Abstract:
Progenitor cell proliferation is ubiquitous in the subventricular zone and subgranular zone of adult mammalian brains. However, the abundance and distribution of this proliferation is surprisingly heterogeneous between species. Furthermore, changes in proliferation in response to neurodegenerative diseases like Huntington’s disease have demonstrated a poor correlation between animal models of disease and human disease. In the subventricular zone, animal models of Huntington’s disease have revealed no change in cell proliferation compared to wild types, while in humans there is a distinct increase in cell proliferation in Huntington’s disease cases. On the other hand, numerous transgenic mouse models of Huntington’s disease demonstrate a decrease in proliferation in the subgranular zone, while reports on cell proliferation in the human subgranular zone have yet to be made. We hypothesised that Huntington’s disease cases with mainly mood symptomatology would show a greater change in hippocampal proliferation, which has previously been implicated in mood disorders such as depression. Therefore, we examined and compared proliferation in the subgranular zone in normal versus Huntington’s disease, Huntington’s disease mood, and Huntington’s disease motor affected cases. Our results demonstrate that very little proliferation is present in the adult human subgranular zone and that in humans the subgranular zone is far less proliferative than the subventricular zone. In search of a better animal model of progenitor proliferation, we characterised the neurogenic niches of the adult sheep, an animal with a longer lifespan than rodents and a highly gyrencephalic brain, using 5-bromo-2'-deoxyuridine (BrdU) as a mitotic marker and neuronal nuclear antigen (NeuN) to identify neuronal lineage cells. We demonstrate that our proposed animal model, the sheep, may be a suitable alternative to rodent and nonhuman primate animal models. The sheep subventricular zone was organised into distinct layers that are comparable to what has been described in humans. There was also much greater proliferation in the sheep subventricular zone than in the subgranular zone, and the rate of maturation of new neurons was slower in sheep than in previous reports in rodents, with only 20% of BrdU-positive cells showing neuronal phenotype at 4 months survival after BrdU administration. Overall, we demonstrate that proliferation in the adult human brain is not well represented by current animal models and we propose that the sheep is a much better and more relevant model to further our understanding of the mechanisms governing proliferation in the adult human brain.