Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmacology and Experimental Therapeutics

Abstract

Estimates indicate that over 5 million Americans are currently living with Traumatic Brain Injury (TBI) related disability. Much effort has been put into enhancing functional recovery with physical therapy and other rehabilitative approaches. These strategies are thought to function by facilitating the brain’s innate capacity for neuroregeneration and neuroplasticity. However, the success of these strategies may be limited due the presence of growth- and plasticity- inhibiting factors expressed in the adult brain.

The presence of the membrane protein Nogo-A has been associated with reduced neurite outgrowth in vitro, identifying it as one such molecule. In addition, rodents treated with antibodies raised against Nogo-A have been reported to show a greater degree of axonal growth and motor performance after a variety of injuries to the spinal cord and brain. Here, the effect of anti-Nogo-A immunotherapy was studied using the controlled cortical impact (CCI) model of TBI.

Rats received CCIs to the sensorimotor cortex opposite the preferred forelimb. Beginning one week later, anti-Nogo-A antibody (11c7) was administered to the lateral cerebral ventricle for two weeks. Recovery of these animals was assessed using the skilled reaching task and compared to controls from one day post-injury until eight weeks later.

The anti-Nogo-A treated animals recovered an average of 90% baseline skill, while controls recovered only 60%, suggesting that the treatment may be beneficial. However, this conclusion depends on the assumption that performance on the reaching task is a measure of capability. If so, after a period of re-learning the skill, the individual rat should enter a plateau phase that reflects maximal performance. During this phase, the distribution of day-to-day success rate for each individual should follow a specific probability distribution (binomial). However, in our study the scores during the plateau phase were often much more consistent than predicted, a strong indication that capability was not measured. Further, neither the final performance nor profile of recovery were uniform within each group. When fit with a sigmoidal curve, the distribution of the plateau skill levels appeared multimodal.

It is possible that performance was determined by some neurological characteristic of the rats, perhaps related to the brain injury. However, total lesion size and cortical lesion location were not well correlated with performance and could not explain the greater degree of recovery observed for anti-Nogo-A treated animals.

Another possibility is that performance was determined by neuroplastic processes, previously proposed to be influenced by anti-Nogo-A antibody. To this end, the brains of the same rats were stained using the Golgi-Cox procedure. The degree of dendritic branching and soma area was measured for pyramidal neurons from the contra-lesional cortex. However, these measurements also did not correlate with performance on the reaching task nor differ between groups.

While any number of unmeasured neurological aspects could be responsible for differences in performance that were not examined in this study, it is also possible that there are none. The low day-to-day variance and multimodality indicated that there were at least two strategies that could be used by the rats during the reaching task. Therefore, a simple stochastic model of two-strategy habit learning is proposed, as follows:

The model required only four parameters shared amongst all rats: 1) probability strategy A is successful; 2) probability strategy B is successful, 3) initial probability of choosing strategy A; 4) rate of learning strategy A. Despite the low number of parameters, this model is capable of generating recovery profiles similar to those observed for each rat. Further work is required to determine the best set of parameters to consistently capture the low plateau variance and other aspects the data. However, this result does show that differences in plateau performance need not be related to any underlying neurological difference.

In conclusion, anti-Nogo-A immunotherapy administered one week following TBI was associated with average recovery of 90% baseline skill (controls: 60%) on the forelimb reaching task. However, no correlation between reaching score and lesion size/location, or number of dendritic branches was found. Further study is needed to determine the mechanism of recovery and a better approach to behavioral modeling of recovery profiles.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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