of the muscles in the mouth and throat which are required for articulation.
It is well established that functional recovery following stroke occurs as a result of the brain’s ability to reorganize itself. Functional neuroimaging shows that unaffected regions can adopt the functions of those parts of the brain that have perished during the insult. However, it is unclear exactly how this process occurs at the cellular level.
Now, Canadian researchers have used sophisticated single cell imaging techniques to observe the responses to stroke of individual cells in the rat brain. These elegant experiments show for the first time how cells which were previously believed to be “hardwired” can contribute to functional recovery by reorganizing their connections.
Ian Winship of the University of Alberta and Tim Murphy of the University of British Columbia in Vancouver used a technique called photothrombosis to induce stroke-like damage in a specific part of the primary somatosensory cortex, which receives sensory inputs the forelimbs. This involved first injecting the mice with a staining chemical called Rose Bengal, and then illuminating the underlying somatosensory cortex with green laser light through the window, which causes the Rose Bengal molecules to clump together and disrupt the blood supply to a targeted region of the brain.
The activity of approximately 10,000 individual cells in layers 2 and 3 of the cortex, which receive sensory inputs from the limbs, was then examined. The researchers identified these cells and characterized their function before inducing the stroke, and then determined their function afterwards, using in vivo two-photon laser scanning microscopy to detect increases in calcium levels, a characteristic response of neurons to stimulation. They achieved this by creating a “cranial window” – a 4 x 4 mm opening in the skull covered with a piece of glass, through which they could peer into the brains of the conscious animals as their limbs were stimulated.
Before the stroke was induced, it was found that mechanical stimulation of either the forelimb or the hindlimb on the opposite side of the body elicited a response in one of two distinct groups of cells. The cells precisely mapped the limbs onto the somatosensory cortex – those receiving sensory inputs from the hindlimb (labelled red in the image) were immediately behind those receiving inputs from the forelimb (labelled green); there was a sharp boundary between the two groups of cells, with only a little overlap.
Calcium imaging performed 2, 4, or 8 weeks following induction of stroke showed that the representation of the limbs in the somatosensory cortex had been disrupted – the receptive fields of some of the cells had changed, so that they received sensory inputs from both the hindlimb and forelimb. Between 10-30% of the neurons that normally receive inputs from only the hindlimb were now also receiving inputs from the forelimb, as shown by an increase in calcium levels in response to stimulation of the forelimb. They had rearranged their connections so that they could receive and process the sensory information normally received from the cells that had died.
These changes were most marked at the boundary between the affected and unaffected region, with the biggest changes in the small number of cells within the overlapping region. They were observed in mice that had recovered for at least 4 weeks after stroke induction; by 8 weeks, the cells’ responses had become more sharply tuned, and most cells in the reorganized area, while responsive to stimulation of both limbs, preferred inputs from or the other. Significantly, similar changes were also seen in astrocytes.
These results suggest that, rather than taking on their new function at the expense of their original role, the cells had instead adapted themselves to carry out both functions simultaneously. It is, however, possible that those cells responsive to inputs from both limbs were in a transition phase between their old and new functions.
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Winship, I. R. & Murphy, T. H. (2008). In Vivo Calcium Imaging Reveals Functional Rewiring of Single Somatosensory Neurons after Stroke. J. Neurosci. 28: 6592- 6606. [Abstract]