Cranial radiotherapy is associated with progressive cognitive decline that disrupts quality of life for long- term cancer survivors. Adult hippocampal neurogenesis, in which neurons are born and integrated into the hippocampal circuitry, is important for learning, memory, and mood regulation. Adult hippocampal neurogenesis is persistently reduced following cranial irradiation and may contribute to post-irradiation cognitive decline. Data from our laboratory confirm that neuroblasts and their precursors are reduced acutely after irradiation in the adult hippocampus. Interestingly, deficits in neurogenesis continue for many months despite the survival of radial glial cells (RGCs), the stem cell of the adult hippocampus, after irradiation. The long-term response of individual neurogenic cell types to cranial irradiation is not well characterized. I hypothesize that cranial irradiation impairs the ability of RGCs to divide and give rise to intermediate progenitor cells (IPCs). I will test this hypothesis in Aim 1, where I will quantify RGC BrdU incorporation and Ascl1+ and Tbr2+ IPC population size in the hippocampus three months after 8 Gy cranial gamma irradiation.
This aim will utilize transgenic NestinCreERT2 YFP reporter mice and immunohistochemistry to fate- map RGCs and their progeny. Endogenous bone morphogenic proteins 2, 4, and 6 (BMP2/4/6) inhibit RGC division. Data from other models show that long-term increases in BMP2/4/6 contribute to persistent deficits in adult hippocampal neurogenesis. Furthermore, blocking BMP2/4/6 activity has been shown to effectively increase neurogenesis in healthy and aged mice. Based on this evidence, together with my preliminary data showing an increase in BMP6 mRNA in whole brain homogenates after irradiation, I hypothesize that a long-term increase in BMP2/4/6 activity following irradiation reduces RGC division, and that blocking this pathway will promote RGC division and rescue neurogenesis.
In Aim 2, I will test this hypothesis by 1) quantifying changes in mRNA of BMP2/4/6 and downstream targets three months after 8 Gy cranial gamma irradiation, and 2) quantifying changes in RGC BrdU incorporation and IPC population size in response to intraventricular administration of noggin, a BMP inhibitor, three months after 8 Gy cranial gamma irradiation. Together, experimental results achieved in these aims will contribute to our over-arching goal of reducing the side effects of cranial irradiation on the hippocampus. Ultimately, this work will enhance our understanding of adult hippocampal stem cells and may inform future development of therapies to mitigate cognitive decline in individuals exposed to radiation. Techniques mastered through the proposed experiments will help me achieve my next goal of obtaining a competitive academic post-doctoral position.
Patients with primary and metastatic brain tumors are commonly treated with cranial radiotherapy. Unfortunately this treatment is associated with progressive cognitive decline, which impairs quality of life especially in long-term cancer survivors. Previous studies suggest that post-irradiation cognitive impairment may be due to persistent reductions in adult hippocampal neurogenesis, a function which is integral to learning and memory. Few treatments have demonstrated an ability to mitigate the detrimental effect of irradiation on adult hippocampal neurogenesis and little is known how discrete steps in the neurogenic process are specifically impaired. The goal of this study is to characterize changes that occur in different neurogenic cell populations after irradiation and pharmaceutically manipulate pathways that regulate neural stem cell division in an attempt to rescue post-irradiation neurogenesis. Results from this study may contribute to the development of future therapies to mitigate cognitive decline after cranial radiotherapy.
