Downregulation of hypothalamic insulin receptor expression elicits depressive-like behaviors in rats

Abstract

Ongoing epidemiological studies estimate that greater than 60% of the adult US population may be categorized as either overweight or obese. There is a growing appreciation that the complications of obesity extend to the central nervous system (CNS) and may result in increased risk for neurological co-morbidities like depressive illness. One potential mechanistic mediator linking obesity and depressive illness is the adipocyte derived hormone leptin. We previously demonstrated that lentivirus-mediated downregulation of hypothalamic insulin receptors increases body weight, adiposity and plasma leptin levels, which is consistent with features of the metabolic syndrome. Using this novel model of obesity, we examined performance in the forced swim test (FST), the sucrose preference test and the elevated plus maze (EPM), approaches that are often used as measures of depressive-like and anxiety-like behaviors, in rats that received third ventricular injections of either an insulin receptor antisense lentivirus (hypo-IRAS) or a control lentivirus (hypo-Con). Hypo-IRAS rats exhibited significant increases in immobility time and corresponding decreases in active behaviors in the FST and exhibited anhedonia as measured by decreased sucrose intake compared to hypo-Con rats. Hypo-IRAS rats also exhibited increases in anxiety-like behaviors in the EPM. Plasma, hippocampal and amygdalar brain-derived neurotrophic factor (BDNF) levels were reduced in hypo-IRAS rats, suggesting that the obesity/hyperleptinemic phenotype may elicit this behavioral phenotype through modulation of neurotrophic factor expression. Collectively, these data support the hypothesis for an increased risk for mood disorders in obesity, which may be related to decreased expression of hippocampal and amygdalar BDNF.

Hippocampal GSK3β as a Molecular Link Between Obesity and Depression

“…phosphorylation of Akt and GSK3β. As it has been previously demonstrated, the impairment of insulin and/or leptin signaling due to inappropriate diet (e.g., HF diet) [33,34,37], or the under-expression of the insulin receptor [38] or leptin receptor [39] promotes depressive-like symptoms in rodents. Leptin receptor deletion in the hippocampus results in depressive-like behaviors in mice [39], while leptin treatment reduces depressive-like symptoms and inhibits hippocampal GSK3β via phosphorylation on Ser9 in rats [40].…”

A neuronal MCT2 knockdown in the rat somatosensory cortex reduces both the NMR lactate signal and the BOLD response during whisker stimulation

“…This reduction was sufficient to suppress the brain lactate increase in the barrel cortex during whisker stimulation, to modify 13 C-SE lactate C3 and glutamate C4 as well as the ratios of different carbons in glutamate and glutamine. A 40% decrease in protein content was described previously to be sufficient to observe a clear phenotype in the case of other target proteins, suggesting that it is not necessary to achieve prominent suppression of protein expression to be able to obtain significant alterations in functional and/or metabolic responses [53,54]. However, it would be desirable to improve the efficiency of the viral vector approach in order to increase the reliability and extent of the effects observed.…”

Therapeutic Effect of Vagus Nerve Stimulation on Depressive-Like Behavior, Hyperglycemia and Insulin Receptor Expression in Zucker Fatty Rats

“…However, at this time it is not conclusive as to whether insulin resistance induces depression or the opposite. Although a study found that downregulation of hypothalamic insulin receptor expression elicits depressive-like behaviors in rats [21], others found that the occurrence of depression precede the onset of diabetes [22], and that insulin resistance can be reversed by antidepressant treatment [23]. Meanwhile, not only are depressive symptoms a risk factor for the development of T2D, they have also been shown to contribute to hyperglycemia, diabetic complications, functional disability and all-cause mortality among diabetic patients [4], [5].…”