The effect of insulin receptor deletion in neuropeptide Y neurons on hippocampal dependent cognitive function in aging mice

Insulin is known to act in the central nervous system to regulate several physiological and behavioural outcomes, including energy balance, glucose homeostasis and cognitive functioning. However, the neuronal populations through which insulin enhances cognitive performance remain unidentified. Insulin receptors are found in neuropeptide-Y (NPY) expressing neurons, which are abundant in the hypothalamus and hippocampus; regions involved in feeding behaviour and spatial memory, respectively. Here we show that mice with a tissue specific knockout of insulin receptors in NPY expressing neurons (IR ${}^{lox/lox}$ ; NPY ${}^{Cre/+}$ ) display an impaired performance in the probe trial of the Morris Water Maze compared with control mice at both the 6 and the 12, but not at the 24 months time point, consistent with a crucial role of insulin and NPY in cognitive functioning. By 24 months of age all groups demonstrated similar reductions in spatial memory performance. Together, these data suggest that the mechanisms through which insulin influences cognitive functioning are, at least in part, via insulin receptor signaling in NPY expressing neurons. These results also highlight that cognitive impairments observed in aging may be due to impaired insulin signaling.

Keywords

Insulin receptors

NPY

Spatial memory

Hippocampus

Morris Water Maze

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Fig. 1.

Body weight and energy intake. (A) IR ${}^{lox/lox}$ ;NPY ${}^{Cre/+}$ and littermate control mice (IR ${}^{lox/lox}$ ) gained weight over time. Male IR ${}^{lox/lox}$ ;NPY ${}^{Cre/+}$ mice displayed significantly increased body weight compared to male IR ${}^{lox/lox}$ mice at 6 months of age. No differences in body weight between genotypes were observed at 12 or 24 months of age. Female mice did not show any body weight differences between genotypes at any time points. (B) Female mice displayed overall lower energy intake than male mice, however energy intake at 6, 12, or 24 months did not differ between genotypes. Values are expressed as mean $\pm{}$ SEM. * = interaction effect between IR ${}^{lox/lox}$ and IR ${}^{lox/lox}$ ;NPY ${}^{Cre/+}$ genotypes, p $<$ 0.05. ${}^{+}$ = main effect of time, p $<$ 0.05. Analysed by 2-way ANOVA followed by Tukey’s honest significance difference (HSD) test. 6 and 12 months, n = 59 IR ${}^{lox/lox}$ (30 F and 29 M) and 56 IR ${}^{lox/lox}$ ;NPY ${}^{Cre/+}$ (28 F and 28 M). 24 months, n = 54 IR ${}^{lox/lox}$ (28 F and 26 M) and 52 IR ${}^{lox/lox}$ ;NPY ${}^{Cre/+}$ (26 F and 26 M).

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J. Integr. Neurosci. Print ISSN 0219-6352 Electronic ISSN 1757-448X