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.
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.
