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 (IRl⁢o⁢x/l⁢o⁢x; NPYC⁢r⁢e⁣/+) 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.

An intermittent hypercaloric diet alters gut microbiota, prefrontal cortical gene expression and social behaviours in rats.

Objectives: Excessive consumption of high fat and high sugar (HFHS) diets alters reward processing, behaviour, and changes gut microbiota profiles. Previous studies in gnotobiotic mice also provide evidence that these gut microorganisms may influence social behaviour. To further investigate these interactions, we examined the impact of the intermittent access to a HFHS diet on social behaviour, gene expression and microbiota composition in adolescent rats. Methods: Male rats were permitted intermittent daily access (2 h / day) to a palatable HFHS chow diet for 28 days across adolescence. Social interaction, social memory and novel object recognition were assessed during this period. Following testing, RT-PCR was conducted on hippocampal and prefrontal cortex (PFC) samples. 16S ribosomal RNA amplicon sequencing was used for identification and relative quantification of bacterial taxa in faecal samples. Results: We observed reduced social interaction behaviours, impaired social memory and novel object recognition in HFHS diet rats compared to chow controls. RT-PCR revealed reduced levels of monoamine oxidase A (Maoa), catechol-O-methyltransferase (Comt) and brain derived neurotrophic factor (Bdnf) mRNA in the PFC of HFHS diet rats. Faecal microbiota analysis demonstrated that the relative abundance of a number of specific bacterial taxa differed significantly between the two diet groups, in particular, Lachnospiraceae and Ruminoccoceae bacteria. Discussion: Intermittent HFHS diet consumption evoked physiological changes to the brain, particularly expression of mRNA associated with reward and neuroplasticity, and gut microbiome. These changes may underpin the observed alterations to social behaviours.

The effect of high fat, high sugar, and combined high fat-high sugar diets on spatial learning and memory in rodents: A meta-analysis.

Evidence from human and animal studies suggests that high-energy diets impair cognitive function. However, the conditions for such impairments are unclear as studies have differed in the type and duration of diet exposure as well as in the tasks used to assess deficits in cognition. Here, we focused on hippocampal-dependent tasks. We conducted separate meta-analyses of the results from rodent studies using: 1) different diets (high in fat, high in sugar, or high in both fat and sugar); and 2) different tasks to assess hippocampal-dependent spatial learning and memory (water maze, place recognition, radial arm maze, and spontaneous alternation). We focused on the effects of relatively short-term dietary manipulations and, therefore, restricted our analyses to studies that provided the diet for 2 months or less. The meta-analyses showed that each type of diet and task adversely affected performance, with the largest effect produced by exposure to a combined high fat-high sugar diet and the use of the radial arm maze to assess the effect of such diets on cognition.

A high-fat high-sugar diet in adolescent rats impairs social memory and alters chemical markers characteristic of atypical neuroplasticity and parvalbumin interneuron depletion in the medial prefrontal cortex.

Brain plasticity is a multifaceted process that is dependent on both neurons and extracellular matrix (ECM) structures, including perineuronal nets (PNNs). In the medial prefrontal cortex (mPFC) PNNs primarily surround fast-spiking parvalbumin (PV)-containing GABAergic interneurons and are central to regulation of neuroplasticity. In addition to the development of obesity, high-fat and high-sugar (HFHS) diets are also associated with alterations in brain plasticity and emotional behaviours in humans. To examine the underlying involvement of PNNs and cortical plasticity in the mPFC in diet-evoked social behaviour deficits (in this case social recognition), we exposed adolescent (postnatal days P28-P56) rats to a HFHS-supplemented diet. At P56 HFHS-fed animals and age-matched controls fed standard chow were euthanized and co-localization of PNNs with PV neurons in the prelimbic (PrL) and infralimbic (IL) and anterior cingulate (ACC) sub regions of the PFC were examined by dual fluorescence immunohistochemistry. ΔFosB expression was also assessed as a measure of chronic activity and behavioural addiction marker. Consumption of the HFHS diet reduced the number of PV+ neurons and PNNs in the infralimbic (IL) region of the mPFC by -21.9% and -16.5%, respectively. While PV+ neurons and PNNs were not significantly decreased in the ACC or PrL, the percentage of PV+ and PNN co-expressing neurons was increased in all assessed regions of the mPFC in HFHS-fed rats (+33.7% to +41.3%). This shows that the population of PV neurons remaining are those surrounded by PNNs, which may afford some protection against HFHS diet-induced mPFC-dysregulation. ΔFosB expression showed a 5-10-fold increase (p < 0.001) in each mPFC region, supporting the hypothesis that a HFHS diet induces mPFC dysfunction and subsequent behavioural deficits. The data presented shows a potential neurophysiological mechanism and response to specific diet-evoked social recognition deficits as a result of hypercaloric intake in adolescence.

