Inhibition of Adult Hippocampal Neurogenesis by Sustained Interleukin-1B

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Neurobiology & Anatomy, 2012.Neurogenesis persists throughout adulthood in rodents and is speculated to be important in learning and memory, responses to stress, repair/regeneration, and normal maintenance of the adult CNS. Alterations in adult hippocampal neurogenesis have been observed in numerous neurological diseases that contain a neuroinflammatory component. Interleukin-1 (IL-1) is a pro-inflammatory cytokine that contributes to neuroinflammation in many CNS disorders and could play an important role in modulating adult hippocampal neurogenesis. Indeed, IL-1 has been recently shown to negatively affect adult hippocampal neurogenesis when infused acutely into the cerebroventricular system. Furthermore, there is evidence that IL-1 can bind directly to neural precursors to cause cell cycle arrest in vitro. Despite this information, little is known about the effects of sustained neuroinflammation, as occurs in neurodegenerative and other disorders, on adult hippocampal neurogenesis. Our results reveal a severe reduction in adult hippocampal neurogenesis due to focal and chronic expression of IL-1 in a transgenic mouse model, IL-1XAT, that evokes a complex neuroinflammatory response. Furthermore, we found that sustained IL-1 caused a skewing of cell fate from a neuronal to astroglial lineage. Running, a known stimulus for adult neurogenesis, was not beneficial in increasing neurogenesis in the presence of sustained IL-1 expression. In addition, conditional knockout of an adapter protein necessary for IL-1 signaling, MyD88, in nestin+ neural precursor cells (NPCs) did not prevent the IL-1-induced reduction in neuroblasts. Interestingly, MyD88 deficiency in nestin+ NPCs caused an increase in astrogliosis in the presence of IL-1, suggesting that MyD88-dependent signaling is important in limiting astroglial differentiation due to inflammation. In the absence of inflammation, MyD88 deficiency did not alter the fate of NPCs. Thus, sustained IL-1 causes a reduction in adult hippocampal neurogenesis that is unlikely due to a direct effect on nestin+ NPCs