Defining functional changes in the brain caused by targeted stereotaxic radiosurgery.

Brain tumor patients routinely undergo cranial radiotherapy, and while beneficial, this treatment often results in debilitating cognitive dysfunction. This serious and unresolved problem has at present, no clinical recourse, and has driven our efforts to more clearly define the consequences of different brain irradiation paradigms on specific indices of cognitive performance and on the underlying cellular mechanisms believed to affect these processes. To accomplish this we have developed the capability to deliver highly focused X-ray beams to small and precisely defined volumes of the athymic rat brain, thereby providing more realistic simulations of clinical irradiation scenarios. Using this technique, termed stereotaxic radiosurgery, we evaluated the cognitive consequences of irradiation targeted to the hippocampus in one or both hemispheres of the brain, and compared that to whole brain irradiation. While whole brain irradiation was found to elicit significant deficits in novel place recognition and fear conditioning, standard platforms for quantifying hippocampal and non-hippocampal decrements, irradiation targeted to both hippocampi was only found to elicit deficits in fear conditioning. Cognitive decrements were more difficult to demonstrate in animals subjected to unilateral hippocampal ablation. Immunohistochemical staining for newly born immature (doublecortin positive) and mature (NeuN positive) neurons confirmed our capability to target irradiation to the neurogenic regions of the hippocampus. Stereotaxic radiosurgery (SRS) of the ipsilateral hemisphere reduced significantly the number of doublecortin and NeuN positive neurons by 80% and 27% respectively. Interestingly, neurogenesis on the contralateral side was upregulated in response to stereotaxic radiosurgery, where the number of doublecortin and NeuN positive neurons increased by 22% and 36% respectively. Neuroinflammation measured by immunostaining for activated microglia (ED1 positive cells) was significantly higher on the ipsilateral versus contralateral sides, as assessed throughout the various subfields of the hippocampus. These data suggest that certain cognitive decrements are linked to changes in neurogenesis, and that the unilaterally irradiated brain exhibits distinct neurogenic responses that may be regulated by regional differences in neuroinflammation. Compensatory upregulation of neurogenesis on the contralateral hemisphere may suffice to maintain cognition under certain dose limits. Our results demonstrate unique cognitive and neurogenic consequences as a result of targeted stereotaxic radiosurgery, and suggest that these irradiation paradigms elicit responses distinct from those found after exposing the whole brain to more uniform radiation fields.