The Effect of Intrahippocampal Insulin Infusion on Spatial Cognitive Function and Markers of Neuroinflammation in Diet-induced Obesity.

Obesity and high fat diet consumption contribute to the development of metabolic disorders, insulin resistance, neuroinflammation, and cognitive impairments. CNS administration of insulin into the brain can attenuate these cognitive impairments. The present study investigated whether hippocampal-dependent spatial memory impairments in a dietary induced mouse model of obesity could be improved by the direct administration of insulin into the hippocampus and whether this was associated with markers of hippocampal inflammation. C57Bl/6J mice consumed a low fat or high fat diet for 16 weeks and continuous intrahippocampal saline or insulin infusion for the final 4 weeks, during a period of behavioral testing, before gene expression analysis was performed. The high fat diet group demonstrated poorer spatial memory performance in the Morris water maze and Y-maze, supporting the hypothesis that high fat diet leads to hippocampal dependent cognitive impairment. Insulin infusion into the hippocampus reversed the deficit of high fat diet consumption on both of the tasks. Increased expression of inflammatory markers was detected in the hippocampus in the high fat diet group and expression of these markers was ameliorated in insulin infused mice. This demonstrates that CNS insulin can improve hippocampal-dependent memory and that hippocampal inflammation may be a factor in the development of cognitive deficits associated with diet-induced obesity. Furthermore, these data suggest that insulin may act to attenuate high fat diet induced cognitive deficits by reducing neuroinflammation.

Differential motivational profiles following adolescent sucrose access in male and female rats.

Adolescents are the highest consumers of sugar sweetened drinks. Excessive consumption of such drinks is a likely contributor to the development of obesity and may be associated with enduring changes in the systems involved in reward and motivation. We examined the impact of daily sucrose consumption in young male and female rats (N=12 per group) across the adolescent period on the motivation to perform instrumental responses to gain food rewards as adults. Rats were or were not exposed to a sucrose solution for 2 h each day for 28 days across adolescence [postnatal days (P) 28-56]. They were then trained as adults (P70 onward) to lever press for a palatable 15% cherry flavored sucrose reward and tested on a progressive ratio (PR) schedule to assess motivation to respond for reinforcement. Female rats exposed to sucrose had higher breakpoints on the PR schedule than controls, whereas male rats exposed to sucrose had lower breakpoints than controls. These results show that consumption of sucrose during adolescence produced sex-specific behavioral changes in responding for sucrose as adults.

Sex-specific effects of daily exposure to sucrose on spatial memory performance in male and female rats, and implications for estrous cycle stage.

Excessive consumption of sugar sweetened drinks is proposed to produce functional changes in the hippocampus, leading to perturbations in learning and memory. In this study we examined the impact of 2h daily access to 10% sucrose (or no sucrose in controls) on recognition memory tasks in young male and female rats. In Experiment 1 we tested rats on memory tasks reliant on the hippocampus (place recognition), perirhinal cortex (object recognition), and a combination of hippocampus, prefrontal cortex and perirhinal cortex (object-in-place memory). Exposure to sucrose for 2h a day for 14days prior to behavioral testing did not affect object recognition, but impaired spatial memory to an extent in both male and female rats. Male rats exposed to sucrose were impaired at both place recognition and object-in-place recognition, however female rats showed no impairment in object-in-place performance. Plasticity within the hippocampus is known to increase during the proestrus phase of the estrous cycle and is related to higher levels of circulating estrogens. In Experiment 2 we tested place recognition and object-in-place memory in 10% sucrose exposed or non-exposed control female rats both during the metestrus (low estrogen) and proestrus (high estrogen) phases of their cycle on place recognition and object-in-place memory. Both sucrose exposed and control female rats were able to perform place object-in-place recognition correctly during metestrus and proestrus, however sucrose exposed rats were only able to perform place recognition correctly during proestrus. This indicates that when hippocampal function is compromised, endogenous estrogens may boost memory performance in females, and that males may be at more risk of high sugar diet induced cognitive deficits.