Neuroinflammation and insulin resistance underly cognitive impairment. Sex differences and potential treatments

Abstract

Neuroinflammation and insulin resistance are two correlated processes. Abscisic acid(ABA) is a phytohormone also found in mammals. In a model of neuroinflammation induced by high fat diet(HFD), ABA administration rescued memory alterations and prevented pro-inflammatory markers’ increase. Furthermore, ABA restored the HFD-induced changes in insulin receptor substrates, IRS1 and IRS2. Inflammation has been proposed a contributing factor in attention-deficit-hyperactivity-disorder(ADHD). In a pilot study, female and male mice seem to display differences in ADHD symptomatology. ABA administration appeared to also affect differentially males and females. The role of IRS1 and IRS2 isolated from inflammation has not been fully established.We used AAV expressing shRNA targeting IRS1 into hippocampus of female and male rats. Female rats showed spatial and recognition memory deficits but males only showed spatial memory alterations. In medial septum, we observed reduced synaptophysin levels on shIRS1-AAV fibers, suggesting impaired synaptic plasticity. Thus, IRS1 is required for proper neuronal activity.