Neural stem cells (NSCs) respond to inflammatory cues induced during brain injury and are thought to be involved in recovery from brain damage. Little is known about NSC response during brain infections. The present study evaluated NSC proliferation during Herpes Simplex Virus-1 brain infection. Total numbers of nestin(+) NSCs increased significantly in infected brains at 6. days post infection (p.i.). However, by 15. days p.i. the nestin(+) population decreased significantly below levels observed in uninfected brains and remained depressed through 30. days p.i. This initial increase in NSC population occurred concurrently with increased brain cell proliferation, which peaked at 3. days p.i. On closer examination, we found that while actively proliferating Sox2(+) NSCs increased in number at 6. days p.i., proliferating DCX(+) neuroblasts contributed to the increased response at 3. days p.i. However, overall proliferation decreased steadily from 15. days p.i. to below control levels. To determine the mechanisms involved in altering NSC proliferation, neurotrophin and growth factor expression profiles were assessed. FGF-2 gene expression increased at 5. days p.i. and was robustly down-regulated at 15. days p.i. (>. 1000-fold), which was further confirmed by increased FGF-2 immunostaining around the lateral ventricles. Furthermore, supplementing infected animals with recombinant FGF-2, at 15. days p.i., significantly increased the number of proliferating brain cells. These findings demonstrate that the temporal changes in NSC proliferation are mediated through the regulation of FGF-2 and that the NSC niche may benefit from supplementation with FGF-2 during HSV-1 brain infection.
Bibliographical noteFunding Information:
These studies were funded in part by NIH grants RO1 NS065817 and T32 DA007097 , and the AHC Faculty Development Grant, University of Minnesota . The authors thank Dianna Cheney-Peters for technical assistance and Aaron Rendahl at the Statistical Consulting Service, University of Minnesota for assistance with statistical analyses of data presented.
- Adult neurogenesis
- Herpes Simplex encephalitis
- Neural stem cells