Chronic Stress Effects on Cerebral Glucose Transporters: Adolescent Specific?

慢性压力对脑葡萄糖转运蛋白的影响：青少年特异性？

• 批准号: 8103206
• 负责人: Gretchen N Neigh
• 金额: $ 19.18万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8103206
• 关键词: Adolescence; Adolescent; Adult; Affective; Alzheimer' s Disease; Astrocytes; Behavior; Blood - brain barrier anatomy; Brain; Brain region; Cerebrum; Chronic stress; Data; Depressed mood; Depressive disorder; Development; Disease; Endothelial Cells; Energy Supply; Exposure to; Family; Female; Female Adolescents; GLUT-3 protein; Glucose; Glucose Transporter; Glutamates; Goals; Hereditary Disease; Hippocampus (Brain); Human; Ketones; Lead; Life; Life Stress; Link; Major Depressive Disorder; Male Adolescents; Mediating; Mental Depression; Metabolic; Metabolism; Modeling; Mood Disorders; Neurologic; Neurons; Pathology; Patients; Pattern; Phase; Positron-Emission Tomography; Prevalence; Proteins; Rattus; Risk; Role; SLC2A1 gene; Series; Source; Stress; System; Techniques; Tissues; Traumatic Brain Injury; Work; acute stress; base; depressive symptoms; early onset; glucose transport; glucose uptake; male; member; overexpression; protein expression; protein function; public health relevance; research study; sex

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.

描述（由申请人提供）：在青春期发作的重度抑郁症（MDD）可能特别有害，因为它容易使人随后抑郁发作。在正电子发射断层扫描研究中，MDD患者和暴露于压力的大鼠都表现出脑代谢活动的改变。代谢活性的降低通常归因于神经元释放的谷氨酸减少，从而降低了局部葡萄糖转运。与这一传统的教条相反，有可能促进葡萄糖转运的主要减少随后抑制神经元活动。促进葡萄糖转运由转运蛋白家族（GLUT）介导。GLUT负责葡萄糖转运穿过血脑屏障的内皮细胞，并将葡萄糖摄取到星形胶质细胞和神经元中。GLUT的关键作用由体内疾病中表现出的严重神经缺陷说明，体内疾病是一种罕见的遗传疾病，其中GLUT 1不表达。此外，GLUT家族成员的表达和易位的缺陷与神经病理学状况有关，包括阿尔茨海默病病理学、缺血后脑功能和创伤后脑损伤缺陷。血脑屏障内皮细胞、星形胶质细胞或神经元中GLUT家族成员表达或易位的改变可改变神经元能量供应，从而改变神经元功能，随后改变行为。在快速发展和可塑性增加的时期，如青春期，系统的能量需求会提高。在大鼠青春期开始时，葡萄糖取代酮作为大脑的主要燃料来源，并且在星形胶质细胞和内皮细胞中，GLUT 3表达增加，随后GLUT 1表达增加。因此，在青少年发育期间GLUT表达的变化可能导致神经元功能的长期变化。目前尚不清楚在青春期大鼠中诱导抑郁样行为的慢性应激是否也会改变大脑GLUT蛋白的表达或功能，或者发育期间大脑GLUT的改变是否足以改变情感行为。考虑到GLUT蛋白在将能量底物运输到脑组织中的关键作用，PET研究中抑郁症患者边缘脑区代谢改变的大量证据（一种依赖于葡萄糖运输的技术），以及成年大鼠应激暴露后葡萄糖转运蛋白改变的证据，我建议使用大鼠模型研究大脑GLUT在青少年抑郁症中的作用。本提案所述实验的目标有两个方面：（1）确定早期生活压力，特别是已知为抑郁源性的青春期压力，是否以不同于成年大鼠慢性压力暴露的模式改变边缘脑区域中葡萄糖转运蛋白的表达，以及（2）评估海马中GLUT1表达的改变是否足以诱导青少年与成年大鼠的抑郁样行为。 公共卫生关系：早期生活压力增加了情感障碍的风险，青少年中抑郁症的患病率也在增加。早发性抑郁症的神经病理机制尚未完全了解，但考虑到这一生命阶段的能量需求，大脑中的代谢变化可能导致青少年抑郁症。这项研究的目的是检验青少年大脑中的葡萄糖转运蛋白被压力改变的假设，这些变化能够诱导抑郁样行为。