Awake, long-term intranasal insulin treatment does not affect object memory, odor discrimination, or reversal learning in mice

Abstract

Intranasal insulin delivery is currently being used in clinical trials to test for improvement in human memory and cognition, and in particular, for lessening memory loss attributed to neurodegenerative diseases. Studies have reported the effects of short-term intranasal insulin treatment on various behaviors, but less have examined long-term effects. The olfactory bulb contains the highest density of insulin receptors in conjunction with the highest level of insulin transport within the brain. Previous research from our laboratory has demonstrated that acute insulin intranasal delivery (IND) enhanced both short- and long-term memory as well as increased two-odor discrimination in a two-choice paradigm. Herein, we investigated the behavioral and physiological effects of chronic insulin IND. Adult, male C57BL6/J mice were intranasally treated with 5 μg/μl of insulin twice daily for 30 and 60 days. Metabolic assessment indicated no change in body weight, caloric intake, or energy expenditure following chronic insulin IND, but an increase in the frequency of meal bouts selectively in the dark cycle. Unlike acute insulin IND, which has been shown to cause enhanced performance in odor habituation/dishabituation and two-odor discrimination tasks in mice, chronic insulin IND did not enhance olfactometry-based odorant discrimination or olfactory reversal learning. In an object memory recognition task, insulin IND-treated mice performed no different from controls regardless of task duration. Biochemical analyses of the olfactory bulb revealed a modest 1.3X increase in IR kinase phosphorylation but no significant increase in Kv1.3 phosphorylation. Substrate phosphorylation of IR Kinase downstream effectors (MAPK/ERK and Akt signaling) proved to be highly variable. These data indicate that chronic administration of insulin IND in mice fails to enhance olfactory ability, object memory recognition, or a majority of systems physiology metabolic factors – as reported to elicit a modulatory effect with acute administration. This leads to two alternative interpretations regarding long-term insulin IND in mice: 1) It causes an initial stage of insulin resistance to dampen the behaviors that would normally be modulated under acute insulin IND, but ability to clear a glucose challenge is still retained, or 2) There is a lack of behavioral modulation at high concentration of insulin attributed to the twice daily intervals of hyperinsulinemia caused by insulin IND administration without any insulin resistance, per se.

Intranasal insulin reverts central pathology and cognitive impairment in diabetic mother offspring

“…Limited differences observed might be due to the fact that determinations were performed days and weeks after insulin administration. Therefore, we also performed determinations 4 h after insulin administration and we detected that phospho-Akt/total AKt ratios were significantly increased in those regions located in the proximity of the administration site: the hippocampus and the striatum after ICV administration, and the olfactory bulb after intranasal administration, in line with previous observations [ 41 ].…”

Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications

“…Can you please define.] 87,88 ; however, a similar treatment had less effect in diabetic mice [Au: were these studies conducted in mice or rats? Can you please define.]…”

Combined Effect of Fatty Diet and Cognitive Decline on Brain Metabolism, Food Intake, Body Weight, and Counteraction by Intranasal Insulin Therapy in 3×Tg Mice

“…However, there is much heterogeneity in the animal models and intervention protocols used, and in the level of efficacy attained. The current evidence suggests that short-term intra-cerebral insulin therapy results in cognitive improvements (Park et al, 2000; Marks et al, 2009; Vandal et al, 2014; Salameh et al, 2015), but efficacy of protracted insulin regimens has been less explored and not confirmed in most of the existing studies, in which phenomena of desensitization due to overdosing have been advocated (Kamal et al, 2012; Nazarians-Armavil et al, 2013; Bell and Fadool, 2017).…”