Compensatory Regulation of Energy Balance by Neurogenesis in Adult Hypothalamus

描述（由申请人提供）：在不断变化的环境中维持能量平衡需要大脑应对各种遗传和生理损伤。能量平衡的补偿性调节经常被观察到，但其潜在的机制在很大程度上仍然未知。我们最近的研究表明，对能量平衡调节重要的下丘脑神经元可以在成年下丘脑中再生，以响应摄氧AgRP/NPY神经元的进行性变性，并且抑制突变大脑中的细胞增殖影响摄食和肥胖。我们的研究结果表明，成人下丘脑细胞增殖的调节可能作为维持下丘脑摄食功能的代偿机制。迄今为止，成人神经发生在能量平衡调节中的功能作用在很大程度上仍未被探索。下丘脑在成年期通常被认为是非神经源性的，尽管存在大量的神经祖细胞。然而，在啮齿类动物和人类中，神经变性已被证明是大脑正常非神经发生区域的神经发生的有力刺激。在本提案中，我们将验证成人下丘脑细胞增殖的调节作为一种修复机制，在病理生理条件下限制能量失衡的程度。具体来说，我们将研究成人下丘脑神经祖细胞的时空激活，以响应特定下丘脑神经元的退化。我们将确定成年出生的下丘脑神经元是否能对能量平衡状态和外周代谢激素的改变做出适当的反应。我们将研究这些成年出生的神经元的存活和投射生长及其突触连通性。此外，我们将评估慢性肥胖和糖尿病期间下丘脑神经源性活动，这些疾病与啮齿动物和人类的脑容量减少和神经元细胞死亡有关。通过暂时诱导和细胞类型特异性的细胞消融方法，我们将确定成人神经祖细胞在正常、肥胖和糖尿病条件下能量平衡代偿调节中的功能意义。最后，我们将研究成人下丘脑移植神经祖细胞的神经发生活性，并探讨神经祖细胞移植治疗下丘脑神经元神经变性所致肥胖的治疗潜力。总之，我们的研究将为神经发生在能量平衡的代偿调节中的作用提供关键信息。这将为神经干细胞在治疗与多种慢性疾病和脑损伤相关的下丘脑神经变性方面的治疗潜力提供新的见解。

DESCRIPTION (provided by applicant): Maintenance of energy balance in an ever-changing environment requires the brain to cope with a variety of genetic and physiologic insults. Compensatory regulation of energy balance is frequently observed but its underlying mechanisms remain largely unknown. We have recently shown that hypothalamic neurons important for energy balance regulation can be regenerated in adult hypothalamus in response to progressive degeneration of orexigenic AgRP/NPY neurons, and that inhibition of cell proliferation in the mutant brain affects feeding and adiposity. Our results suggest that regulation of cell proliferation in the adult hypothalamus could serve as a compensatory mechanism to maintain hypothalamic feeding functions. To date, the functional role of adult neurogenesis in energy balance regulation remains largely unexplored. Hypothalamus is generally considered non-neurogenic in the adulthood although abundant neural progenitor cells are present. However, neurodegeneration has been shown to be a potent stimulus of neurogenesis in normally non-neurgenic regions of the brain in both rodents and humans. In this proposal, we will test the hypothesis that modulation of cell proliferation in the adult hypothalamus serves as a repair mechanism to limit the extent of energy imbalance under pathophysiologic conditions. Specifically, we will examine the spatiotemporal activation of neural progenitor cells in the adult hypothalamus in response to degeneration of specific hypothalamic neurons. We will determine whether adult born hypothalamic neurons can respond appropriately to alteration of energy balance status and peripheral metabolic hormones. We will examine survival and projection outgrowth of these adult born neurons and their synaptic connectivity. In addition, we will evaluate hypothalamic neurogenic activity during chronic obesity and diabetes, conditions that are associated with decreased brain volume and neuronal cell death in rodents and humans. By using a temporally inducible and cell type specific cell ablation approach, we will determine the functional significance of adult neural progenitors in compensatory regulation of energy balance under normal, obese and diabetes conditions. Finally, We will investigate neurogenic activity of transplanted neural progenitor cells in adult hypothalamus, and explore therapeutic potential of neural progenitor cell transplantation in treatment of obesity caused by neurodegeneration of hypothalamic neurons. Together, our study will provide critical information on the role of neurogenesis in compensatory regulation of energy balance. It will provide novel insight into therapeutic potential of neural stem cells in treatment of hypothalamic neurodegeneration that are associated with a variety of chronic diseases and brain injuries. PUBLIC HEALTH RELEVANCE: In this proposal, we will test the hypothesis that modulation of cell proliferation in the adult hypothalamus serves as a repair mechanism to limit the extent of energy imbalance under pathophysiologic conditions such as chronic obesity and diabetes. Our study will determine functional connections between neurodegeneration, neurogenesis and body weight regulation. It will provide novel insight into therapeutic potential of neural stem cells in treatment of hypothalamic neurodegeneration that are associated with a variety of chronic diseases and brain injuries.