Awake Intranasal Insulin Delivery Modifies Protein Complexes and Alters Memory, Anxiety, and Olfactory Behaviors

Abstract

The role of insulin pathways in olfaction is of significant interest with the widespread pathology of diabetes mellitus and its associated metabolic and neuronal comorbidities. The insulin receptor (IR) kinase is expressed at high levels in the olfactory bulb, in which it suppresses a dominant Shaker ion channel (Kv1.3) via tyrosine phosphorylation of critical N-and C-terminal residues. We optimized a 7 d intranasal insulin delivery (IND) in awake mice to ascertain the biochemical and behavioral effects of insulin to this brain region, given that nasal sprays for insulin have been marketed notwithstanding our knowledge of the role of Kv1.3 in olfaction, metabolism, and axon targeting. IND evoked robust phosphorylation of Kv1.3, as well as increased channel protein-protein interactions with IR and postsynaptic density 95. IND-treated mice had an increased short-and long-term object memory recognition, increased anxiolytic behavior, and an increased odor discrimination using an odor habituation protocol but only moderate change in odor threshold using a two-choice paradigm. Unlike Kv1.3 gene-targeted deletion that alters metabolism, adiposity, and axonal targeting to defined olfactory glomeruli, suppression of Kv1.3 via IND had no effect on body weight nor the size and number of M72 glomeruli or the route of its sensory axon projections. There was no evidence of altered expression of sensory neurons in the epithelium. In mice made prediabetic via diet-induced obesity, IND was no longer effective in increasing long-term object memory recognition nor increasing anxiolytic behavior, suggesting state dependency or a degree of insulin resistance related to these behaviors.

Intranasal Delivery of a Peptide with Antidepressant-Like Effect

“…However, we observed an antidepressant effect in the FST at an IN D1-D2 interfering peptide dose of X1.67 nmol/g, B100-fold larger than that given directly to the prefrontal cortex (5 nmol per injection) in our previous study (Pei et al, 2010). We chose this starting dose based on previous studies of IN administration of small proteins such as NGF and insulin to the CNS that indicated that the efficiency of delivery to the CNS is between 1 and 5% (De Rosa et al, 2005;Dhuria et al, 2010;Francis et al, 2008;Marks et al, 2009). Although the proportion of the original IN dose of the D1-D2 interfering peptide present in the PFC after IN administration remains unknown, our results suggest that the efficiency of delivery to the CNS after IN administration using the POD device is at least 1-5%.…”

Acute, short-term hyperinsulinemia increases olfactory threshold in healthy subjects

“…12,13 Orexogenic hormones tended to increase and anorexogenic hormones tended to decrease olfactory sensitivity, modulating olfactory performance in a similar way as fasting and satiation. 12 Insulin, when administered intranasally to mice, leads to greater difficulty in discriminating two odors, 14 but there was a trend toward decreased odor threshold. However, intranasal insulin was administered over several days before testing odor thresholds, therefore rather reflecting chronic hyperinsulinemia in the brain than an acute response to food intake.…”

Huperzine A Activates Wnt/β-Catenin Signaling and Enhances the Nonamyloidogenic Pathway in an Alzheimer Transgenic Mouse Model

“…After treatment, mice were kept in supine position for 1 min to ensure that nasal gel was inhaled. This drug delivery process was repeated daily through the other nostril alternately (Marks et al, 2009). To evaluate the effect of nasal gel HupA on APP/PS1 mouse brain, mice at the age of 10 months were anaesthetized with sodium pentobarbital (50 mg/kg, i.p.)…”