Research Focus
The research that the BRL is currently involved in revolves around approaches to understanding neuroplasticity after damage to the brain. The four primary areas of interest are: 1) environmental factors in recovery from traumatic brain injury, 2) the role of non-human embryonic stem cell therapy and environmental factors in recovery from brain injury, 3) the serial lesion effect (SLE).
The Impact of Enriched Environment and Transplantation of Neuronal and Glial Precursors on Recovery. We (and many others) have shown previously that the environment the subject is placed in greatly affects recovery of an injured rat, clearly the literature supports these findings as well. In addition, many have now shown that transplanting embryonic stem cells (eSC, neural progenitor cells) also positively enhances the rate of recovery in several models of traumatic injury. The natural progression of the research was to combine these two therapeutic approaches to determine if combining the two would significantly improve outcomes beyond what each approach was capable of improving independently.
What we found was that early on in training, the EE animals performed at a improved level (as compared to the standard housed animals) regardless of eSC treatment. However, by the last behavioral test, the roto-rod, the animals that received both EE and eSC therapy performed at the same level as the uninjured animals. In addition, many of the transplanted cells in the brains of the EE/eSC treated animals appeared to have differentiated so that they express neural phenotypes, whereas the cells of the animals placed in standard housing appear to express characteristics of glial cells.
The Serial Lesion Effect. Observed recovery from injury has now been shown to occur in several situations. One intriguing example of functional savings following CNS damage is the observed savings in function following multiple staged lesions when compared to single stage lesions of equal size. This phenomenon has become known as the serial lesion effect. In an early example of the serial lesion effect, Adametz (1959) was able to demonstrate functional savings following staged damage to the rostral reticular midbrain in the cat. Cats prepared with single stage lesions to this area rarely survived the procedure and, if they did, they remained in a coma after surgery until death. However, if the same amount of tissue was removed over several operations spaced 3 weeks apart, the animals demonstrated rapid recovery, walking, grooming, and eating normally.
The basic paradigm for testing the serial lesion effect is as follows. One group of rats would receive a serially placed lesion where a portion of one hemisphere is lesioned followed by damaging the homologous tissue on the contralateral hemisphere during a second procedure. Additional groups would receive bilateral lesions either before or after a sham preparation, as well as a sham control preparations. After the surgical preparations are complete the animals are tested in order to determine the amount, if any, of behavioral savings.
Our data show that the rats that are prepared with staged (serial) lesion perform at the same level as their sham prepared counterparts whereas those that were prepared with a single bilateral lesion expressed significant functional loss. Following the behavioral portion of the study, we performed a series of histological preparations to try to determine if these functional savings were mirrored by savings of tissue/cells. We were able to determine that though the size of the lesion cavity was the same across groups, the transient cell death (in areas distal to the lesion site) was significantly reduced in the serial lesion group as well as were the signs of pathology (gliosis).
The Effects of Acute Voluntary Motor Enrichment on Recovery of Function Following Medial Frontal Cortical Contusions in Rats. In this study we employed the stop-signal reaction time (SSRT) task which measures the ability of the subject to inhibit a behavior that has already been initiated. By shaping the subject to perform rapid responses (go trials) in order to obtain reinforcement, and then introducing a novel stimulus which acts to signal subjects to perform stop (or inhibition) trials. Weight restricted male Long-Evans rats received either bilateral cortical contusions to the medial frontal cortex or sham preparations following the acquisition of the stop-signal task. Following surgery the rats were randomly assigned to either a post-surgical housing environment that included free access to running wheels or traditional single housing environments without running wheels.
Our results suggest that in the animals that were able to reach pre-surgical criteria on the SSRT task, the contused rodents performed significantly worse during the initial post-surgical trials as compared to the intact controls though all animals improved to pre-surgical levels by the end of training. However, contrary to our original hypothesis, rats receiving access to running wheels immediately post-injury performed significantly worse on the complex response task than those that did not have access the running wheels.
As the laboratory comes online, we hope to continue to explore these areas, as well as expand our research into stroke models of injury.