Characterization of Neural Stem Cells in the Postnatal Mammalian Hypothalamus

描述(由申请人提供)：神经干细胞存在于出生后哺乳动物大脑的特殊缝隙中，是一种有助于损伤区域再生的细胞群。在侧脑室室下区和海马齿状回颗粒下区生发活跃的生发区和海马齿状回颗粒下生发区生发活跃的生发区中，不断有新的神经元诞生。尽管存在争议，但新的证据开始表明，出生后的神经发生在哺乳动物的下丘脑，传统上被认为是一个非神经源性的区域。尽管有下丘脑神经发生的证据，但这一过程的相关性以及这些新神经元的细胞来源的问题完全不清楚。新的下丘脑神经元是来自下丘脑室带(HVZ)还是来自实质来源，这是有很大争议的。我们假设，HVZ有一个静止神经干细胞的储藏库。我们还假设，这些神经干细胞可以促进下丘脑损伤后的再生神经发生。我们建议在这里1)表征低水平的下丘脑神经发生在出生后的哺乳动物的大脑中的存在。我们将在小鼠模型中使用可诱导的细胞命运映射策略来前瞻性地标记HVZ内的细胞。使用这一策略，我们将能够确定HVZ是否含有神经干细胞，这些干细胞可能会产生各种新生的细胞。2)我们将确定在下丘脑损伤后，HVZ内的神经干细胞是否有助于神经元的再生。我们将使用一种化学损伤来消除弓状核的神经元，弓状核是下丘脑腹侧的一个亚结构。我们将使用溴脱氧尿嘧啶核苷给药，以前瞻性地确定出生后HVZ内的增殖细胞是否会产生新的神经元，这些神经元稍后会在损伤部位重新出现。拟议的实验将集中于确定HVZ是否包含神经干细胞或前体细胞，并确定这些细胞在脑细胞再生中可能发挥的作用。与公共卫生相关：确定新的神经干细胞种群是否存在于出生后的下丘脑中，为了解神经发生在健康和疾病中的作用以及开发可能的治疗或预防性疗法以减轻各种神经退行性疾病或损伤的影响提供了令人兴奋的途径。

DESCRIPTION (provided by applicant): Neural stem cells residing in specialized niches of the postnatal mammalian brain represent a cell population that can aid in the regeneration of injured areas. While new neurons continue to be born postnatally in the constitutively active germinal zones of the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampal dentate gyrus, other more quiescent germinal zones may exist. Although controversial, emerging evidence is beginning to suggest that postnatal neurogenesis occurs in the mammalian hypothalamus, traditionally considered a non-neurogenic region. Despite this evidence for hypothalamic neurogenesis, the question of the relevance of this process, as well as the cell of origin of these new neurons is entirely unclear. It is highly contentious whether new hypothalamic neurons are derived from the hypothalamic ventricular zone (HVZ) or from a parenchymal source. We hypothesize that the HVZ harbors a reservoir for quiescent neural stem cells. We also hypothesize that these neural stem cells can contribute to regenerative neurogenesis following hypothalamic injury. We propose here to 1) characterize the existence of low levels of hypothalamic neurogenesis in the postnatal mammalian brain. We will use an inducible cell fate mapping strategy in a mouse model to prospectively label cells within the HVZ. Using this strategy, we will be able to determine if HVZ contains neural stem cells that may be able to give rise to a variety of newly born cells. 2) We will characterize if neural stem cells within the HVZ aid in the regeneration of neurons following hypothalamic injury. We will employ a chemical lesion that eliminates neurons of the arcuate nucleus, a substructure within the ventral hypothalamus. We will use bromodeoxyuridine administration, to prospectively determine if proliferating cells within the postnatal HVZ may give rise to new neurons that reappear later at the injury site. The proposed experiments will focus on identifying if the HVZ contains neural stem or precursor cells, and to determine the role that these cells may play in cell regeneration of the brain. Relevance to Public Health: The identification of whether novel neural stem cell populations exist in the postnatal hypothalamus presents exciting avenues for understanding the role of neurogenesis in health and disease, as well as developing possible treatments or preventative therapies to mitigate the effects of a wide variety of neurodegenerative diseases or injuries.