Central Insulin Administration Improves Odor-Cued Reactivation of Spatial Memory in Young Men

Brünner, Yvonne F.; Kofoet, Anja; Benedict, Christian; Freiherr, Jessica

doi:10.1210/jc.2014-3018

Cited by 63 publications

(48 citation statements)

References 44 publications

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“…By causing a significant reduction in the AHP, we predict insulin may be able to enhance cellular excitability in aging and offset cognitive decline. Indeed, several clinical studies have provided robust evidence that increasing brain insulin availability through intranasal delivery of the hormone is able to enhance recall in young subjects [76; 77] or MCI patients [78; 79; 80]. Similarly, we have shown beneficial effects of intranasal insulin on memory recall in aged animals in the Morris water maze [74].…”

Section: The Impact Of Disappearing Hormones In the Brain Of Aged mentioning

confidence: 59%

Calcium's role as nuanced modulator of cellular physiology in the brain

Frazier

Maimaiti

Anderson

et al. 2017

Biochemical and Biophysical Research Communications

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Neuroscientists studying normal brain aging, spinal cord injury, Alzheimer’s disease (AD) and other neurodegenerative diseases have focused considerable effort on carefully characterizing intracellular perturbations in calcium dynamics or levels. At the cellular level, calcium is known for controlling life and death and orchestrating most events in between. For many years, intracellular calcium has been recognized as an essential ion associated with nearly all cellular functions from cell growth to degeneration. Often the emphasis is on the negative impact of calcium dysregulation and the typical worse-case-scenario leading inevitably to cell death. However, even high amplitude calcium transients, when executed acutely can alter neuronal communication and synaptic strength in positive ways, without necessarily killing neurons. Here, we focus on the evidence that calcium has a subtle and distinctive role in shaping and controlling synaptic events that underpin neuronal communication and that these subtle changes in aging or AD may contribute to cognitive decline. We emphasize that calcium imaging in dendritic components is ultimately necessary to directly test for the presence of age- or disease-associated alterations during periods of synaptic activation.

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Section: The Impact Of Disappearing Hormones In the Brain Of Aged mentioning

confidence: 59%

Calcium's role as nuanced modulator of cellular physiology in the brain

Frazier

Maimaiti

Anderson

et al. 2017

Biochemical and Biophysical Research Communications

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“…This contradicts reports of enhanced memory in healthy human subjects after insulin IND [27, 44, 65]. Insulin IND has been shown to be an effective treatment for mild cognitive impairment and Alzheimer’s disease (AD) [43, 66].…”

Section: Discussionmentioning

confidence: 98%

“…Beyond altered Kv1.3 phosphorylation state, insulin IND also induces behavioral modifications, as evident by enhanced object memory recognition and increased performance in the two-odor discrimination task. [16, 25–27]. These studies demonstrate insulin’s ability to influence MC activity [18, 20] and therefore olfactory functioning [16, 28].…”

Section: Introductionmentioning

confidence: 96%

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

Bell

Fadool

2017

Physiology & Behavior

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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.

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“…refs 16–18). Studies on cognitive effects indicate that hippocampal-dependent memory processes benefit particularly from intranasal insulin in humans 19–24 . Similarly, rodent studies have shown that insulin plays an important role in regulating synaptic plasticity in the hippocampus 25, 26 .…”

Section: Introductionmentioning

confidence: 99%

Intranasal insulin enhances brain functional connectivity mediating the relationship between adiposity and subjective feeling of hunger

Kullmann

Heni

Veit

et al. 2017

Sci Rep

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Brain insulin sensitivity is an important link between metabolism and cognitive dysfunction. Intranasal insulin is a promising tool to investigate central insulin action in humans. We evaluated the acute effects of 160 U intranasal insulin on resting-state brain functional connectivity in healthy young adults. Twenty-five lean and twenty-two overweight and obese participants underwent functional magnetic resonance imaging, on two separate days, before and after intranasal insulin or placebo application. Insulin compared to placebo administration resulted in increased functional connectivity between the prefrontal regions of the default-mode network and the hippocampus as well as the hypothalamus. The change in hippocampal functional connectivity significantly correlated with visceral adipose tissue and the change in subjective feeling of hunger after intranasal insulin. Mediation analysis revealed that the intranasal insulin induced hippocampal functional connectivity increase served as a mediator, suppressing the relationship between visceral adipose tissue and hunger. The insulin-induced hypothalamic functional connectivity change showed a significant interaction with peripheral insulin sensitivity. Only participants with high peripheral insulin sensitivity showed a boost in hypothalamic functional connectivity. Hence, brain insulin action may regulate eating behavior and facilitate weight loss by modifying brain functional connectivity within and between cognitive and homeostatic brain regions.

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Central Insulin Administration Improves Odor-Cued Reactivation of Spatial Memory in Young Men

Abstract: These findings suggest that acute intranasal insulin improves odor-cued reactivation of spatial memory in young men.

Cited by 63 publications

References 44 publications

Calcium's role as nuanced modulator of cellular physiology in the brain

Calcium's role as nuanced modulator of cellular physiology in the brain

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

Intranasal insulin enhances brain functional connectivity mediating the relationship between adiposity and subjective feeling of hunger

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