Deep Brain Stimulation Improves Spatial Memory in Rat Model of Global Ischemia

Post by: Amanda McFarlan

What's the science?

Global cerebral ischemia is a condition causing limited oxygen supply in the brain, and can be triggered by a number of events including cardiac arrest or stroke. Studies have shown that global cerebral ischemia can lead to neuronal (cell) death, particularly in the hippocampal CA1 region, which can lead to impairments in spatial learning and memory. Recently, deep brain stimulation has been shown to have positive effects in treating memory deficits in patients with Alzheimer’s disease, suggesting it may also be a useful tool in treating ischemia-induced memory impairments. This week in the Journal of Neuroscience, Gondard and colleagues investigated the effect of deep brain stimulation in the entorhinal cortex on improving memory deficits induced by global ischemia.

How did they do it?

Global ischemia was induced in adult male rats in the experimental group by occluding vertebral and carotid arteries, whereas rats in the control group underwent surgery with no occlusion of the arteries. Two weeks later, all rats underwent bilateral surgical implantation of electrodes in the entorhinal cortex (a region of the hippocampus that projects to the CA1 region). Half of the rats received one hour of electrical stimulation and the other half received no stimulation. The rats were then divided into four experimental groups: ischemia + stimulation, ischemia + no stimulation, no ischemia + stimulation, and no ischemia + no stimulation. Next, the authors injected animals in all four groups with BrdU to assess neurogenesis. BrdU can replace thymidine in DNA, therefore, its presence in DNA in post-hoc tests indicates that the cell has undergone DNA replication. Animals from all four groups were randomly assigned to continue in either path A or path B. Animals in path A underwent one day of testing in the open field test to assess locomotor activity, followed by the Morris water maze task to assess spatial memory and finally, animals were sacrificed for histology and immunohistochemistry. Animals in path B were sacrificed and used for slice in-vitro electrophysiological recordings in the hippocampus.

What did they find?

The authors determined that there were no significant differences in locomotor activity across groups, suggesting that global ischemia and electrical stimulation of the entorhinal cortex had no effect on movement. During the Morris water maze task, however, they revealed that animals in the ischemia + no stimulation group performed significantly worse compared to the no ischemia + stimulation and no ischemia + no stimulation groups, suggesting that global ischemia results in spatial memory impairment. Not only did animals in the ischemia + stimulation group perform significantly better than the animals in the ischemia + no stimulation group, but their performance levels were similar to animals in the no ischemia groups. Together, these findings suggest that ischemia-induced memory impairments can be reversed with electrical stimulation of the entorhinal cortex.

Next, the authors used histology and immunohistochemistry to investigate whether neurogenesis or increased synaptic activity were involved in rescuing ischemia-induced memory deficits. They determined that animals in the ischemia groups had significantly less BrdU (marker for dividing cells) positive cells in the dentate gyrus of the hippocampus compared to animals without ischemia, suggesting that improved memory performance was not neurogenesis-dependent. Interestingly, they found that synaptophysin (a synaptic vesicle protein found at the synapse) expression in the hippocampal CA1 region was significantly decreased in the ischemia + no stimulation group compared to the no ischemia groups, suggesting that ischemia induces a decrease in synaptophysin. Synaptophysin expression in the ischemia + stimulation group, however, was not significantly different from the ischemia groups, suggesting that electrical stimulation of the entorhinal cortex acts to preserve synaptophysin in the CA1 region of the hippocampus.

Finally, the authors determined that local field potential amplitudes recorded in the dendritic area of the hippocampal CA1 region were significantly smaller in the ischemia groups compared to the no ischemia groups. Moreover, the amplitudes in the ischemia + stimulation group were significantly larger compared to the ischemia + no stimulation group, suggesting that electrical stimulation in the entorhinal cortex improves electrophysiological behaviour in the dendritic region of CA1 hippocampal neurons.

What's the impact?

This is the first study to show that one session of deep brain stimulation in the entorhinal cortex, provided two weeks after ischemia, is sufficient to rescue ischemia-induced spatial memory deficits in rats. The authors also revealed that deep brain stimulation after ischemia attenuated the reduction of synaptic density and improved electrophysiological properties in CA1 hippocampal neurons. Altogether, these findings provide insight into the mechanisms of deep brain stimulation and illustrate how it might be a useful therapeutic tool for treating memory and cognitive deficits related to ischemia.

Gondard et al. Deep Brain Stimulation rescues memory and synaptic activity in a rat model of global ischemia. Journal of Neuroscience (2019). Access the original scientific publication here.