An Assessment of Deficits in Simple Discrimination Following Frontal Traumatic Brain Injury in Rats: The Relative Contribution of Motor Deficits, Motivation Deficits and Neuroprotective Drug Administration
Date of Award
Doctor of Philosophy
Traumatic brain injury (TBI) is a serious problem facing the medical community. Every year, over 1.7 million TBIs occur in the United States alone (CDC, 2010). Over 25 years of research and 21 major clinical trials have failed to yield a pharmaceutical treatment for this complicated injury (Maas et al., 2007). One of the possible reasons for the many clinical failures is a lack of behavioral assessment at the level of animal models. In particular, there is typically only one type of cognitive measure employed in most studies, usually a measure of spatial learning (e.g. Morris water maze). In other fields, alternative measures have been utilized for many years, including non-spatial discriminations. The primary goal of this study was to evaluate the use of a visual discrimination in a model of frontal TBI and determine whether or not administering a neuroprotectant could alleviate deficits in discrimination. Long-Evans rats were trained on a simple visual discrimination task and a progressive ratio schedule of reinforcement (PR). After assessing their baseline discrimination performance, motor ability and PR performance, they were advanced to surgery and given either a bilateral frontal controlled cortical impact TBI or sham procedure. Following TBI, injured rats were given either doses of the neuroprotectant nicotinamide (NAM; 150 mg/kg, i.p.) or a saline solution (1 ml/kg, i.p.). They were then assessed for 35 days on the discrimination and progressive ratio. On days 7, 14 and 27, motor abilities were assessed in automated motor activity monitors. On days 15-18 and 21-23 post-surgery, rats were also assessed on the Morris water maze (MWM). On day 43 post-surgery, rats were transcardially perfused and brains extracted. Brains were briefly post-fixed and then sliced on a sliding microtome at 40 µm. These slices were then mounted to slides and stained with cresyl violet to examine the extent of the lesion. Brain injury impaired performance on the discrimination task and PR task. In the discrimination task, deficits were primarily driven by an inability to complete chains of responses. On the PR task, deficits were characterized by reduced break points and low rates of responding. Administration of NAM reduced deficits in discrimination and PR performance. There were no gross motor deficits as a result of the injury. On the MWM task and measures of lesion size, there were no improvements due to NAM administration. Based on the outcome of this study, operant measures such as discrimination or progressive ratio could be incorporated into the testing battery for experimental TBI. Despite some of the challenges of adapting tasks designed for single-subject analysis, it is well worth the time spent due to the robust ability to detect deficits. Additionally, this study showed that nicotinamide administration was neuroprotective across multiple tasks, suggesting that these tasks are indeed well suited for the assessment of pharmacological agents and that nicotinamide has treatment potential for clinical populations.
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