Chronic Stress Effects on Cerebral Glucose Transporters: Adolescent Specific?

描述(由申请人提供)：在青春期发作的严重抑郁障碍(MDD)可能特别有害，因为它使一个人容易发生随后的抑郁发作。在正电子发射断层扫描研究中，MDD患者和暴露在应激中的大鼠都表现出大脑代谢活动的改变。代谢活性的降低通常归因于神经元谷氨酸释放的减少，从而减少了局部葡萄糖的运输。与这一传统教条相反的是，葡萄糖转运的初级减少可能会随后抑制神经元的活动。促进葡萄糖转运是由一系列转运蛋白(Glut)调节的。谷氨酸负责葡萄糖通过血脑屏障内皮细胞的运输，并负责将葡萄糖吸收到星形胶质细胞和神经元中。GLUT的关键作用体现在De Vivo病所表现的严重的神经缺陷上，De Vivo病是一种罕见的遗传疾病，GLUT1在这种疾病中不表达。此外，GLUT家族成员的表达和易位缺陷与神经病理状况有关，包括阿尔茨海默病、脑缺血后功能和创伤后脑损伤缺陷。GLUT家族成员在血脑屏障内皮细胞、星形胶质细胞或神经元中的表达或移位的改变可以改变神经元的能量供应，从而改变神经元的功能，从而改变行为。在快速发展和可塑性增强的时期，如青春期，该系统的能量需求会增加。在大鼠青春期开始，葡萄糖取代酮作为大脑的主要燃料来源，GLUT 3在星形胶质细胞和内皮细胞中的表达增加，随后GLUT 1的表达增加。因此，在青少年发育期，过量表达的变化可能会导致神经元功能的长期变化。目前尚不清楚，导致青春期大鼠抑郁样行为的慢性应激是否也会改变大脑过剩蛋白的表达或功能，或者发育过程中大脑过剩的变化是否足以改变情感行为。鉴于GLUT蛋白在能量底物向脑组织运输中的关键作用，来自PET研究的大量证据表明抑郁症患者边缘脑区的新陈代谢改变(一种依赖于葡萄糖运输的技术)，以及证据表明成年大鼠在应激暴露后葡萄糖转运体发生变化，我建议使用大鼠模型来研究大脑过剩在青春期抑郁症中的作用。这项建议中描述的实验的目标有两个：(1)确定早期生活应激，尤其是青春期应激，是否会以一种与成年大鼠慢性应激暴露不同的模式改变边缘脑区域葡萄糖转运蛋白的表达；(2)评估海马区GLUT1表达变化是否足以诱导青春期与成年大鼠的抑郁样行为。 公共卫生相关性：早期生活压力增加了情感障碍的风险，青少年中抑郁障碍的患病率也在增加。早发性抑郁症的神经病理机制尚不完全清楚，但考虑到这一生命阶段的能量需求，大脑中的新陈代谢变化可能会导致青少年抑郁症。这项拟议的工作检验了一种假设，即青少年大脑中的葡萄糖转运蛋白会因压力而改变，并且这些变化能够诱导抑郁样行为。

DESCRIPTION (provided by applicant): Onset of Major Depressive Disorder (MDD) during adolescence can be particularly detrimental because it predisposes one to subsequent depressive episodes. Both patients with MDD and rats exposed to stress demonstrate altered cerebral metabolic activity in positron emission tomography studies. The reduction in metabolic activity is generally attributed to reduced glutamate release from neurons which thereby decreases regional glucose transport. Counter to this traditional dogma, it is possible that a primary reduction in facilitated glucose transport subsequently suppresses neuronal activity. Facilitated glucose transport is mediated by a family of transporters (GLUT). GLUTs are responsible for glucose transport across the endothelial cells of the blood brain barrier, and for uptake of glucose into astrocytes and neurons. The crucial role of GLUT is illustrated by the profound neurological deficits manifested in De Vivo disease, a rare genetic condition in which GLUT1 is not expressed. Furthermore, deficits in the expression and translocation of members of the GLUT family have been linked to neuropathological conditions including Alzheimer pathology, post-ischemic brain function, and post-traumatic brain injury deficits. Alterations in the expression or translocation of members of the GLUT family in either the endothelial cells of the blood brain barrier, astrocytes, or neurons could alter neuronal energy supply and thereby neuronal function, subsequently altering behavior. During periods of rapid development and increased plasticity, such as adolescence, the energetic demands of the system are heightened. At the onset of adolescence in the rat, glucose replaces ketones as the main fuel source of the brain and GLUT 3 expression increases, followed by an increase in GLUT 1 expression, in both astrocytes and endothelial cells. Therefore, changes in GLUT expression during the adolescent developmental period, could lead to longstanding changes in neuronal function. It is unknown whether chronic stress which induces depressive-like behavior in adolescent rats also alters cerebral GLUT protein expression or function, or whether alterations in cerebral GLUT during development are sufficient to change affective behavior. Given the crucial role of GLUT proteins in the transport of energy substrates into cerebral tissue, substantial evidence from PET studies of altered metabolism in limbic brain regions of depressed humans (a technique which depends on glucose transport), and evidence that glucose transporters are altered after stress exposure in adult rats, I propose to study the role of cerebral GLUT in adolescent depression using a rat model. The goals of the experiments described in this proposal are two-fold: (1) to determine if early life stress, specifically adolescent stress, which is known to be depressogenic, alters expression of glucose transporters in limbic brain regions in a pattern distinct from chronic stress exposure in adult rats, and (2) to assess the sufficiency of alterations in GLUT1 expression in the hippocampus to induce depressive-like behavior in adolescent versus adult rats. PUBLIC HEALTH RELEVANCE: Early life stress increases the risk of affective disorders and the prevalence of depressive disorders is increasing among adolescents. The neuropathological mechanisms of early onset depressive disorders are not fully understood, but given the energy demands of this life phase, metabolic changes in the brain may contribute to adolescent depression. The proposed work examines the hypothesis that glucose transporters in the adolescent brain are altered by stress and that these changes are capable of inducing depressive-like behaviors.