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

Abstract

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 in luences 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.

The Effect of Dietary Fat and Sucrose on Cognitive Functioning in Mice Lacking Insulin Signaling in Neuropeptide Y Neurons

“…There was no effect of genotype on blood glucose (including AUC values) and plasma insulin levels following peripheral glucose injection. These results could be considered surprising due to the conditional IR knockout, however, the current data aligns with previous GTT results using this IR lox/lox ;NPY Cre/+ mouse model ( Goodman et al, 2022 ). To specify, knocking out IRs on NPY neurons does not elicit any obvious effects on peripheral insulin sensitivity and glucose tolerance.…”

“…Therefore, despite expression of NPY within other regions of the brain, such as the hypothalamus, the deficits observed in the current study appear to be predominately mediated by NPY-located hippocampal neurons. This is supported by immunohistochemical validation experiments from a recent publication of ours, which demonstrated that insulin signaling within the dentate gyrus of the hippocampus is significantly downregulated in IR lox/lox ;NPY Cre/+ mice ( Goodman et al, 2022 ). Although these results do suggest that insulin signaling on NPY neurons plays a key role in spatial memory, they do not rule out the possibility that additional neuronal subtypes are involved in potentiating hippocampal cognitive functioning.…”

“…Additionally, there were body weight differences observed at 4–6 weeks of age, with this effect plateauing with increased age ( Loh et al, 2017 ). Results from a recent study of ours ( Goodman et al, 2022 ) found that 6 month old IR lox/lox ;NPY Cre/+ mice, but not 12 or 24 month old mice, had increased body weight compared to controls. From these data, it appears that knocking out IR on NPY neurons causes alterations in energy balance, but only during specific stages of the life cycle.…”

“…Intracerebroventricular infusion of insulin was administered to mice which caused downstream activation of p-Akt in the brain of IR lox/lox mice but not IR lox/lox ;NPY Cre/+ mice ( Loh et al, 2017 ). Additionally, immunohistochemical labeling of p-Akt reveals a substantial downregulation of insulin signaling within the hippocampus of IR lox/lox ;NPY Cre/+ mice ( Goodman et al, 2022 ).…”

Neuropeptide Y Neurons Integrate the Metabolic and Cognitive Effects of Brain Insulin Signaling

“…In the current issue, Goodman et al [10] report investigations of a role for IR signaling in NPY neurons of the hippocampus in the context of cognitive functioning. The authors used a mouse model of cell-specific knockout for IR in NPY-expressing neurons using Cre-LoxP technology.…”