A THERAPEUTIC MODEL FOR CEREBRAL ISCHEMIA

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Approximately 2 million people suffer traumatic brain injury (TBI) annually and of these TBI victims, greater than 90 percent have had episodes of dramatic fluctuations in blood flow to the brain (cerebral ischemia). Human and animal studies have shown that cerebral ischemia results in damage to brain cells (neurons) which can eventually lead to cell death. Learning and memory impairments are the most common behavioral problems seen following cerebral ischemia. The objective of the proposed study is to determine if environmental therapy can ameliorate the behavioral and anatomical effects of cerebral ischemia and promote the regeneration of neurons. The proposed study will examine if: 1) environmental therapy can mitigate the damage to neurons in the hippocampus (brain region involved in the processing of memories and also the most vulnerable region to dramatic changes in blood flow) caused by cerebral ischemia, 2) environmental therapy can promote neurogenesis in the hippocampus (formation of new neurons) after ischemic damage, 3) growth factors are possible mechanisms that mediate neurogenesis in the adult brain, and 4) timing of implementation of environmental therapy following cerebral ischemia has an influence on the degree of anatomical and behavioral recovery. A morphological group and a behavioral group will be used in the proposed study to optimize the experimental design and to ensure that morphological (anatomical) measures are not influenced by behavioral testing. Adult rats will be assigned to receive either ischemia or sham (control) surgery. Within these groups, animals will be assigned to either one of 3 therapeutic conditions: complex environment, inactive group, and physical activity. Furthermore, animals in the complex environment and physical activity conditions will be randomly assigned to receive either early (immediately following ischemia) or late (four days following ischemia) intervention. Animals will be housed in their assigned environment for 14 days following surgery. Rats assigned to late timing of therapy will be housed in pairs in standard laboratory cages after surgery and before starting environmental manipulation. After environmental therapy, the animals in the morphology group will be euthanized. The brains will be prepared for quantitative analysis using electron microscopy, immunocytochemistry and unbiased stereological methods (physical and optical dissector). Animals in the behavior group will be tested in the water maze for 18 days before euthanasia. Electron microscopy and the physical dissector method will be used to assess neuron damage while immunocytochemistry and the optical dissector method will be used to assess neurogenesis and expression of growth factors. Data from the water maze will be used to assess short-term spatial learning, long-term spatial memory, and nonspatial learning. From a nursing perspective, results from this study are important clinically because the needs of most survivors of brain injury often times are for continuous nursing, while use of medical services may be intermittent.