Experimental and Clinical Therapeutics

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP177) Whole brain irradiation leads to cognitive impairment in Fischer 344 X Brown Norway rats.

Shi, Lei*,1, Sonntag, William2, Carter, Christy2, Robbins, Michael 3, Long, Ashley1, Bennett, Colleen 2, Brunso-Bechtold, Judy1, 1 Department of Neurobiology and Anatomy, Winston-Salem, NC2 Department of Physiology and Pharmacology, Winston-Salem, NC3 Department of Radiation Oncology, Winston-Salem, NC

ABSTRACT- Introduction: Large field or whole brain irradiation (WBI) is used widely in the treatment of CNS malignancies. However, such treatment is associated with significant neurobiological changes including cognitive impairment. The present study investigated WBI-induced cognitive changes and neural abnormalities in Fischer 344 X Brown Norway rats. Methods: Twelve month-old rats were anesthetized and received either 9 fractions of 5 Gy 137Cs rays WBI over 4.5 weeks (N=20) or sham-irradiation (N=20). Twelve months later, all rats were tested on the hippocampal-dependent Morris water maze (MWM) task, after which they were sacrificed and their brains collected for structural analysis. Results: The present study revealed that escape latency and swimming distance decreased throughout the training sessions (1 trial/day X 18 days) for irradiated and control rats, indicating acquisition of the task for both groups. However, there was a WBI-induced impairment of spatial learning as revealed by longer escape latencies and swim distances in irradiated compared to control rats. There were no differences between the groups in performance of the sensorimotor aspects of the task as indicated by similar swimming velocities and visual acuity assessed using a visible, raised platform. In the probe trial, control rats spent significantly more time in the quadrant where the platform previously was located. This quadrant preference was not seen in irradiated rats, which indicates a WBI-induced impairment in the memory component of MWM. Studies of WBI-induced myelin and synapse changes in the hippocampus currently are underway to evaluate structural changes that underlie the decline in learning and memory following WBI. Conclusions: The present results indicate deficits in spatial learning and spatial reference memory 12 months following a clinically relevant regime of WBI. Studies to reveal the pathogenic mechanism(s) underlying these deficits are essential for the development of interventional therapies to reduce the severity of radiation-induced brain injury.

Key words: morris water maze, spatial learning and memory, hippocampus, myelin and synapse

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2005 RRS