Chronic Stress Effects on Cerebral Glucose Transporters: Adolescent Specific?

描述（由申请人提供）：青春期重度抑郁障碍（MDD）的发作尤其有害，因为它使人容易出现随后的抑郁发作。在正电子发射断层扫描研究中，重度抑郁症患者和暴露于压力下的大鼠都表现出大脑代谢活动的改变。代谢活动的减少通常归因于神经元中谷氨酸释放的减少，从而减少了区域葡萄糖运输。与这一传统教条相反，可能是葡萄糖转运的初级减少随后抑制了神经元活动。葡萄糖转运是由转运蛋白家族（GLUT）介导的。GLUTs负责通过血脑屏障内皮细胞的葡萄糖运输，并将葡萄糖摄取到星形胶质细胞和神经元。在De Vivo疾病（一种罕见的遗传病，其中GLUT1不表达）中表现出的严重神经功能缺陷说明了GLUT的关键作用。此外，GLUT家族成员的表达和易位缺陷与阿尔茨海默病、缺血性脑功能和创伤后脑损伤缺陷等神经病理状况有关。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易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，系统的能量需求提高了。在大鼠青春期开始时，葡萄糖取代酮类成为大脑的主要燃料来源，在星形胶质细胞和内皮细胞中，GLUT 3的表达增加，随后GLUT 1的表达增加。因此，青春期发育期间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引起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，或者发育过程中大脑GLUT的改变是否足以改变情感行为。鉴于GLUT蛋白在能量底物转运到脑组织中的关键作用，从PET研究中获得的抑郁症患者边缘脑区域代谢改变的大量证据（一种依赖于葡萄糖转运的技术），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。本实验的目的有两个方面：(1)确定早期生活压力，特别是青春期压力，已知是致抑郁的，是否以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)评估海马中GLUT1表达的改变是否足以诱导青少年大鼠和成年大鼠的抑郁样行为。

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.