Fatigue and depression are common symptoms after stroke. Animal models of poststroke fatigue (PSF) and poststroke depression (PSD) would facilitate the study of these symptoms. Spontaneous locomotor activity is as an objective measure of fatigue and learned helplessness an accepted correlate of depression. We used different rat strains to evaluate stroke-induced changes in behavior in hopes that interstrain differences would provide insights into the biological basis of these symptoms. Male Lewis, Wistar, and Sprague-Dawley (SD) rats underwent experimental stroke. Spontaneous activity was assessed continually after stroke (for up to 50 days). In a subset of animals, the forced swim test was performed prior to and 1 month after stroke to assess learned helplessness; blood was obtained at sacrifice for cytokine assay. Stroke induced strain-related differences in activity; Lewis rats increased spontaneous activity during the dark cycle, while Wistar and SD rats increased activity during the light cycle. The velocity of movement decreased during the dark cycle in Wistar and SD rats and during the light cycle in Lewis rats. Stroke also led to an increase in learned helplessness in Lewis rats. In summary, different patterns of behaviors emerge in different rat strains after stroke. Lewis rats displayed behavior consistent with depression but not fatigue, while Wistar and SD rats displayed behavior consistent with fatigue but not depression. These data argue that PSF and PSD are different biological constructs and suggest that analysis of strain-related differences may provide insight into symptom pathophysiology.

Animals that have myelin basic protein (MBP) specific lymphocytes with a Th1(+) phenotype have worse stroke outcome than those that do not. Whether these MBP specific cells contribute to worsened outcome or are merely a consequence of worse outcome is unclear. In these experiments, lymphocytes were obtained from donor animals one month after stroke and transferred to naïve recipient animals at the time of cerebral ischemia. The MBP specific phenotype of donor cells was determined prior to transfer. Animals that received either MBP specific Th1(+) or Th17(+) cells experienced worse neurological outcome, and the degree of impairment correlated with the robustness of MBP specific Th1(+) and Th17(+) responses. These data demonstrate that the immunologic phenotype of antigen specific lymphocytes influences stroke outcome.

Pre-clinical models of stroke therapeutics depend upon the ability to detect differences in infarct volume as well as in the short- and long-term outcomes of treated animals. Little attention has been paid to interstrain differences in these outcomes and the importance of defining the most appropriate behavioral tests. In this study, we evaluate long-term outcome from stroke in three different rat strains. Lewis, Wistar, and Sprague Dawley (SD) rats were subjected to 2-h middle cerebral artery occlusion and survived for up to 49 days. Behavioral tests were performed weekly. There was continuous assessment of rotational/circling activity in the home cage by use of an automated software program. A separate group of animals was sacrificed at 24 h to determine infarct volume. Infarct volume was similar in all three strains. Mortality was significantly higher in SD rats (P < 0.001). Rotational/circling activity at 24 h was correlated with cortical infarct volume in Wistar and SD rats (ρ = 0.67, P = 0.04 and ρ = 0.72, P = 0.01, respectively). Wistar and SD rats displayed more rotational/circling activity following stroke than Lewis rats, but Lewis rats evidenced more impairment on complex motor tasks like the rotarod. Further, computer automated analysis of rotational activity was more sensitive than subjective assessment, with SD rats showing a preference for clockwise rotations to 49 days after stroke despite normalization of the neurological score after 21 days. There are significant interstrain differences in survival and in the patterns of neurological impairment and recovery after stroke. These differences must be taken into account in pre-clinical studies, but may also be capitalized upon to understand genetic contributions to injury. Finally, computerized assessment of behavior is more sensitive than subjective assessment for detecting behavioral changes.

Background: Assessment of long-term behavioral outcome after experimental cerebral ischemia is important for evaluating potential therapeutic interventions. In this study, we explored strain related differences in baseline behavior and in response to stroke. Methods: Spontaneous cage activity was monitored (cm moved per hr) and analyzed before and after 2 hour middle cerebral artery occlusion (MCAO) in male Lewis, Wistar, and Sprague Dawley (SD) rats using the Noldus PhenoTyper® cages and EthoVision® Software system. Stroke severity was assessed using the neuroscore, foot fault errors, and performance on the rotarod. Infarct volume at 24 hours was determined in a second cohort of animals. Animals were sacrificed 56 days after MCAO. Data are analyzed using non-parametric statistics. Results: Prior to stroke, the median distance moved per hour during the dark was similar among the 3 strains, but Lewis rats were more active during the light cycle (P=0.001). Neuroscores did not differ between strains at 3 hrs after MCAO nor did infarct volumes at 24 hours after MCAO. Lewis rats, however, performed worse on the rotarod in the month following MCAO (P<0.05 at each time point). Foot fault errors were similar throughout the study period. After stroke, Lewis rats became more active during the dark cycle while Wistar and SD rats became more active during the light cycle (Figure). Summary: The 3 strains of rats evaluated in this study had different patterns in the change in activity after MCAO. Lewis rats showed an increase in activity during the dark cycle while Wistar and SD rats showed an increase in activity during the light cycle. This observation suggests that there are genetic differences in the response to stroke that may alter the circadian rhythm after stroke.