Compensatory regulation of energy balance by neurogenesis in adult hypothalamus

描述(申请人提供)：在不断变化的环境中保持能量平衡需要大脑应对各种遗传和生理上的侮辱。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不清楚。我们最近发现，对能量平衡调节至关重要的下丘脑神经元可以在成人下丘脑再生，以响应增食性AgRP/NPY神经元的进行性退化，而突变脑中细胞增殖的抑制会影响摄食和肥胖。我们的结果表明，调节成人下丘脑的细胞增殖可能是维持下丘脑摄食功能的一种代偿机制。到目前为止，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。尽管存在丰富的神经前体细胞，但成年期的下丘脑通常被认为是非神经源性的。然而，在啮齿动物和人类中，神经退行性变被证明是正常的非神经源性脑区神经发生的有力刺激因素。在这项提议中，我们将检验这一假设，即成年下丘脑中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。具体地说，我们将研究成人下丘脑中神经前体细胞对特定下丘脑神经元退化的时空激活。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变化做出适当的反应。我们将检查这些成年出生的神经元的存活和投射生长以及它们的突触连接。此外，我们将评估慢性肥胖和糖尿病期间的下丘脑神经原活动，这些情况与啮齿动物和人类的脑体积减少和神经细胞死亡有关。通过使用时间诱导和细胞类型特异的细胞消融方法，我们将确定在正常、肥胖和糖尿病条件下，成年神经前体细胞在能量平衡代偿调节中的功能意义。最后，我们将研究移植的神经前体细胞在成人下丘脑的神经生成活性，并探索神经前体细胞移植治疗下丘脑神经元变性所致肥胖的治疗潜力。总之，我们的研究将提供关于神经发生在能量平衡的代偿调节中的作用的关键信息。这将为神经干细胞在治疗与各种慢性病和脑损伤相关的下丘脑神经退行性变的治疗潜力提供新的见解。 与公共健康相关：在这项提案中，我们将测试这一假设，即成年下丘脑细胞增殖的调节作为一种修复机制，在慢性肥胖症和糖尿病等病理生理条件下限制能量失衡的程度。我们的研究将确定神经退变、神经发生和体重调节之间的功能联系。这将为神经干细胞在治疗与各种慢性病和脑损伤相关的下丘脑神经退行性变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.