Cranial radiation therapy causes progressive deficits in the hippocampal-dependent functions of learning, short-term memory and spatial information processing. Hippocampal neurogenesis, which occurs throughout adulthood and is believed to be important to normal hippocampal function, is ablated following therapeutic doses of radiation. Our preliminary work demonstrates that irradiation inhibits neurogenesis by disrupting the microenvironment that supports neurogenesis, this disruption is associated with a chronic microglial inflammatory response, that anti-inflammatory therapy partially restores neurogenesis following irradiation. This proposal seeks to explore further the relationship between inflammation and neurogenesis. Specifically, we seek to demonstrate that inflammation is necessary and sufficient to inhibit neurogenesis, activated microglia directly mediate the effects of inflammation on neurogenesis, and the proinflammatory cytokine interleukin-6 (IL-6) plays a significant role in this disease process. The information we glean from the proposed studies will provide valuable insights into the microenvironmental conditions required for neurogenesis and may highlight therapeutic approaches for the cognitive side effects of cranial radiation therapy.
