There is a growing appreciation that the complications of diabetes extend to the central nervous system (CNS), including structural and functional deficits in the hippocampus. Deficits in hippocampal synaptic plasticity are also observed in experimental models of diabetes. One complication that may result from these deficits in hippocampal synaptic plasticity is neurological co-morbidities. In this regard, diabetic patients have higher risk to develop mood disorders like depressive illness when compared to non-diabetic individuals. Unfortunately, the underlying mechanistic links between co-morbid diabetes and depression remain to be identified. One limitation in the use of experimental models of diabetes in the identification of these mechanistic mediators is that diabetic animals exhibit a complex physiology that includes deficits in insulin receptor (IR) signaling, hyperglycemia and neuroendocrine dysfunction. In order to more selectively asses the role of insulin receptor signaling, we recently developed a novel and innovative lentivirus vector that contains an antisense sequence selective for IR (IRAS) that examines the effects of decreasing IR signaling without affecting these other parameters. In this regard, our studies demonstrate that downregulation of hypothalamic IR expression and signaling increases body weight, peripheral adiposity and plasma leptin levels. Downregulation of hypothalamic IRs also elicits deficits in hippocampal synaptic plasticity and impairments in hippocampal-dependent behaviors. As such, downregulation of hypothalamic IRs may provide a novel and innovative approach to examine the mechanistic links between co- morbid diabetes and depression. One potential mechanistic mediator of co-morbid diabetes and depression is leptin. Leptin enhances hippocampal synaptic plasticity and performance of hippocampal-dependent behaviors under normal physiological conditions. Conversely, these parameters are impaired in rodents with genetic deficits in leptin receptor expression. Moreover, leptin resistance in the hypothalamus is proposed to be a hallmark feature of and contributor to diabetes/obesity phenotypes. In view of these observations, we hypothesize that leptin resistance occurs in the hippocampus of rats treated with the IRAS construct that develop an obese/hyperleptinemic phenotype, thereby impairing hippocampal synaptic plasticity and promoting co-morbid depression in diabetic subjects. Hippocampal plasticity in co-morbid diabetes and depression Epidemiological and clinical studies determined that the incidence of major depressive disorder is greater than two fold higher in diabetic patients when compared with non-diabetic patients. These results illustrate that the development and progression of depressive illness is a long-term complication associated with diabetes. Our previous and current data demonstrate that deficits in hippocampal synaptic plasticity are common features of both depressive illness and diabetes. Since leptin is an important mediator of hippocampal synaptic plasticity, while hyperleptinemia is associated with deficits in hippocampal plasticity, the overarching goal of the proposed studies is to determine whether reductions in hypothalamic insulin receptors induces `leptin resistance'in the hippocampus, thereby impairing hippocampal synaptic plasticity. Successful completion of these studies will identify impaired leptin signaling in the hippocampus is an essential mechanistic link between co-morbid diabetes and depression.