Glial Cell Glycogen and Stress-induced Depression

描述(申请人提供)：在这个探索性项目中，我们建议测试一个新的假设，即大脑能量储备的不足使其容易受到压力的影响，并构成抑郁症发展的风险因素。正常的大脑功能依赖于大量能量的消耗(高达人类所有能量需求的20%)，其中大部分能量被消耗在维持神经元细胞膜上的电位和离子梯度上。暴露在应激条件下会极大地增加大脑特定区域的能量消耗，神经元对应激源做出正常反应并在应激源产生的兴奋状态下存活的能力依赖于周围的神经胶质细胞以葡萄糖和葡萄糖代谢物的形式提供能量。神经胶质细胞为神经元提供能量来源的能力不仅依赖于血液中葡萄糖的运输，还取决于自身糖原能量储备的动员。作为对兴奋性神经递质的反应，神经胶质细胞将糖原分解为葡萄糖和乳酸，并将它们输出到神经元。我们将确定当大脑暴露在足够强度和持续时间的应激条件下，耗尽大脑特定区域的胶质糖原储备时，是否会导致抑郁。枯竭的神经胶质细胞将无法为附近的神经元提供足够的葡萄糖和乳酸，而对能量不足的神经保护反应将减少局部神经活动，并导致抑郁症状。我们用一种公认的抑郁症动物模型提供了新的数据，该模型支持糖原假说。这些数据表明，足以导致行为抑郁的压力条件不仅会耗尽大脑糖原，还会导致严重的代谢缺陷。在计划中的实验中，我们将(A)检查抑郁诱导应激源对不同脑区糖原水平的影响，(B)监测在应激源暴露期间以及在行为抑郁的发展和恢复期间大脑葡萄糖和乳酸的释放，以及(C)检查操纵脑糖原水平的神经化学和行为影响。研究结果将为应激导致抑郁的机制提供全新的见解，并将为治疗和预防这种毁灭性疾病提供新的方法。

DESCRIPTION (provided by applicant): In this exploratory project, we propose to test a new hypothesis that deficiencies in the brain's reserves of energy make it vulnerable to stress and constitute a risk factor in the development of depression. Normal brain function is dependent on the expenditure of large amounts of energy (up to 20 percent of all energy needs in the human) and most of this energy is consumed in maintaining electrical potentials and ionic gradients across neuronal cell membranes. Exposure to stressful conditions induces greatly increased energy consumption in specific areas of the brain, and the ability of a neuron to respond normally to stressors and to survive the excited state that stressors produce is dependent on surrounding glial cells providing energy in the form of glucose and glucose metabolites. The glial cell's ability to provide energy sources to neurons is not only dependent on the transport of glucose from the blood but also on the mobilization of its own glycogen energy reserves. In response to excitatory neurotransmitters, glial cells break down glycogen into glucose and lactic acid and export them to neurons. We will determine if depression results when the brain is exposed to stressful conditions of sufficient intensity and duration as to deplete the glial glycogen reserve in specific regions of the brain. Depleted glial cells would then be unable to provide nearby neurons with sufficient glucose and lactic acid, and neuroprotective responses to the energy deficit would reduce local neural activity and cause symptoms of depression. We present new data using a well-established animal model of depression that support the glycogen hypothesis. These data indicate that stressful conditions sufficient to cause behavioral depression not only deplete cerebral glycogen but also cause a profound metabolic deficit. In the planned experiments, we shall (a) examine the effects of depression-inducing stressors on levels of glycogen in different brain areas, (b) monitor brain glucose and lactic acid release during exposure to the stressor and during the development and recovery from behavioral depression, and (c) examine the neurochemical and behavioral effects of manipulating brain glycogen levels. Results will provide entirely new insights into the mechanisms of stress induced depression and should suggest new approaches to the treatment and prevention of this devastating disease.