Radiation therapy for tumors in the central nervous system is accompanied by delayed cognitive decline that can severely impact the quality of life for patients in remission. These deficits are most dramatic in children and one of the early and prominent signs is difficulty with learning and memory tasks that are largely mediated by the hippocampus. The hippocampus is a late-developing area where neural stem and progenitor cell-mediated neurogenesis continue to play a significant role in postnatal neural development. Neural progenitor cells in the hippocampus also provide homeostatic and cell replacement functions in the adult. The continued generation of new neurons in the hippocampus throughout life is believed to be positively correlated with learning and memory tasks. In mouse models of cranial irradiation there is a permanent reduction in progenitor cell activity and neurogenesis in the hippocampus following irradiation, and it has been proposed that radio-ablation of stem cell activity may contribute to deficits in learning and memory. The cranial irradiation model provides a distinct opportunity to study the functional role of adult neurogenesis. By examining the performance in a battery of behavioral tests, we identify unique changes in learning in the absence of hippocampal neurogenesis, providing evidence in support of a functional role of newborn neurons. Upon establishing a model of cognitive deficit, we investigate possible therapeutic interventions using both pharmacological and genetic approaches to rescue both hippocampal neurogenesis and behavior. Earlier work has shown that cranial irradiation induces a neuroinflammatory response that is slow to resolve and that this chronic inflammatory environment alters neural progenitor cell function. Here we show that persistence of the disabling inflammatory state is dependent on monocyte chemoattractant protein-1 (MCP-1) and that interruption of the MCP-1 signaling pathway allows neurogenesis to recover following cranial radiation in mice. This identifies MCP-1 signaling as a potential clinical target for patients impaired by delayed cognitive decline and suggests that CCR2 antagonists currently under clinical evaluation may be effective for improving cognitive function following cancer therapy.
|School Location:||United States -- California|
|Source:||DAI-B 69/10, Dissertation Abstracts International|
|Keywords:||Cranial irradiation, Hippocampus, Inflammation, Neurogenesis|
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